DEPT OF PHARMACOLOGY

Researcher : Chan LY

List of Research Outputs

 

Chan L.Y., Keung W.Y.W., Yeung K.Y., Leung S.W.S., Che C.M. and Man R.Y.K., The vasorelaxation effect of an extract of chinese medicinal herb, radix angelica pubescens in porcine coronary artery, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 77.

 

Chan L.Y., Keung W.Y.W., Yeung K.Y., Leung S.W.S., Che C.M. and Man R.Y.K., The vasorelaxation effect of osthole, derived from radix angelicae pubescentis, in porcine coronary artery, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Researcher : Chan PS

List of Research Outputs

 

Chan P.S., Leung S.W.S. and Man R.Y.K., Modulation of vasoconstriction by testosterone in porcine coronary artery, Experimental Biology 2007, Washington, DC, April 28 - May 2, 2007.

 

Chan P.S., Leung S.W.S. and Man R.Y.K., Modulation of vasoconstriction by testosterone in porcine coronary artery, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 86.

 

Researcher : Cho CH

Project Title:

Nicotine and its active metabolite in the tumorigenesis of colon cancer

Investigator(s):

Cho CH

Department:

Pharmacology

Source(s) of Funding:

Competitive Earmarked Research Grants (CERG)

Start Date:

11/2004

Completion Date:

10/2006

 

Abstract:

To investigate the differential roles of nicotinic receptor and B-adrenoceptor in the tumorigenesis of colon cancer cells; to investigate pathogenic signal pathway of nicotine and its metabol NNK in the development of colon cancer; to investigate the therapeutic strategy to target the oncogenes involved in this carcinogenic pathway to treat and prevent cancer formation especially in cigarette smokers.

 

Project Title:

Cyclooxygenase-2 and its upstream signal transduction mediators in the promotion of gastric cancer development by cigarette smoke

Investigator(s):

Cho CH, Chu KM

Department:

Pharmacology

Source(s) of Funding:

Competitive Earmarked Research Grants (CERG)

Start Date:

09/2005

Completion Date:

01/2007

 

Abstract:

To provide direct evidence that CS and nicotine does indeed promote gastric cancer growth; to define the mechanistic cascade from CS to gastric cancer growth; to substantiate the importance of COX-2 and its upstream signal transduction mediators in gastric cancer development in cigarette smokers.

 

Project Title:

Adrenaline and its receptor activation on colon cancer growth

Investigator(s):

Cho CH

Department:

Pharmacology

Source(s) of Funding:

Seed Funding Programme for Basic Research

Start Date:

02/2006

 

Abstract:

B-Adrenoceptor, a G-protein coupled receoptr, has recently been implicated in the carcinogenesis of different kinds of cancers. It has been reported that actiavtion of B-adrenoceptors could stimulate pulmonary, pancreatic and colon carcinoma cell growth ( Carcinogenesis 1898, 10:1753; Carcinogenesis 2001, 22: 473; Cancer Res. 2005, 65: 5272). Polymorphisms in B-adrenoceptor genes are also associated with increased risk of breast, colon and endometrial cancers (Cancer Res. 2001, 3:264; Int. J. Clin. Oncol 2001, 6:117; Obstet. Gynecol 2003, 102: 506; J.Exp. Clin. Cacner Res. 2004, 23: 669). In addition, B-blockers could inhibit the migration of colon cancer cells induced by noradrenaline (Cancer Res. 2001, 61: 2866). Recent clincial studies also reveal that using B-blockers is negatively associated cancer risk (Rev. Epidemiol. Sante Publiqu 2004, 52: 53; Lancet 1997, 349: 525; Am. J. Hypertens. 1996, 9: 695). All thes findings converge to suggest that adrenoceptors especially B-adrenoceptors indeed play a crucial role in the development of cancer. On the other hand, biobehavioral stresses may influence growth and progression of cancer (Clin. Can. Res. 2003, 9:4514). It has also been demonstrated that altered hormonal and neuronal secretion during stress have a strong impact on the biological activities of breast cancer (Breast Can. Res. Treat. 2003, 80: 63). Among the various stress hormones, adreanline and noradrenaline play an important role in mediating the effect of stress on target cells via adrenergic receptors (Caner 2003, 98: 1547). Indeed our recent study demostrates that cigarette smoke which has been closely associated with cancer development also stimulates colon cancer growth through B-adrenoceptors activation (Cancer Res. 2005, 65:5272). The relationship between stress mediator adrenaline and B-adrenoceptor on colon cancer growth has not been defined. In this study we shall delineate this action and the signal transduction pathway involved will also be investigated. In addition we shall examine the pharmacological action of nicotine, the major active component in cigarette smoke also shown to stimulate adrenaline release in the body, on colon cancer growth.

 

Project Title:

Cathelicidin: a potential peptide for gastric ulcer healing

Investigator(s):

Cho CH, Xia HHX, Chung SSM

Department:

Pharmacology

Source(s) of Funding:

Competitive Earmarked Research Grants (CERG)

Start Date:

09/2006

Completion Date:

01/2007

 

Abstract:

(1) Establish a new role for cathelicidiningastric ulcer, especially associated with HP infection; (2) define the complete signal transduction pathway for the action of cathelicidin on epithelial cell proliferation; (3) provide a new type of therapeutic agent that combines antibacterial and ulcer healing action in the treatment of gastric ulcer.

 

List of Research Outputs

 

Chan O.O., Huang C.Y., Hui W.M., Cho C.H., Yuen R.M.F., Lam S.K., Rashid A. and Wong B.C.Y., Stability of E-cadherin methylation status in gastric mucosa associated with histology changes. , Alimentary Pharmacology and Therapeutics. 2006, 24(5): 831-6.

 

Kopaniszen M., Tai K.K., So H.L., Cho C.H. and Koo M.W.L., The effects of green tea polyphenols on dinitrobenzene sulphonic acid (DNBS)-induced colitis in mice, Experimental Biology, Annual Meeting, Washington, DC., USA. 2007.

 

Lam K.Y., Tai K.K., Koo M.W.L., Wong P.S.H., Wu K.K., So H.L., Woo P.C.Y. and Cho C.H., Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG, Life Sciences. Elsevier, 2007, 80: 2128-2136.

 

Mak J.C.W., Hui W.S., Ho S.P., So H.L., Chan M.M.W., Lam W.K., Cho C.H. and Ip M.S.M., Best Poster - Systemic oxidative stress and inflammation in cigarette smoke-exposed rat model, 12th Medical Research Conference. 2007.

 

Shin V.Y., Wu K.K., Chu K.M., Koo M.W.L., Wong H.P.S., Lam K.Y., Tai K.K. and Cho C.H., Functional role of b-adrenergic receptor in the mitogenic action of nicotine on gastric cancer cells, Toxicological Sciences. 2007, 96: 21-29.

 

Tai K.K., Wu K.K., Wong P.S.H., Lam K.Y., Yu L., Liu X., So H.L. and Cho C.H., Study of cathelicidin on ulcerative colitis in mice, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Tang L.P., Cho C.H., Hui W.M., Huang C., Chu K.M., Xia H.H.X., Lam S.K., Rashid A., Wong B.C.Y. and Chan O.O., An inverse correlation between IL-6 and select gene promoter methylation in patients with gastric cancer, Digestion. 2006, 74: 85-90.

 

Researcher : Keung WYW

List of Research Outputs

 

Chan L.Y., Keung W.Y.W., Yeung K.Y., Leung S.W.S., Che C.M. and Man R.Y.K., The vasorelaxation effect of an extract of chinese medicinal herb, radix angelica pubescens in porcine coronary artery, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 77.

 

Chan L.Y., Keung W.Y.W., Yeung K.Y., Leung S.W.S., Che C.M. and Man R.Y.K., The vasorelaxation effect of osthole, derived from radix angelicae pubescentis, in porcine coronary artery, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Leung S.W.S., Teoh H., Keung W.Y.W. and Man R.Y.K., Non-genomic vascular actions of female sex hormones: physiological implications and signalling pathways., Clinical and Experimental Pharmacology and Physiology. 2007, 34: 822-826.

 

Researcher : Koo MWL

Project Title:

Effects of antioxidants and the roles of heat shock protein 32 on cognitive functions in aging

Investigator(s):

Koo MWL

Department:

Pharmacology

Source(s) of Funding:

Small Project Funding

Start Date:

11/2002

 

Abstract:

To carify the roles of HOs in aging and its involvement in cognitive functions; to elucidate the usefulness of antioxidants in delaying cognitive function loss during aging.

 

Project Title:

Alleviating effect of Bu-zhong-yi-qi-tang on chemotherapy-induced bone marrow suppression in mice

Investigator(s):

Koo MWL

Department:

Pharmacology

Source(s) of Funding:

Small Project Funding

Start Date:

11/2003

 

Abstract:

To investigate the mechanisms of action from herbs particularly on bone marrow recovery and CSFs production.

 

Project Title:

Effect of tea on lipoprotein lipase and lipid metabolism

Investigator(s):

Koo MWL

Department:

Pharmacology

Source(s) of Funding:

Small Project Funding

Start Date:

03/2006

 

Abstract:

Key issues and problems More and more people in developed countries are becoming obese. In the United States, about a third of adults are obese with a body mass index above 27 kg/m2. The prevalence is increasing in all major races and sex groups including younger adults age 25 to 44. Obesity is also an important risk factor for the development of cardiovascular diseases. A positive imbalance of energy intake and expenditure resulted in obesity (1, 2). Dietary intake of free fatty acid (FFA) are esterified to form triglyceride (TG) and assembled into large lipoprotein particles (chylomicrons), which are excreted from intestinal cells into lymph and then to the general circulation. TC rich, very low density lipoproteins (VLDL), are assembled in a similar manner in the liver and secreted into the blood. Both of these TG rich particles (chylomicrons and VLDL) are substrates for the lipolytic action of lipoprotein lipase (LPL) as they pass through the capillary space and be converted into low density lipoproteins (LDL) (3, 4). LPL is synthesized by fat cells and its activity is regulated by catecholamines and insulin. We have shown that chronic tea consumption reduced cAMP level in fat cells (5), thus tea may modulate LPL activity and lower the risk of atherosclerosis. LDL when oxidized and taken up by the macrophages will become foam cells and deposited in the arterial walls, therefore excessive consumption of high fat diet can lead to atherosclerosis and cardiovascular diseases. In our previous studies, we have shown that tea drinking can decrease plasma cholesterol level (6) prevent low density lipoprotein (LDL) oxidation and elevate the high density lipoprotein to total cholesterol ratio (7). Animals given tea treatment have a lower risk of atherosclerosis induced by feeding with hypercholesterol diet (7). Recently, one of our population studies in Hong Kong has found a strong inverse correlation of tea consumption with obesity (1). Unpublished data obtained from our clinical investigation on obese patients has suggested an inhibitory effect of tea on lipoprotein lipase, which is important for the metabolism of very low density lipoproteins and contributes to cardiovascular disorders (8). There is also report of tea in suppressing the activities of other lipase systems in the gastrointestinal tract (9). Since cardiovascular disorders induced more death than another other diseases in Hong Kong and tea seems to be beneficial in preventing these disorders, it is thus important to establish the health-promoting role of tea in a more scientific manner. Purpose of the project The objectives of this project are to investigate if tea consumption can inhibit lipoprotein lipase in rats fed with hypercholesterol diet and reduce the risk of atherosclerosis since lipoprotein lipase is required also for the uptake of oxidized LDL into the blood vessel wall. References: 1. Fong, KK. (2004). Correlation of obesity with tea consumption in a Hong Kong general practice population: a cross-sectional survey. M. Med. Sc. dissertation, The University of Hong Kong 2. Despres JP., Moorjani S., Lupien PJ., et al., (1990). Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis, 10:493-6 3. Bjorntorp, P., Bradoff BN. (1992). In: Obesity, Philadelphia Penn: Lippincott JB Company, pp3-12 4. Dan M. (2001). Effect of green tea on diet-induced obesity in rats. M.Med.Sc. dissertation, The University of Hong Kong] 5. Chiu WY. (2002). Effect of chronic green tea consumption on lipolysis in rats. M.Med.Sc. Dissertation, The University of Hong Kong 6. Yang, TTC., Koo, MWL. (2000). Chinese green tea lowers cholesterol level through an increase in fecal lipid excretion. Life Sci. 66:411-4231 7. Yang, TTC., Koo, MWL. (2000). Inhibitory effect of Chinese green tea on endothelial cell-induced LDL oxidation. Atherosclerosis 148:67-732 8. Chan, CCW., Koo, MWL., Ng, EHY., Tang, OS., Yeung WSB., Ho, PC. Effects of Chinese green tea on weight, hormonal and biochemical profiles in obese patients with polycystic ovary syndrome – a randomized placebo controlled trial 9. Chantre, P., Laison, D. (2002). Recent findings of green tea extract AR25 (Exolise) and its activity for the treatment of obesity. Phytomedicine, 9:3-8

 

List of Research Outputs

 

Kopaniszen M., Tai K.K., So H.L., Cho C.H. and Koo M.W.L., The effects of green tea polyphenols on dinitrobenzene sulphonic acid (DNBS)-induced colitis in mice, Experimental Biology, Annual Meeting, Washington, DC., USA. 2007.

 

Lam K.Y., Tai K.K., Koo M.W.L., Wong P.S.H., Wu K.K., So H.L., Woo P.C.Y. and Cho C.H., Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG, Life Sciences. Elsevier, 2007, 80: 2128-2136.

 

Shin V.Y., Wu K.K., Chu K.M., Koo M.W.L., Wong H.P.S., Lam K.Y., Tai K.K. and Cho C.H., Functional role of b-adrenergic receptor in the mitogenic action of nicotine on gastric cancer cells, Toxicological Sciences. 2007, 96: 21-29.

 

Researcher : Kopaniszen M

List of Research Outputs

 

Kopaniszen M., Tai K.K., So H.L., Cho C.H. and Koo M.W.L., The effects of green tea polyphenols on dinitrobenzene sulphonic acid (DNBS)-induced colitis in mice, Experimental Biology, Annual Meeting, Washington, DC., USA. 2007.

 

Researcher : Ku DD

List of Research Outputs

 

Shi Y., Ku D.D., Man R.Y.K. and Vanhoutte P.M.G.R., Oxygen-derived free radicals mediate endothelium-dependent contractions in the femoral artry from streptozotocin-treated rats, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006 Hong Kong. 2006, 14:2: 74.

 

Shi Y., Feletou M., Ku D.D., Man R.Y.K. and Vanhoutte P.M.G.R., The calcium ionophore A23187 induces endothelium-dependent contractions in femoral arteries from rats with streptozotocin-induced diabetes, British Journal of Pharmacology. 2007, 150: 624-632.

 

Researcher : Lam KY

List of Research Outputs

 

Lam K.Y., Tai K.K., Koo M.W.L., Wong P.S.H., Wu K.K., So H.L., Woo P.C.Y. and Cho C.H., Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG, Life Sciences. Elsevier, 2007, 80: 2128-2136.

 

Shin V.Y., Wu K.K., Chu K.M., Koo M.W.L., Wong H.P.S., Lam K.Y., Tai K.K. and Cho C.H., Functional role of b-adrenergic receptor in the mitogenic action of nicotine on gastric cancer cells, Toxicological Sciences. 2007, 96: 21-29.

 

Tai K.K., Wu K.K., Wong P.S.H., Lam K.Y., Yu L., Liu X., So H.L. and Cho C.H., Study of cathelicidin on ulcerative colitis in mice, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Researcher : Lam KY

List of Research Outputs

 

Lam K.Y., Tai K.K., Koo M.W.L., Wong P.S.H., Wu K.K., So H.L., Woo P.C.Y. and Cho C.H., Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG, Life Sciences. Elsevier, 2007, 80: 2128-2136.

 

Shin V.Y., Wu K.K., Chu K.M., Koo M.W.L., Wong H.P.S., Lam K.Y., Tai K.K. and Cho C.H., Functional role of b-adrenergic receptor in the mitogenic action of nicotine on gastric cancer cells, Toxicological Sciences. 2007, 96: 21-29.

 

Tai K.K., Wu K.K., Wong P.S.H., Lam K.Y., Yu L., Liu X., So H.L. and Cho C.H., Study of cathelicidin on ulcerative colitis in mice, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Researcher : Lau CT

List of Research Outputs

 

Lau C.T. and Man R.Y.K., Isoflavone metabolite equol enhances sodium nitroprusside induced vasorelaxation in the rat thoracic aorta via cyclic AMP cascade, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006 Hong Kong. 2006, 14:2: 80.

 

Researcher : Lee YKM

List of Research Outputs

 

Leung S.W.S., Teoh H., Quan A., Lee Y.K.M., Yeung K.Y., Xu Y.C. and Man R.Y.K., Gonadal hormones and vascular reactivity, Frontiers in Biomedical Research, HKU Scientific Meeting of the Research Centre of Heart, Brain, Hormone and Healthy Aging. 2006.

 

Researcher : Leung GPH

Project Title:

Cloning and characterization of novel equilibrative nucleoside transporter type 4 (ENT4)

Investigator(s):

Leung GPH

Department:

Pharmacology

Source(s) of Funding:

Seed Funding Programme for Basic Research

Start Date:

03/2005

 

Abstract:

Background: The physiological important nucleoside, adenosine, acts through adenosine receptors to exert diverse effects on cellular functions such as inhibition of platelet aggregation, slowing of heart rate and vasodilation. Nucleoside transporters are important in adenosine functions by fine-tuning its concentration in the vicinity of adenosine receptors. There are two classes of nucleoside transporters: Na+-dependent concentrative nucleoside transporters (CNTs) and Na+-independent equilibrative nucleoside transporters (ENTs). So far three equilibrative nucleoside transporters (ENTs) have been cloned and characterized. Both ENT1 and ENT2 are broadly selective, transporting purine and pyrimidine nucleosides. Nevertheless, ENT1 is nitrobenzylmercaptopurine ribonucleoside (NBMPR)-sensitive and has an IC50 of 1nM while ENT2 is relatively NBMPR-insensitive and has an IC50 > 1µM. Unlike ENT1 and ENT2, which are plasma membrane proteins, ENT3 is an intracellular protein. It may be responsible for salvaging nucleosides between the cytoplasm and the lumen of Golgi apparatus. Adenosine transport in endothelial cells is Na+-independent. Interestingly, we found that in physiological levels of adenosine (0.1 to 1µM), high concentrations of NBMPR (> 200µM, a concentration that can completely inhibit both ENT1 and ENT2) only reduce 20% of the adenosine transport. It indicates that another nucleoside transporter, which is characteristically distinct from the ENT1 and ENT2, is present in the endothelial cells. Recently, we have cloned a protein from endothelial cells which has 18% amino acid identity with ENT1. We term it ENT4 and hypothesize that it may be a novel isoform of nucleoside transporter. Objectives: In this grant application, we propose to characterize ENT4. In aim I, we will stably transfect ENT4 into nucleoside transporter-deficient cells. In aim II, we will functionally characterize ENT4. We will determine its affinities to different nucleosides and its sensitivities to different inhibitors such as NBMPR. In aim III, we will study the tissue distribution of ENT4.

 

Project Title:

Physiological and pharmacological studies of equilibrative nucleoside transporter-2

Investigator(s):

Leung GPH, Man RYK

Department:

Pharmacology

Source(s) of Funding:

Seed Funding Programme for Basic Research

Start Date:

03/2006

 

Abstract:

Adenosine is an endogenous purine nucleoside and modulates a variety of physiological functions by interacting with the adenosine receptors on cell surface. Under adverse conditions such as ischemia, hypoxia, stress and inflammation, extracellular levels of adenosine are increased. The increased extracellular adenosine protects tissues from excessive damage. It has been demonstrated that adenosine attentuates the ischemic heart injury, reduces inflammation and is vasodilatory. However, the therapeutic application of adenosine is limited because extracellular adenosine usually disappears quickly due to its rapid uptake into adjacent cells and subsequent metabolism. Adenosine is taken up from the extracellular space into adjacent cells through the nucleoside transporters on plasma membrane. Equilibrative nucleoside transporter (ENT)-1 and ENT2 are the major nucleoside transporters found in heart, endothelial cells and vascular smooth muscle cells. Physiologically, ENT1 is regulated by protein kinase A, protein kinase C, tyrosine kinase, nitrogen-activating protein kinase and casein kinase II. Pharmacologically, ENT1 is potently inhibited by nitrobenzylmercaptopurine riboside (NBMPR), dipyridamole and dilazep. In contrast, little is known about the physiological regulation of ENT2. Specific inhibitor for ENT2 is also not available. Therefore, in this grant application, we propose to 1) study the regulation of ENT2 2) screen for the potential lead compounds for the development of specific ENT2 inhibitor.

 

Project Title:

Development of a high-thoughput screening system for prediction of drug interactions

Investigator(s):

Leung GPH, Man RYK, Vanhoutte PMGR

Department:

Pharmacology

Source(s) of Funding:

Seed Funding Programme for Applied Research

Start Date:

01/2007

 

Abstract:

Cytochrome P450 (CYP) comprises a superfamily of enzymes, which can metabolise both endogenous compounds and drugs. Induction and inhibition of CYP are undesirable characteristics for therapeutic agents. For instance, induction of CYP may increase the metabolism of co-administrated drugs, causing drug-drug interactions. Induction of drug metabolism enzymes may also predispose the individual to chemical carcinogenesis because many known procarcinogens are activated by CYP. We can examine the effects of liver enzymes on drugs easily by studying the drug metabolites after enzymatic digestion. However, it is more difficult to study the inducing and inhibitory effects of drugs on liver enzymes. Many models have been used but all of them have limitations. The liver enzyme preparations (i.e. liver S9 fraction, microsomes and supersomes) show a low sensitivity of the endpoints. More importantly, the use of such pure enzyme systems is unable to measure the impact of pre-translational modifications on reaction. The use of primary human hepatocytes, is often said to represent the closest possible model to the in vivo situation. Unfortunately, it is apparent that CYP expression diminishes during cell culture so the drug metabolizing enzyme profile cannot accurately represent that observed in vivo. Batch-to-batch variation is also seen in the primary cultured hepatocytes. Besides, even all the CYP isoforms are stably expressed in the primary cultured hepatocytes, the specificity of probe substrates used in the assays is always questioned. The data is only indicative of the role of an enzyme family but not of which isoform. In addition, the expensive cost and the need of fresh human livers do not lend them well to high-throughput system. Taken together, therefore, the development of another system is necessary. The aim of our project is to develop a stable, reliable, cost effecive and high-throughput system which can evaluate the effects of drugs on specific drug metabolizing enzymes and predict the possibility of drug interactions.

 

List of Research Outputs

 

Leung G.P.H., Tse C.M. and Man R.Y.K., Characterization of adenosine transport in H9c2 cardiomyoblasts, International Journal of Cardiology. 2006, 116: 186-193.

 

Li R.W.S., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Effects of inflammation on adenosine transport and ecto-5’-nucleotidae in endothelial cells, Meeting the Challenges of an Aging Population, Hong Kong, March 3-4, 2007. 2007, 62.

 

Li W.S.R., Tse C.M., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Inhibition of human equilibrative nucleoside transporters by dihydrophyridine-type calcium channel antagonists, European Journal of Pharmacology. 2007, 568: 75-82.

 

Li W.S.R., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Regulation of extracellular adenosine in inflammation, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 90.

 

Seto S.W., Au A.L.S., Tam T.Y., Chim S.S.C., Lee S.M.Y., Wan S., Tjiu D.C.S., Shigemura N., Leung G.P.H. and Kwan Y.W., Modulation by simvastatin of iberiotoxin-sensitive, Ca2+-activated K+ channels of porcine coronary artery smooth muscle cells, British Journal of Pharmacology. 2007, 151: 987-997.

 

Xu Y.C., Leung S.W.S., Leung G.P.H., Vanhoutte P.M.G.R. and Man R.Y.K., Kaempferol potentiated relaxation in porcine coronary arteries and stimulated large-conductance potassium channes in HUVEC, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 83.

 

Xu Y.C., Leung S.W.S., Leung G.P.H. and Man R.Y.K., Kaempferol, a compound from chinese medicine Carthamus tinctorius, potentiated relaxation in porcine coronary arteries and activated potassium channel in HUVEC, 2006 Hong Kong-Macau Postgraduate Symposium on Chinese Medicine, Hong Kong, August 17, 2006. 130-131.

 

Researcher : Leung SWS

Project Title:

The role of calcium calmodulin dependent protein kinase II in the regulation of endothelial-derived hyperpolarizing factor-mediated responses

Investigator(s):

Leung SWS, Man RYK

Department:

Pharmacology

Source(s) of Funding:

Seed Funding Programme for Basic Research

Start Date:

02/2005

 

Abstract:

Introduction: The endothelium plays an important role in the regulation of the vascular tone, through the release of many vasoactive substances such as nitric oxide, endothelial-derived hyperpolarizing factor (EDHF), prostaglandins and endothelin-1. Of the endothelial-derived relaxing factors, EDHF is the least characterized. Several putative EDHF candidates are the metabolites of arachidonic acid, including anandamide [1], epoxyeicosatrienoic acids (EET) [2] and hydrogen peroxide (H2O2) [3]. Anandamide is the metabolic product of the action of amidohydrolase on arachidonic acid, whereas both EET and H2O2 are generated by cytochrome P450 epoxygenase. It appears that the release of EDHF, like other vasoactive agents, can be activated by an increase of intracellular concentration of free calcium, which then associates with calmodulin in the endothelial cells [4]. While most research effort has been devoted to identify the chemical entity and the mechanisms of action of EDHF, little is known regarding the regulation of the production of EDHF. Objectives: In view of the involvement of the calcium/calmodulin complex in the stimulation of the production of EDHF, it is hypothesized that calcium/calmodulin dependent protein kinase II (CaMK II) plays a role in regulating the release of EDHF. Therefore, the aim of the present study is to investigate the contributions of CaMK II to the regulation of EDHF-mediated relaxation. References: 1. Randall MD, Alexander SP, Bennett T et al., Biochem Biophys Res Commun 1996; 229: 114-120. 2. Campbell WB, Gebremedhin D, Pratt PF et al., Circ Res 1996; 78: 415-423. 3. Matoba T, Shimokawa H, Nakashima M et al., J Clin Invest 2000; 106: 1521-1530. 4. Illiano S, Nagao T, Vanhoutte PM. Br J Pharmacol 1992; 107: 387-392.

 

Project Title:

The role of extracellular signal-regulated kinases in the pathophysiology of hypertension

Investigator(s):

Leung SWS, Man RYK

Department:

Pharmacology

Source(s) of Funding:

Seed Funding Programme for Basic Research

Start Date:

02/2006

 

Abstract:

Introduction: Hypertension is a disease characterized by spontaneous arterial tone, enhanced contraction, reduced relaxation and vascular smooth muscle hypertrophy. If not managed properly, hypertension is associated with vascular complications such as arteriosclerotic lesions and further increase in arterial pressure. Elevation of blood pressure is associated with increased sheer stress [1], which is generated by the streaming blood on the endothelial layer. Acute increases in sheer stress in rat arteries in vitro and in vivo lead to activation of extracellular signal-regulated kinase-1/2 (ERK 1/2) [2-4], and this, in turn, results in vascular smooth muscle cell growth [5]. In addition to the involvement of vascular remodeling, recent studies suggest that ERK 1/2 modulate vascular contraction and relaxation. These latter actions of ERK 1/2 may also play an important role in the progress of vascular disease in hypertension [6-10]. Hypothesis: We hypothesize that the activity of ERK 1/2 in endothelial cells is increased in hypertension and this changes in endothelial ERK1/2 activity is related to changes in the vascular responses in this pathological state. Purpose of the proposed investigation: Endothelial ERK 1/2 is likely to relate to changes in the vascular responses in hypertension, as suggested by its association with prostaglandin synthesis, eNOS activity and EDHF level. While ERK 1/2 has been implicated in smooth muscle cell hypertrophy during arterial remodeling in hypertension, the involvement of ERK 1/2 in endothelial dysfunction and hence the pathogenesis of hypertension has not been clearly examined. Therefore, in this proposal, we sought to use multiple approaches to study the relationship between endothelial ERK 1/2 and hypertension in more details. Key issues and problem addressed: i. The importance of endothelial ERK 1/2 in the regulation of the vascular tone will be examined under physiological condition, as well as in hypertensive state. ii. The expression, phosphorylation and activity of ERK 1/2 in the endothelium will be studied in healthy and hypertensive animals, and the results will be correlated to the degree of endothelial dysfunction in hypertension. Reference [1] Thubrikar MJ, Robicsek F. Ann Thorac Surg 1995; 59: 1594-1603. [2] Xu Q, Liu Y, Gorospe M, et al. J Clin Invest 1996; 97: 508-514. [3] Birukov KG, Lehoux S, Birukova AA, et al. Circ Res 1997; 81: 895-903. [4] Pyles JM, March KL, Franklin M, et al. Circ Res 1997; 81: 904-910. [5] Numaguchi K, Eguchi S, Yamakawa T, et al. Circ Res 1999; 85: 5-11. [6] Bhattacharya S, Patel R, Sen N, et al. Am J Physiol 2001; 280: L1049-1056. [7] Brandes RP, Popp R, Ott G. Br J Pharmacol 2002; 136: 709-716. [8] Bernier SG, Haldar S, Michel T. J Biol Chem 2000; 275: 30707-30715. [9] Schmidt K, Gibraeil HD, Mayer B. Biochem Pharmacol 2002; 63: 1137-1142 [10] Fleming I, Fisslthaler B, Dimmeler S, et al. Circ Res 2001; 88: E68-E75.

 

Project Title:

Investigation on the role of phosphatidylinositol 3-kinase in endothelial dysfunction induced by atherogenic lipids

Investigator(s):

Leung SWS, Man RYK

Department:

Pharmacology

Source(s) of Funding:

Seed Funding Programme for Basic Research

Start Date:

04/2007

 

Abstract:

Background Oxidation of low-density lipoprotein is a key event in the pathogenesis of atherosclerosis, and this process is associated with a dramatic increase in lysophosphatidylcholine (LPC). Both oxidized low-density lipoprotein and LPC have been known to disturb the regulation of vascular tone, resulting in increased constriction and reduced dilation [1-3]. Current consensus recognizes nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) as two major relaxing factors responsible for mediating endothelium-dependent relaxation [4, 5]. The mechanisms of actions through which LPC interferes with NO and EDHF pathways have not been identified [6-12]. Recent evidence suggests that LPC can activate phosphatidylinositol-3-kinase (PI3K) in monocytes, and this action is related to the initiation of chemotaxis, leading to the formation of foam cells hence atherosclerotic plague [13]. The enzyme, PI3K, has also been implicated in modulation of vasomotor tone [14-17]. Hypothesis We hypothesize that activation of PI3K by atherogenic phospholipids is responsible for endothelial dysfunction that is associated with hypercholesterolemia. Purpose of the proposed investigation: The mechanism(s) through which atherogenic lipids in impairing endothelium-dependent relaxation remains unclear. The present proposed study aims at investigating the regulation of endothelium-dependent relaxation by PI3K, an enzyme shown to be activated by atherogenic lipids. The influence of atherogenic lipids on the activity and expression of PI3K, as well as its downstream enzymes, will also be examined. Key issues and problem addressed: i. The importance of the signaling mechanisms of PI3K and its downstream targets, namely protein kinase B (PKB, also known as Akt) and extracellular signal-regulated kinase-1/2 (ERK 1/2), in the regulation of the vascular tone will be examined under physiological conditions, as well as under the influence of the atherogenic phospholipid, LPC. ii. Alteration of the expression, phosphorylation and activity of these enzymes due to acute and chronic exposure to atherogenic phospholipids will be studied in isolated porcine coronary artery, and the results will be correlated to the degree of endothelial dysfunction as indicated by the decrease in endothelium-dependent relaxation. iii. The potential of interfering PI3K signaling pathway using pharmacological approaches to reverse the influence of atherogenic phospholipid on endothelium-dependent relaxation will be examined. Reference: [1] Kugiyama K, Kerns SA, Morrisett JD, et al. Nature 1990; 344: 160-162. [2] Tanner FC, Noll G, Boulanger CM, et al. Circulation 1991; 83: 2012-2020 [3] Yokoyama M, Hirata K-I, Miyake R, et al. Biochem Biophys Res Comm 1990; 168: 301–308. [4] Palmer RMJ, Ferrige AG, Moncada S. Nature 1987; 327: 524-526. [5] Chen G, Suzuki H, Weston AH. Br J Pharmacol 1988; 95: 1165-1174. [6] Cox DA, Cohen ML. Am J Physiol 1996; 271: H1706–H1710. [7] Freeman JE, Kuo WY, Drenger B, et al. J Cardiovasc Pharmacol 1996; 28: 345–352. [8] Miwa Y, Hirata K-i, Kawashima S, et al. Arterioscler Thromb Vasc Biol 1997; 17: 1561–1567. [9] Kikuta K-i, Sawamura T, Miwa S, et al. Circ Res 1998; 83: 1088–1096. [10] Fukao M, Hattori Y, Kanno M, et al. Br J Pharmacol 1995; 116: 1541-1543. [11] Cowan CL, Steffen RP. Arterioscler Thromb Vasc Biol 1995; 15: 2290–2297. [12] Eizawa H, Yui Y, Inoue R, Kosuga K, et al. Circulation 1995; 92: 3520–3526. [13] Jing Q, Xin SM, Zhang WB, et al. Cir Res 2000; 87: 52-59. [14] Macrez N, Mironneau C, Carricaburu V, et al. Circ Res 2001; 89: 692-699. [15] Viard P, Exner T, Maier U, et al. FASEB J 1999; 13: 685-694. [16] Cantrell DA. J Cell Sci 2002; 114: 1439-1445. [17] Cantley LC. Science 2002; 296: 1655-1657.

 

List of Research Outputs

 

Chan L.Y., Keung W.Y.W., Yeung K.Y., Leung S.W.S., Che C.M. and Man R.Y.K., The vasorelaxation effect of an extract of chinese medicinal herb, radix angelica pubescens in porcine coronary artery, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 77.

 

Chan L.Y., Keung W.Y.W., Yeung K.Y., Leung S.W.S., Che C.M. and Man R.Y.K., The vasorelaxation effect of osthole, derived from radix angelicae pubescentis, in porcine coronary artery, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Chan P.S., Leung S.W.S. and Man R.Y.K., Modulation of vasoconstriction by testosterone in porcine coronary artery, Experimental Biology 2007, Washington, DC, April 28 - May 2, 2007.

 

Chan P.S., Leung S.W.S. and Man R.Y.K., Modulation of vasoconstriction by testosterone in porcine coronary artery, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 86.

 

Leung S.W.S., Teoh H., Quan A., Lee Y.K.M., Yeung K.Y., Xu Y.C. and Man R.Y.K., Gonadal hormones and vascular reactivity, Frontiers in Biomedical Research, HKU Scientific Meeting of the Research Centre of Heart, Brain, Hormone and Healthy Aging. 2006.

 

Leung S.W.S., Teoh H., Keung W.Y.W. and Man R.Y.K., Non-genomic vascular actions of female sex hormones: physiological implications and signalling pathways., Clinical and Experimental Pharmacology and Physiology. 2007, 34: 822-826.

 

Xu Y.C., Leung S.W.S., Leung G.P.H., Vanhoutte P.M.G.R. and Man R.Y.K., Kaempferol potentiated relaxation in porcine coronary arteries and stimulated large-conductance potassium channes in HUVEC, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 83.

 

Xu Y.C., Leung S.W.S., Leung G.P.H. and Man R.Y.K., Kaempferol, a compound from chinese medicine Carthamus tinctorius, potentiated relaxation in porcine coronary arteries and activated potassium channel in HUVEC, 2006 Hong Kong-Macau Postgraduate Symposium on Chinese Medicine, Hong Kong, August 17, 2006. 130-131.

 

Xu Y.C., Leung S.W.S., Yeung K.Y., Hu L., Chen G., Che C.M. and Man R.Y.K., Structure-activity Relationships of Flavonoids for Vascular Relaxation in Porcine Coronary Artery, Phytochemistry. 2007, 68: 1179-1188.

 

Yeung K.Y., Leung S.W.S., Xu Y.C., Vanhoutte P.M.G.R. and Man R.Y.K., Puerarin, an isoflavonoid derived from Radix puerariae, potentiates endothelium-independent relaxation via the cyclic AMP pathway in porcine coronary artery. , European Journal of Pharmacology. 2006, 287: 101-105.

 

Researcher : Li RWS

List of Research Outputs

 

Li R.W.S., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Effects of inflammation on adenosine transport and ecto-5’-nucleotidae in endothelial cells, Meeting the Challenges of an Aging Population, Hong Kong, March 3-4, 2007. 2007, 62.

 

Researcher : Li WSR

List of Research Outputs

 

Li W.S.R., Tse C.M., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Inhibition of human equilibrative nucleoside transporters by dihydrophyridine-type calcium channel antagonists, European Journal of Pharmacology. 2007, 568: 75-82.

 

Li W.S.R., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Regulation of extracellular adenosine in inflammation, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 90.

 

Researcher : Man RYK

Project Title:

Cloning and characterization of phytoestrogen receptors in vascular cells

Investigator(s):

Man RYK, Leung GPH, Leung SWS

Department:

Pharmacology

Source(s) of Funding:

Small Project Funding

Start Date:

12/2005

 

Abstract:

Epidemiological studies have demonstrated that women are less vulnerable to cardiovascular diseases during their pre-menopausal years. However, the incidence of cardiovascular diseases increases after menopause, stating the importance of female hormone in cardiovascular protective effects. Estrogen replacement therapy has been demonstrated to be beneficial to the cardiovascular system. For instance, it can decrease low-density lipoprotein and increase high density lipoprotein. Besides, estrogen shows antioxidant and vasodilatory effects. Unfortunately, the actual benefit of estrogen therapy is questionable because it increases the risk of endometrial and breast cancer. The hormonal effects also make estrogen not useful in male. Phytoestrogens are an alternative. Soybean is rich in phytoestrogens. A number of studies have suggested the beneficial effects of soy-rich diet in lowering the mobility and mortality of cardiovascular diseases. Same as estrogen, soybean products reduce the blood levels of low density lipoprotein and triglyceride. Our laboratory has also proved that genistein, a phytoestrogen, enhances the endothelium-independent relaxation in coronary artery. These effects may contribute to the prevention of cardiovascular disorders. Most importantly, although genistein is structurally similar to estrogen, its affinity to the genomic estrogen receptors is 100-1000 times less than the estrogen. Therefore, it is assumed that phytoestrogens, while producing beneficial cardiovascular effects, should show negligible hormonal effects. Our tissue bath studies have demonstrated the vasodilatory effects of several other phytoestrogens. Interestingly, the actions of all those phytoestrogens occur within 30 minutes. It is too rapid to have been attributed to the genomic action. This notion is supported by the lack of effect of actinomycin D, a DNA transcription inhibitor, or cycloheximide, a mRNA translation inhibitor, to block the vascular effects of phytoestrogens. Moreover, the inability of the classic estrogen receptor antagonist, ICI 182,780, to block the effects of phytoestrogens further indicates that phytoestrogen may act on receptors which are distinct from the classic genomic estrogen receptors. In this grant application, we propose to clone and characterize phytoestrogen receptors in vascular cells. In aim I, we will clone phytoestrogen receptors. In aim II, we will express the cloned phytoestrogen receptors in COS-7 cells. We will study their molecular sizes, cellular localization and affinities to phytoestrogens and estrogen. If they show high affinities to phytoestrogen, we will study if they are linked to cAMP or cGMP production in vascular smooth muscle. In aim III, we will determine the tissue distribution of phytoestrogen receptors.

 

Project Title:

Gender differences in the regulation of endothelium-dependent contracting factor

Investigator(s):

Man RYK, Vanhoutte PMGR, Leung SWS

Department:

Pharmacology

Source(s) of Funding:

Competitive Earmarked Research Grants (CERG)

Start Date:

09/2006

 

Abstract:

(1) Gender differences exist in the production and/or actions of EDCF, in particular in hypertensive and aging rats. This different between male and female are caused by the non-genomic action of the major female hormone, estrogen. (2) Estrogen modulates the changes in the key proteins that are involved in the production and the action of EDCF in arteries from hypertensive and aging rats. Examples of these proteins are muscarinic receptor(s) in endothelial cells, prostanoid receptors in vascular smooth muscle cells and prostanoid synthase(s) in both cell types. (2) The activation of soluble guanylyl cyclase in endothelial cells has an autocrine effect to diminish the activity and/or expression of prostanoid synthase(s) resulting in inhibition of the production of EDCF. The extent of activation of this enzyme is influenced by the hormonal status of rats.

 

Project Title:

Hormonal effects of flavonoids with selective vascular actions: comparison with estrogen

Investigator(s):

Man RYK, Leung SWS, Leung GPH

Department:

Pharmacology

Source(s) of Funding:

Small Project Funding

Start Date:

12/2006

 

Abstract:

Prior to menopause, women have a lower incidence of coronary heart disease (CHD) compared to age-matched men [1-3]. Estrogen replacement therapy reduces CHD mortality in post-menopausal women [4,5]. The protective effects of estrogen are partially attributable to its favorable vascular effects. Unfortunately, the therapeutic potential of estrogen for cardiovascular protection is complicated by its hormonal actions, which make it an inappropriate agent for male. Moreover, the hormonal actions of estrogen results in an increased risk of endometrial and breast cancer. Being structurally similar to estrogen, some flavonoids have been considered as phytoestrogens and are likely to provide similar cardiovascular benefit to estrogen. Indeed, a number of studies have suggested that flavonoid-rich diet reduced the mobility and mortality of cardiovascular diseases. Our previous studies have demonstrated that several flavonoids, such as genistein, puerarin and kaempferol, favourably modulated vascular responses in a similar manner to 17beta-estradiol [6-9]. These effects were rapid in onset (occuring within 30 minutes) and were not affected by the classical estrogen receptor antagonist, ICI 182,780. Therefore, the modulatory actions of flavonoids, like 17beta-estradiol, on vascular reactivity were likely to be non-genomic in nature. Moreover, these vascular effects of flavonoids appeared to be mediated through a cyclic AMP-dependent signaling cascade similar to that involved in the vascular actions of 17beta-estradiol [7,10]. Hence, some flavonoids may act at the same cellular targets, possibly membrane-bounded receptors, as 17beta-estradiol in vascular tissues. While the above suggested a non-genomic actions of estrogen, estrogen has well known genomic actions via intracellular estrogen receptors. These include stimulation of breast and uterine tissues, lowering of LDL and raising HDL cholesterol levels, and maintanence of bone density. If flavonoids possess significant genomic effects of estrpgen, they may increase the risk of breast and uterine cancers, and increase the risk of thrombosis. While our findings on the non-genomic vascular actions of flavonoids suggested a likely therapeutic potential of flavonoids against the development of vascular diseases, the potential of these compounds to exert genomic hormonal effects that are similar to those of 17beta-estradiol needed to be taken into account. It is desirable to have flavonoids that possess the vascular action but have little or no hormonal action. Some of the flavonoids, such as genistein and daidzein, have been shown to compete with 17beta-estradiol for the classical genomic estrogen receptors that are responsible for the hormonal effects [11]. However, in those studies, the binding affinity of flavonoids to the genomic estrogen receptors was at least 100-fold less than estrogen. Therefore, it is hypothesized that flavonoids have selectivity in eliciting vascular actions compared to hormonal actions, and that different flavonoids have different vascular-hormonal profiles, which may be determined by their chemical structures. The purpose of the present proposal is to determine the vascular-hormonal profiles of different flavonids, and compared to that of 17beta-estradiol. Specificially, the potency of different flavonoids to elicit hormonal actions, in terms of their ability to stimulate the proliferation of human MCF-7 breast cancer cell line and/or human HEC-1-A endometrial cancer cell line, will be examinied. The order of potency of hormonal actions will be compared with that of vascular actions. The relative potency of the hormonal effects of flavonoids will also be studied in relation to their chemical structures. References: 1. Barrett-Connor E. Circulation 1997; 95: 252-264. 2. Phillips GB, Pinkernell BH, Jing, T-Y. Arterioscler Thromb Vasc Biol 1997; 17: 695-701 3. Van der Schouw YT, Van der Graaf Y, Steyerberg EW, et al. Lancet 1996; 347: 714-718. 4. Ettinger N, Friedman GD, Bush T, et al. Obstet Gynecol 1996; 87: 6-12. 5. Stampfer JM, Colditz FA, Willett WC, et al. N Engl J Med 1991; 325: 756-762. 6. Teoh H, Leung SWS, Man RYK. Cardiovasc Res 1999; 42: 224-231. 7. Teoh H, Man RYK. Br J Pharmacol 2000; 1739-1747. 8. Lee MYK, Man RYK. Eur J Pharmacol 2003; 481: 227-232. 9. Xu YC, Yeung DKY, Man RYK ,et al. Mol Cell Biochem 2006; 287: 61-67. 10. Lee MYK, Leung SWS, Vanhoutte, et al. Eur J Pharmacol 2004; 503: 165-172. 11. Kuiper GGJM, Lemmen JG, Carlsson B, et al. Endocrinology 1998; 139: 4252-4263.

 

List of Research Outputs

 

Chan L.Y., Keung W.Y.W., Yeung K.Y., Leung S.W.S., Che C.M. and Man R.Y.K., The vasorelaxation effect of an extract of chinese medicinal herb, radix angelica pubescens in porcine coronary artery, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 77.

 

Chan L.Y., Keung W.Y.W., Yeung K.Y., Leung S.W.S., Che C.M. and Man R.Y.K., The vasorelaxation effect of osthole, derived from radix angelicae pubescentis, in porcine coronary artery, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Chan P.S., Leung S.W.S. and Man R.Y.K., Modulation of vasoconstriction by testosterone in porcine coronary artery, Experimental Biology 2007, Washington, DC, April 28 - May 2, 2007.

 

Chan P.S., Leung S.W.S. and Man R.Y.K., Modulation of vasoconstriction by testosterone in porcine coronary artery, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 86.

 

Lau C.T. and Man R.Y.K., Isoflavone metabolite equol enhances sodium nitroprusside induced vasorelaxation in the rat thoracic aorta via cyclic AMP cascade, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006 Hong Kong. 2006, 14:2: 80.

 

Leung G.P.H., Tse C.M. and Man R.Y.K., Characterization of adenosine transport in H9c2 cardiomyoblasts, International Journal of Cardiology. 2006, 116: 186-193.

 

Leung S.W.S., Teoh H., Quan A., Lee Y.K.M., Yeung K.Y., Xu Y.C. and Man R.Y.K., Gonadal hormones and vascular reactivity, Frontiers in Biomedical Research, HKU Scientific Meeting of the Research Centre of Heart, Brain, Hormone and Healthy Aging. 2006.

 

Leung S.W.S., Teoh H., Keung W.Y.W. and Man R.Y.K., Non-genomic vascular actions of female sex hormones: physiological implications and signalling pathways., Clinical and Experimental Pharmacology and Physiology. 2007, 34: 822-826.

 

Li R.W.S., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Effects of inflammation on adenosine transport and ecto-5’-nucleotidae in endothelial cells, Meeting the Challenges of an Aging Population, Hong Kong, March 3-4, 2007. 2007, 62.

 

Li W.S.R., Tse C.M., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Inhibition of human equilibrative nucleoside transporters by dihydrophyridine-type calcium channel antagonists, European Journal of Pharmacology. 2007, 568: 75-82.

 

Li W.S.R., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Regulation of extracellular adenosine in inflammation, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 90.

 

Shi Y., Ku D.D., Man R.Y.K. and Vanhoutte P.M.G.R., Oxygen-derived free radicals mediate endothelium-dependent contractions in the femoral artry from streptozotocin-treated rats, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006 Hong Kong. 2006, 14:2: 74.

 

Shi Y., Feletou M., Ku D.D., Man R.Y.K. and Vanhoutte P.M.G.R., The calcium ionophore A23187 induces endothelium-dependent contractions in femoral arteries from rats with streptozotocin-induced diabetes, British Journal of Pharmacology. 2007, 150: 624-632.

 

Tang H.C., Feletou M., Huang Y., Man R.Y.K. and Vanhoutte P.M.G.R., Acetylcholine and sodium nitroprusside cause long-term inhibition of EDCF-mediated contractions, American Journal Physiology Heart and Circulatory Physiology. 2006, 289: H2434-H2440.

 

Tang H.C., Leung F.P., Huang Y., Feletou M., So K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Calcium and rea tive oxygen species increase in endothelial cells in response to releasers of endothelium-derived contracting factor, British Journal of Pharmacology. 2007, 151(1): 15-23.

 

Tang H.C., Man R.Y.K. and Vanhoutte P.M.G.R., Cellular changes in aortas of spontaneously hypertensive rats faciliate the occurrence of endothelium-dependent contractions, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006 Hong Kong. 2006, 14:2: 83.

 

Xu Y.C., Leung S.W.S., Leung G.P.H., Vanhoutte P.M.G.R. and Man R.Y.K., Kaempferol potentiated relaxation in porcine coronary arteries and stimulated large-conductance potassium channes in HUVEC, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 83.

 

Xu Y.C., Leung S.W.S., Leung G.P.H. and Man R.Y.K., Kaempferol, a compound from chinese medicine Carthamus tinctorius, potentiated relaxation in porcine coronary arteries and activated potassium channel in HUVEC, 2006 Hong Kong-Macau Postgraduate Symposium on Chinese Medicine, Hong Kong, August 17, 2006. 130-131.

 

Xu Y.C., Leung S.W.S., Yeung K.Y., Hu L., Chen G., Che C.M. and Man R.Y.K., Structure-activity Relationships of Flavonoids for Vascular Relaxation in Porcine Coronary Artery, Phytochemistry. 2007, 68: 1179-1188.

 

Yeung K.Y., Leung S.W.S., Xu Y.C., Vanhoutte P.M.G.R. and Man R.Y.K., Puerarin, an isoflavonoid derived from Radix puerariae, potentiates endothelium-independent relaxation via the cyclic AMP pathway in porcine coronary artery. , European Journal of Pharmacology. 2006, 287: 101-105.

 

Researcher : Michel FSJ

Project Title:

Prejunctional and endothelial effects of acetylcholine in rat arteries constricted by activation of the sympathetic nerves

Investigator(s):

Michel FSJ

Department:

Pharmacology

Source(s) of Funding:

Small Project Funding

Start Date:

12/2006

 

Abstract:

The autonomic nervous system consists of two usually antagonistic subsystems: the sympathetic and the parasympathetic nervous system. The sympathetic nervous system controls the diameter of the blood vessels, heart rate and the strength of the myocardial contractions. Norepinephrine is the primary neurotransmitter of the peripheral sympathetic nervous system. The physiological role of the release of norepinephrine from nerve endings on blood vessels is to adjust continuously the performance of the cardiovascular system. Norepinephrine acts on adrenoceptors, divided into three main groups: α1-, α2- and β-adrenoceptor. Norepinephrine is the most potent ligand of the vascular smooth muscle α1-adrenoceptors, which play an important role in the regulation of peripheral resistance and systemic arterial blood pressure [1]. Electrical stimulation of the sympathetic nerve endings induces the release of endogenous norepinephrine into the extracellular space in concentrations sufficient to cause contraction of the innervated vascular smooth muscle cells [2]. Thus, electrical stimulation increases the muscle tension and tritiated-norepinephrine efflux in the rat tail artery [3], human and canine veins [4,5] and other vascular beds [6,7]. The peripheral vasoconstrictor response to sympathetic nerve activity is regulated by pre and postjunctional control mechanisms. In canine veins, exogenous acetylcholine evokes relaxation during electrical stimulation and decreases the release of norepinephrine [8]. This is because the activation of muscarinic receptors, located on the postganglionic sympathetic nerve terminals, acetylcholine inhibits the release of the adrenergic neurotransmitter [9] Furchgott and Zawadzki (1980) reported the obligatory role of the endothelium in the relaxation of isolated arteries to acetylcholine [10]. Nitric oxide is the primary endothelium-derived relaxing factor [11] and is formed in endothelial cells in response to vasodilator agents such as acetylcholine, bradykinin or substance P. These agonists activate the endothelial isoform of nitric oxide synthase to synthesize nitric oxide [12,13]. Nitric oxide diffuses out of the endothelium toward the smooth muscle cells to cause their relaxation [14]. The lack of nitric oxide-dependent tonic vasodilatation leaves unopposed the actions of endogenous vasoconstrictors. The constriction evoked by stimulation of sympathetic terminals is enhanced by a nitric oxide synthase inhibitor (L-NAME) or without the endothelium, whereas the release of tritiated-norepinephrine is not modified [15]. After long-term NOS inhibition a persistent activation of the sympathetic nervous system is responsible for the hypertension [16,17]. However, a specific postjunctional interaction between nitric and norepinephrine may exist. The inhibition by the endothelium of the constrictor response to sympathetic nerve stimulation can result from the disposition of norepinephrine by the endothelial cells [18]. L-NAME enhances vasoconstrictor responses to norepinephrine to a greater extent than that to angiotensin II [19]. Atomoxetine is a selective norepinephrine reuptake inhibitor that possesses no antimuscarinic properties. The neuronal reuptake is the reabsorption of the neurotransmitter by presynaptic neurons after they have transmitted the neural impulse. The clearance of the released norepinephrine occurs by such neuronal uptake [20] and the inhibition of norepinephrine reuptake augments sympathetic neuronal responses [21,22]. Atomoxetine increases by a factor of ten the potassium-evoked release of norepinephrine in the lower urinary tract tissues, as compared to non selective reuptake inhibitors [23]. It is approved for the treatment of attention-deficit hyperactivity disorder, but has cardiovascular side effects. In human, acute administrations increase heart rate and arterial blood pressure [24]. A chronic treatment with atomoxetine can induce hypertension in 3 young patients out of 9 [25]. Since the endothelium can attenuate vasoconstrictor responses to norepinephrine, the purpose of the present study will be to determine whether or not nitric oxide released by the endothelium in response to exogenous acetylcholine administration can induce a relaxation of the rat tail artery contracted by electrical stimulation of the adrenergic nerve ending. The contribution of presynaptic inhibition of norepinephrinerelease and the endothelium-dependent formation of nitric oxide, respectively, in the acetylcholine-induced relaxation will be also defined. Preparations will be examined taken from animals with a potentiated response to sympathetic activation, as obtained with a chronic treatment with atomoxetine. The acetylcholine-mediated relaxation during electrical stimulation of the tail artery from rats made hypertensive with atomoxetine will be analyzed. The reactivity will be correlated with the arterial blood pressure to answer whether or not the prejunctional or the endothelial effects of acetylcholine on the response to sympathetic nerve stimulation is modified in the context of an elevation of blood pressure due to a norepinephrine reuptake inhibition. 1. Tanoue A, Koshimizu TA, Shibata K, Nasa Y, Takeo S, Tsujimoto G. Trends Endocrinol Metab. 2003;14(3):107-13. 2. Smith AD. Biochem Soc Symp. 1972;(36):103-31. 3. Hicks PE, Najar M, Vidal M, Langer SZ. Naunyn Schmiedebergs Arch Pharmacol. 1986;333(4):354-61. 4. Rorie DK, Rusch NJ, Shepherd JT, Vanhoutte PM, Tyce GM. Circ Res. 1981;49(2):337-41. 5. Vanhoutte PM, Lorenz RR, Tyce GM. J Pharmacol Exp Ther. 1973;185(2):386-94. 6. Kubo T, Su C. Eur J Pharmacol. 1983;87(2-3):349-52. 7. Su C, Bevan JA. J Pharmacol Exp Ther. 1970;172(1):62-8. 8. Vanhoutte PM, Lorenz RR, Tyce GM. J Pharmacol Exp Ther. 1973;185(2):386-94. 9. Vanhoutte PM, Shepherd JT. Circ Res. 1973;32(2):259-67. 10. Furchgott, R. F. & Zawadzki, J. V. (1980) Nature (London) 288, 373-376 11. Fleming I, Busse R. J Mol Cell Cardiol. 1999;31(1):5-14. 12. Palmer RM, Ashton DS, Moncada S. Nature. 1988;333(6174):664-6. 13. Moncada S, Palmer RM, Higgs EA. Hypertension. 1988;12(4):365-72. Review. 14. Moncada S, Palmer RM, Higgs EA. Pharmacol Rev. 199;43(2):109-42. Review. 15. Bucher B, Ouedraogo S, Tschopl M, Paya D, Stoclet JC. Br J Pharmacol. 1992;107(4):976-82. 16. Cunha RS, Cabral AM, Vasquez EC. Am J Hypertens. 1993;6(9):806-9. 17. Sander M, Hansen PG, Victor RG. Hypertension. 1995;26(4):691-5. 18. Tesfamariam B, Weisbrod RM, Cohen RA. Am. J. Physiol. 1987 (253), H792±H798. 19. Zanzinger J, Czachurski J, Seller H. Circ Res. 1994;75(6):1073-7. 20. Stjärne L, Stjärne E. Prog Neurobiol. 1995;47(1):45-94. Review. 21. Webb RC, Vanhoutte PM. 1982;34(2):134-6. 22. Webb RC, Vanhoutte PM, Bohr DF. J Cardiovasc Pharmacol. 1980;2(2):121-32. 23. Foreman MM, McNulty AM. Life Sci. 1993;53(3):193-200. 24. Kelly RP, Yeo KP, Teng CH, Smith BP, Lowe S, Soon D, Read HA, Wise SD. J Clin Pharmacol. 2005;45(7):851-5. 25. Stojanovski SD, Robinson RF, Baker SD, Casavant MJ, Hayes JR, Nahata MC. Clin Toxicol (Phila). 2006;44(3):243-7.

 

List of Research Outputs

 

Researcher : Shi Y

List of Research Outputs

 

Shi Y., Ku D.D., Man R.Y.K. and Vanhoutte P.M.G.R., Oxygen-derived free radicals mediate endothelium-dependent contractions in the femoral artry from streptozotocin-treated rats, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006 Hong Kong. 2006, 14:2: 74.

 

Shi Y., Feletou M., Ku D.D., Man R.Y.K. and Vanhoutte P.M.G.R., The calcium ionophore A23187 induces endothelium-dependent contractions in femoral arteries from rats with streptozotocin-induced diabetes, British Journal of Pharmacology. 2007, 150: 624-632.

 

Researcher : Shin VY

List of Research Outputs

 

Shin V.Y., Wu K.K., Chu K.M., Koo M.W.L., Wong H.P.S., Lam K.Y., Tai K.K. and Cho C.H., Functional role of b-adrenergic receptor in the mitogenic action of nicotine on gastric cancer cells, Toxicological Sciences. 2007, 96: 21-29.

 

Researcher : So HL

List of Research Outputs

 

Kopaniszen M., Tai K.K., So H.L., Cho C.H. and Koo M.W.L., The effects of green tea polyphenols on dinitrobenzene sulphonic acid (DNBS)-induced colitis in mice, Experimental Biology, Annual Meeting, Washington, DC., USA. 2007.

 

Lam K.Y., Tai K.K., Koo M.W.L., Wong P.S.H., Wu K.K., So H.L., Woo P.C.Y. and Cho C.H., Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG, Life Sciences. Elsevier, 2007, 80: 2128-2136.

 

Mak J.C.W., Hui W.S., Ho S.P., So H.L., Chan M.M.W., Lam W.K., Cho C.H. and Ip M.S.M., Best Poster - Systemic oxidative stress and inflammation in cigarette smoke-exposed rat model, 12th Medical Research Conference. 2007.

 

Tai K.K., Wu K.K., Wong P.S.H., Lam K.Y., Yu L., Liu X., So H.L. and Cho C.H., Study of cathelicidin on ulcerative colitis in mice, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Researcher : Tai KK

List of Research Outputs

 

Kopaniszen M., Tai K.K., So H.L., Cho C.H. and Koo M.W.L., The effects of green tea polyphenols on dinitrobenzene sulphonic acid (DNBS)-induced colitis in mice, Experimental Biology, Annual Meeting, Washington, DC., USA. 2007.

 

Lam K.Y., Tai K.K., Koo M.W.L., Wong P.S.H., Wu K.K., So H.L., Woo P.C.Y. and Cho C.H., Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG, Life Sciences. Elsevier, 2007, 80: 2128-2136.

 

Shin V.Y., Wu K.K., Chu K.M., Koo M.W.L., Wong H.P.S., Lam K.Y., Tai K.K. and Cho C.H., Functional role of b-adrenergic receptor in the mitogenic action of nicotine on gastric cancer cells, Toxicological Sciences. 2007, 96: 21-29.

 

Tai K.K., Wu K.K., Wong P.S.H., Lam K.Y., Yu L., Liu X., So H.L. and Cho C.H., Study of cathelicidin on ulcerative colitis in mice, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Researcher : Tai KK

List of Research Outputs

 

Kopaniszen M., Tai K.K., So H.L., Cho C.H. and Koo M.W.L., The effects of green tea polyphenols on dinitrobenzene sulphonic acid (DNBS)-induced colitis in mice, Experimental Biology, Annual Meeting, Washington, DC., USA. 2007.

 

Lam K.Y., Tai K.K., Koo M.W.L., Wong P.S.H., Wu K.K., So H.L., Woo P.C.Y. and Cho C.H., Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG, Life Sciences. Elsevier, 2007, 80: 2128-2136.

 

Shin V.Y., Wu K.K., Chu K.M., Koo M.W.L., Wong H.P.S., Lam K.Y., Tai K.K. and Cho C.H., Functional role of b-adrenergic receptor in the mitogenic action of nicotine on gastric cancer cells, Toxicological Sciences. 2007, 96: 21-29.

 

Tai K.K., Wu K.K., Wong P.S.H., Lam K.Y., Yu L., Liu X., So H.L. and Cho C.H., Study of cathelicidin on ulcerative colitis in mice, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Researcher : Tang HC

List of Research Outputs

 

Tang H.C., Feletou M., Huang Y., Man R.Y.K. and Vanhoutte P.M.G.R., Acetylcholine and sodium nitroprusside cause long-term inhibition of EDCF-mediated contractions, American Journal Physiology Heart and Circulatory Physiology. 2006, 289: H2434-H2440.

 

Tang H.C., Leung F.P., Huang Y., Feletou M., So K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Calcium and rea tive oxygen species increase in endothelial cells in response to releasers of endothelium-derived contracting factor, British Journal of Pharmacology. 2007, 151(1): 15-23.

 

Tang H.C., Man R.Y.K. and Vanhoutte P.M.G.R., Cellular changes in aortas of spontaneously hypertensive rats faciliate the occurrence of endothelium-dependent contractions, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006 Hong Kong. 2006, 14:2: 83.

 

Researcher : Tang HC

List of Research Outputs

 

Tang H.C., Feletou M., Huang Y., Man R.Y.K. and Vanhoutte P.M.G.R., Acetylcholine and sodium nitroprusside cause long-term inhibition of EDCF-mediated contractions, American Journal Physiology Heart and Circulatory Physiology. 2006, 289: H2434-H2440.

 

Tang H.C., Leung F.P., Huang Y., Feletou M., So K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Calcium and rea tive oxygen species increase in endothelial cells in response to releasers of endothelium-derived contracting factor, British Journal of Pharmacology. 2007, 151(1): 15-23.

 

Tang H.C., Man R.Y.K. and Vanhoutte P.M.G.R., Cellular changes in aortas of spontaneously hypertensive rats faciliate the occurrence of endothelium-dependent contractions, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006 Hong Kong. 2006, 14:2: 83.

 

Researcher : Tom WM

List of Research Outputs

 

Tipoe G.L., Leung T.M., Liong E.C., So H.S.H., Leung K.M., Lau T.Y., Tom W.M., Fung M.L., Fan S.T. and Nanji A.A., Inhibitors of inducible nitric oxide (NO) synthase are more effective than an NO donor in reducing carbon-tetrachloride induced acute liver injury, Histology and Histopathology. 2006, 21(11): 1157-1165.

 

Researcher : Vanhoutte PMGR

Project Title:

Genomic Changes in Regenerated Endothelium

Investigator(s):

Vanhoutte PMGR, Mak WW, Tse HF

Department:

Pharmacology

Source(s) of Funding:

Small Project Funding

Start Date:

08/2005

Completion Date:

07/2006

 

Abstract:

Endothelium-dependent responses of the vasculature are due to the release of diffusible substances [Endothelium-derived relaxing (EDRF) and contracting (EDCF) factors] from the endothelial cells (1, 2). Over the last twenty five years, the laboratory of the PI has examined how the production by endothelial cells of such factors underlies moment-to-moment changes in the tone of the surrounding vascular smooth muscle cells, and how the inability of the endothelial cells to do so properly eventually initiates atherosclerosis where the relative absence of nitric oxide (NO) plays a key role. NO is formed from L-arginine, by endothelial NO-synthase (eNOS). NO diffuses to the underlying smooth muscle cells to stimulate soluble guanylate cyclase which accelerates the formation of cyclic GMP. The latter in turn inhibits the contractile process. NO is released also in the lumen and inhibits the adhesion of platelets and white cells to the endothelium and platelet aggregation. It also inhibits the growth of the vascular smooth muscle cells and prevents the production of adhesion molecules (3-5). The release of NO is triggered by activation of receptors on the endothelial cell membrane. The triggers include autacoids (e.g. bradykinin) and products formed during platelet aggregation; serotonin, ADP and thrombin. The cell membrane receptors for these substances are coupled to the activation of eNOS by different families of G-proteins. Thus, in coronary arteries, adrenergic receptors, serotonin receptors and thrombin receptors are coupled to pertussis toxin-sensitive Gi-proteins. By contrast the receptors for ADP or bradykinin are not (see 6). The activation of eNOS by bradykinin involves low molecular weight G-proteins of the Rho-family (7). In coronary and cerebral arteries, aggregating platelets induce endothelium-dependent relaxations, and the presence of a healthy endothelium inhibits the constriction induced by the platelet products (thromboxane A2 and serotonin). Serotonin, acting on 5-HT1D-serotonin receptors, plays the major role in this response, while ADP, activating P2y-purinoceptors, contributes little. The release of NO, both toward the underlying smooth muscle and at the interface with the blood, in response to thrombin and platelet-derived serotonin is pivotal for the protective role played by the healthy endothelium against the platelet attack (see 3-5).In the course of ageing, and in several types of vascular disease and hypertension, the endothelial cells become dysfunctional (see 3-6). This dysfunction is evidenced by an impairment in endothelium-dependent relaxations, due mainly to a reduced availability of NO. Indeed, the normal aging process induces a turn-over (apoptotic death, desquamation followed by regeneration) of endothelial cells. Unfortunately, regenerated endothelial cells have lost part of the ability to release NO, in response to platelet aggregation (8,9), because they respond minimally to serotonin, and other substances using the Gi-protein dependent pathway controlling the release of NO. The Gi proteins are present, but exhibit a reduced activity (10). The loss of the pertussis toxin-sensitive response is selective, and it does not apply, at least initially, to endothelium-dependent responses mediated by Gq-coupling proteins, in particular that to bradykinin (6-9). It is caused by the greater accumulation of oxidized low density lipoproteins (LDL) by the regenerated endothelial cells (10,11). Hypercholesterolemia also impairs endothelium-dependent relaxations (e.g. 9, 12, 13). In the initial phase of the atherosclerotic process, the endothelial dysfunction is limited to the pertussis toxin-sensitive, Gi protein-dependent pathway. Thus, the ability of regenerated endothelial cells, chronically exposed to high cholesterol levels, to ADP-ribosylate pertussis toxin is reduced (14). Hence, in coronary arteries from hypercholesterolemic pigs, the endothelium-dependent relaxations serotonin; 2-adrenergic agonists, aggregating platelets, or thrombin are depressed while those induced by ADP and bradykinin are maintained (12, 13). Oxidized LDL induces, in vitro, a similar selective endothelial dysfunction while at higher concentrations it inhibits also endothelium-dependent relaxations in response to non-Gi dependent stimulations (e.g.15 ;). The molecular basis underlying the dysfunction of regenerated endothelial cells is unknown. To judge from work comparing primary cell cultures derived from areas of the same coronary arteries covered with either native or regenerated endothelium, the latter has underwent phenotypic changes that include: a) morphological changes (appearance of giant ant multinucleated cells) indicating accelerated senescence; b) greater production of oxygen-derived free radicals; c) enhanced apoptosis; d) accelerated uptake of modified LDL despite normal affinity of the LOX-1 receptors on the cell surface; and e) exaggerated accumulation of oxidized forms of Apoprotein-B-100 ( 10, 11, 16). The proposed research will attempt to define the changes of regenerated endothelial cells at the genomic level which could explain the phenotypic alterations that underlie their dysfunction. REFERENCES: 1) Furchgott RF, Zawadzki JV. Nature 1980; 288: 373-376; 2) Furchgott RF, Vanhoutte PM. FASEB J 1989 ; 3: 2007-2018; 3)Vanhoutte PM In: Panza JA and Cannon III RO, editors. Futura Publishing Co, Inc, Armonk, NY; 1999; 79-95; 4) Vanhoutte PM. Eur Heart J 2002; 4:A8-A17; 5) Vanhoutte PM. Circulation J. 2003; 67:572-575; 6) Flavahan NA and Vanhoutte PM. Am J Hypertens 1995; 8:28S-41S; 7) Shibano T and Vanhoutte PM. Acta Pharmacologica Sinica 2003; 24:1070-1076. 8) Shimokawa H, Aarhus LL, Vanhoutte PM. Circ Res 1987;61:256-270; 9) Shimokawa H, Flavahan NA, Vanhoutte PM. Circ Res 1989; 65:740-753; 10) Borg-Capra C, Fournet-Bourguignon MP, Janiak P, Villeneuve N, Bidouard JP, Vilaine JP, Vanhoutte PM. Br J Pharmacol 1997; 122:999-1008; 11) Castedo-Delrieu M, Fournet-Bourguignon MP, Bidouard JP, Delescluse I, Leonce S , Vilaine JP, Vanhoutte PM. J Vasc Res 1997 ; 34 (suppl 1) : 10; 12) Shimokawa H, Vanhoutte PM. Circ Res.1989; 64:900-914; 13) Shimokawa H, Flavahan NA, Vanhoutte PM. Circulation 1991; 83:652-660; 14) Shibano T, Codina J, Birnbaumer L, Vanhoutte PM. Am J Physiol 1994; 267:H979-H981; 15) Cox DA and Cohen ML. Pharmacol Rev 1996; 48:3-19; 16) Kennedy, S., Fournet-Bourguignon, M-P., Breugnot, C., Castedo-Delrieu, M., Lesage, L., Reure, H., Briant, C., Leonce, S., Vilaine, J-P. ,Vanhoutte, P.M. J. Vasc. Res. 2003;40:389-398.

 

Project Title:

Calcium and the balance between nitric oxide (NO) and endothelium-derived contracting factor (EDCF)

Investigator(s):

Vanhoutte PMGR

Department:

Pharmacology

Source(s) of Funding:

Small Project Funding

Start Date:

09/2006

 

Abstract:

The endothelial cells control the tone and the growth of the underlying vascular smooth muscle by secreting opposing mediators, nitric oxide [NO; produced by endothelial NO synthase (eNOS)] and vasoconstrictor prostanoids [endothelium-derived contracting factors (EDCF); produced by endothelial cyclooxygenase-1 (COX1)]. The production of EDCF is exacerbated in blood vessels of spontaneously hypertensive rats (SHR) compared to those of the normotensive control rat (Wistar-Kyoto rats, WKY) (Vanhoutte et al , 2005). It is unclear how the endothelial cell balances the production of EDRF from eNOS and that of EDCF from COX1. Calcium may activate both enzymes simultaneously producing endothelium-derived relaxing factor (EDRF) and EDCF, which then act as opposing functional antagonists, whereby the dominant one determines the occurrence of either relaxation or contraction. Earlier work of the Principal Investigator (PI) and his collaborators demonstrates that the endothelium-dependent vasodilator acetylcholine causes a modest calcium increase in endothelial cells of the WKY but evokes a full relaxation (Yang et al., 2004; Tang et al., 2006 in revision). Acetylcholine at the same concentration causes a larger increase of calcium in endothelial cells of the SHR than in those of the WKY, and evokes not only an impaired relaxation but also an overt endothelium-dependent contraction. Taken in conjunction, these observations suggest that the preference of activating nitric oxide synthase and cyclooxygenase depends on the level of cytosolic calcium. Moderate increases in calcium favor the activation of nitric oxide synthase, but atypical high calcium release favors that of cyclooxygenase. The proposed research will examine those possibilities.

 

Project Title:

Genomic and proteomic basis of endothelial dysfunction in regenerated endothelium

Investigator(s):

Vanhoutte PMGR, Tse HF, Man RYK

Department:

Pharmacology

Source(s) of Funding:

Competitive Earmarked Research Grants (CERG)

Start Date:

09/2006

 

Abstract:

Unravel the molecular basis of endothelial dysfunction after regeneration, and thus identify potential new targets for further research permitting the design of therapeutic agents aimed at the prevention and the early treatment of vascular disease.

 

List of Research Outputs

 

Chan Y.C., Leung F.P., Yao X.Q., Lau C.W., Vanhoutte P.M.G.R. and Huang Y., Raloxifene modulates pulmonary vascular reactivity in spontaeously hypertensive rats, Journal Cardiovasc Pharmacol. 2007, 49:6: 355-361.

 

Chan Y.C., Leung F.P., Yao X.Q., Lau C.W., Vanhoutte P.M.G.R. and Huang Y., Raloxifene relaxes rat pulmonary arteries and veins: Roles of gender, endothelium, and antagonism of Ca2+ influx, The American Society for Pharmacology and Experimental Therapeutics. 2006, 312:3: 12661271.

 

El-Hamamsy I., Stevens L.M., Vanhoutte P.M.G.R. and Perrault L.P., Injury of the coronary endothelium at implantation increases endothelial dysfunction and intimal hyperplasia after heart transplantation, The Journal of Heart and Lung Transplantation. 2006, 24: 251-258.

 

Gluais P., Paysant J., Badier-Commander C., Verbeuren T., Vanhoutte P.M.G.R. and Feletou M., In SHR aorta, calcium ionophore A-23187 releases prostacyclin and thromboxane A2as emdptje;oi,-derived contracting factors, American Journal of Physiology Heart Circulatory Physiology. 2006, 291: H2255-H2264.

 

Gluais P., Vanhoutte P.M.G.R. and Feletou M., Mechanisms underlying ATP-induced endothelium-dependent contractions in the SHR aorta, European Journal of Pharmacology . 2006, 556: 107-114.

 

Li R.W.S., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Effects of inflammation on adenosine transport and ecto-5’-nucleotidae in endothelial cells, Meeting the Challenges of an Aging Population, Hong Kong, March 3-4, 2007. 2007, 62.

 

Li W.S.R., Tse C.M., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Inhibition of human equilibrative nucleoside transporters by dihydrophyridine-type calcium channel antagonists, European Journal of Pharmacology. 2007, 568: 75-82.

 

Li W.S.R., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Regulation of extracellular adenosine in inflammation, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 90.

 

Perrault L.P., Aubin M.C., Malo O., Thollon C., Villeneuve N., Vilaine J.P. and Vanhoutte P.M.G.R., Status of the endothelium-derived hyperpolarizing factor pathway in coronary arteries after heterotopic heart transplantation, The Journal of Heart and Lung Transplantation. 2006, 26:1: 48-55.

 

Shi Y., Ku D.D., Man R.Y.K. and Vanhoutte P.M.G.R., Oxygen-derived free radicals mediate endothelium-dependent contractions in the femoral artry from streptozotocin-treated rats, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006 Hong Kong. 2006, 14:2: 74.

 

Shi Y., Feletou M., Ku D.D., Man R.Y.K. and Vanhoutte P.M.G.R., The calcium ionophore A23187 induces endothelium-dependent contractions in femoral arteries from rats with streptozotocin-induced diabetes, British Journal of Pharmacology. 2007, 150: 624-632.

 

Svenden O., Ahnfelt-Ronne I. and Vanhoutte P.M.G.R., In vivo pharmacology in durg discovery and development, Basic & Clinical Pharmacology & Toxicology. 2006, 99: 89-90.

 

Tang H.C., Feletou M., Huang Y., Man R.Y.K. and Vanhoutte P.M.G.R., Acetylcholine and sodium nitroprusside cause long-term inhibition of EDCF-mediated contractions, American Journal Physiology Heart and Circulatory Physiology. 2006, 289: H2434-H2440.

 

Tang H.C., Leung F.P., Huang Y., Feletou M., So K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Calcium and rea tive oxygen species increase in endothelial cells in response to releasers of endothelium-derived contracting factor, British Journal of Pharmacology. 2007, 151(1): 15-23.

 

Tang H.C., Man R.Y.K. and Vanhoutte P.M.G.R., Cellular changes in aortas of spontaneously hypertensive rats faciliate the occurrence of endothelium-dependent contractions, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006 Hong Kong. 2006, 14:2: 83.

 

Uhrenholt T.R., Schjerning J., Vanhoutte P.M.G.R., Jensen B.L. and Skott O., Intercellular calcium signaling and nitric oxide feedback during constriction of rabbit renal afferent arterioles, American Journal Physiological Renal Physiology. 2007, 292: 1124-1131.

 

Vanhoutte P.M.G.R., Dysfonctionnement Endothelial Et Pathologie Vasculaire, Bulletin et Memoires de l'Academie royale de Medecine de Belgique. 2006, 161: 529-537.

 

Vanhoutte P.M.G.R., Endothelial function and coronary disease, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006 Hong Kong. 2006, 14:2: 70.

 

Xu Y.C., Leung S.W.S., Leung G.P.H., Vanhoutte P.M.G.R. and Man R.Y.K., Kaempferol potentiated relaxation in porcine coronary arteries and stimulated large-conductance potassium channes in HUVEC, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 83.

 

Yeung K.Y., Leung S.W.S., Xu Y.C., Vanhoutte P.M.G.R. and Man R.Y.K., Puerarin, an isoflavonoid derived from Radix puerariae, potentiates endothelium-independent relaxation via the cyclic AMP pathway in porcine coronary artery. , European Journal of Pharmacology. 2006, 287: 101-105.

 

Yung L.M., Leung F.P., Wong W.T., Lau C.W., Yao X.Q., Chen Z.Y., Vanhoutte P.M.G.R. and Huang Y., Cranberry juice consumption prevents endothelial dysfuntion in ovarlectomized rats, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 86.

 

Researcher : Wong HPS

List of Research Outputs

 

Shin V.Y., Wu K.K., Chu K.M., Koo M.W.L., Wong H.P.S., Lam K.Y., Tai K.K. and Cho C.H., Functional role of b-adrenergic receptor in the mitogenic action of nicotine on gastric cancer cells, Toxicological Sciences. 2007, 96: 21-29.

 

Researcher : Wong PSH

List of Research Outputs

 

Lam K.Y., Tai K.K., Koo M.W.L., Wong P.S.H., Wu K.K., So H.L., Woo P.C.Y. and Cho C.H., Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG, Life Sciences. Elsevier, 2007, 80: 2128-2136.

 

Tai K.K., Wu K.K., Wong P.S.H., Lam K.Y., Yu L., Liu X., So H.L. and Cho C.H., Study of cathelicidin on ulcerative colitis in mice, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Researcher : Wu KK

List of Research Outputs

 

Lam K.Y., Tai K.K., Koo M.W.L., Wong P.S.H., Wu K.K., So H.L., Woo P.C.Y. and Cho C.H., Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG, Life Sciences. Elsevier, 2007, 80: 2128-2136.

 

Shin V.Y., Wu K.K., Chu K.M., Koo M.W.L., Wong H.P.S., Lam K.Y., Tai K.K. and Cho C.H., Functional role of b-adrenergic receptor in the mitogenic action of nicotine on gastric cancer cells, Toxicological Sciences. 2007, 96: 21-29.

 

Tai K.K., Wu K.K., Wong P.S.H., Lam K.Y., Yu L., Liu X., So H.L. and Cho C.H., Study of cathelicidin on ulcerative colitis in mice, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Researcher : Wu KK

List of Research Outputs

 

Lam K.Y., Tai K.K., Koo M.W.L., Wong P.S.H., Wu K.K., So H.L., Woo P.C.Y. and Cho C.H., Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG, Life Sciences. Elsevier, 2007, 80: 2128-2136.

 

Shin V.Y., Wu K.K., Chu K.M., Koo M.W.L., Wong H.P.S., Lam K.Y., Tai K.K. and Cho C.H., Functional role of b-adrenergic receptor in the mitogenic action of nicotine on gastric cancer cells, Toxicological Sciences. 2007, 96: 21-29.

 

Tai K.K., Wu K.K., Wong P.S.H., Lam K.Y., Yu L., Liu X., So H.L. and Cho C.H., Study of cathelicidin on ulcerative colitis in mice, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Researcher : Xu YC

List of Research Outputs

 

Leung S.W.S., Teoh H., Quan A., Lee Y.K.M., Yeung K.Y., Xu Y.C. and Man R.Y.K., Gonadal hormones and vascular reactivity, Frontiers in Biomedical Research, HKU Scientific Meeting of the Research Centre of Heart, Brain, Hormone and Healthy Aging. 2006.

 

Xu Y.C., Leung S.W.S., Leung G.P.H., Vanhoutte P.M.G.R. and Man R.Y.K., Kaempferol potentiated relaxation in porcine coronary arteries and stimulated large-conductance potassium channes in HUVEC, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 83.

 

Xu Y.C., Leung S.W.S., Leung G.P.H. and Man R.Y.K., Kaempferol, a compound from chinese medicine Carthamus tinctorius, potentiated relaxation in porcine coronary arteries and activated potassium channel in HUVEC, 2006 Hong Kong-Macau Postgraduate Symposium on Chinese Medicine, Hong Kong, August 17, 2006. 130-131.

 

Xu Y.C., Leung S.W.S., Yeung K.Y., Hu L., Chen G., Che C.M. and Man R.Y.K., Structure-activity Relationships of Flavonoids for Vascular Relaxation in Porcine Coronary Artery, Phytochemistry. 2007, 68: 1179-1188.

 

Yeung K.Y., Leung S.W.S., Xu Y.C., Vanhoutte P.M.G.R. and Man R.Y.K., Puerarin, an isoflavonoid derived from Radix puerariae, potentiates endothelium-independent relaxation via the cyclic AMP pathway in porcine coronary artery. , European Journal of Pharmacology. 2006, 287: 101-105.

 

Researcher : Yeung KY

List of Research Outputs

 

Chan L.Y., Keung W.Y.W., Yeung K.Y., Leung S.W.S., Che C.M. and Man R.Y.K., The vasorelaxation effect of an extract of chinese medicinal herb, radix angelica pubescens in porcine coronary artery, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 77.

 

Chan L.Y., Keung W.Y.W., Yeung K.Y., Leung S.W.S., Che C.M. and Man R.Y.K., The vasorelaxation effect of osthole, derived from radix angelicae pubescentis, in porcine coronary artery, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Leung S.W.S., Teoh H., Quan A., Lee Y.K.M., Yeung K.Y., Xu Y.C. and Man R.Y.K., Gonadal hormones and vascular reactivity, Frontiers in Biomedical Research, HKU Scientific Meeting of the Research Centre of Heart, Brain, Hormone and Healthy Aging. 2006.

 

Xu Y.C., Leung S.W.S., Yeung K.Y., Hu L., Chen G., Che C.M. and Man R.Y.K., Structure-activity Relationships of Flavonoids for Vascular Relaxation in Porcine Coronary Artery, Phytochemistry. 2007, 68: 1179-1188.

 

Yeung K.Y., Leung S.W.S., Xu Y.C., Vanhoutte P.M.G.R. and Man R.Y.K., Puerarin, an isoflavonoid derived from Radix puerariae, potentiates endothelium-independent relaxation via the cyclic AMP pathway in porcine coronary artery. , European Journal of Pharmacology. 2006, 287: 101-105.

 

Researcher : Yeung KY

List of Research Outputs

 

Chan L.Y., Keung W.Y.W., Yeung K.Y., Leung S.W.S., Che C.M. and Man R.Y.K., The vasorelaxation effect of an extract of chinese medicinal herb, radix angelica pubescens in porcine coronary artery, Journal of the Hong Kong College of Cardiology, Tenth Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 9-10, 2006. 14:2: 77.

 

Chan L.Y., Keung W.Y.W., Yeung K.Y., Leung S.W.S., Che C.M. and Man R.Y.K., The vasorelaxation effect of osthole, derived from radix angelicae pubescentis, in porcine coronary artery, Experimental Biology 2007, Washington, DC, April 28-May 2, 2007.

 

Leung S.W.S., Teoh H., Quan A., Lee Y.K.M., Yeung K.Y., Xu Y.C. and Man R.Y.K., Gonadal hormones and vascular reactivity, Frontiers in Biomedical Research, HKU Scientific Meeting of the Research Centre of Heart, Brain, Hormone and Healthy Aging. 2006.

 

Xu Y.C., Leung S.W.S., Yeung K.Y., Hu L., Chen G., Che C.M. and Man R.Y.K., Structure-activity Relationships of Flavonoids for Vascular Relaxation in Porcine Coronary Artery, Phytochemistry. 2007, 68: 1179-1188.

 

Yeung K.Y., Leung S.W.S., Xu Y.C., Vanhoutte P.M.G.R. and Man R.Y.K., Puerarin, an isoflavonoid derived from Radix puerariae, potentiates endothelium-independent relaxation via the cyclic AMP pathway in porcine coronary artery. , European Journal of Pharmacology. 2006, 287: 101-105.



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