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Effects of Rosiglitazone on Nitroglycerin EFFECTS OF ROSIGLITAZONE ON NITROGLYCERIN- INDUCED ENDOTHELIAL DYSFUNCTION by Kumar Perampaladas B.Sc. A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Pharmacology and Toxicology University of Toronto Supervisor: John D. Parker, MD, FRCP(C) © Copyright by Kumar Perampaladas (2010) Effects of Rosiglitazone on Nitroglycerin-Induced Endothelial Dysfunction Kumar Perampaladas, Master of Science, 2010 Graduate Department of Pharmacology and Toxicology, University of Toronto ABSTRACT Sustained nitroglycerin (GTN) therapy impairs endothelial function in healthy volunteers and patients with cardiovascular disease, caused by an increase in vascular oxidative stress. This study aims to estimate the effect of rosiglitazone on vascular endothelial function in healthy volunteers continuously dosed to transdermal GTN (0.6mg/hr) for 7 days. To assess endothelial function, forearm blood flow was measured by venous occlusion strain-gauge plethysmography in response to intra-brachial infusions of acetylcholine. GTN-treated subjects experienced significant attenuation of endothelium-dependent responses to acetylcholine (p<0.05; compared to placebo), but was reversed with vitamin C (p=ns; compared to placebo). Endothelium-dependent responses to acetylcholine were blunted in groups randomized to rosiglitazone alone (p<0.05; compared to placebo) and rosiglitazone + GTN (p<0.05 compared to placebo). Interestingly, this effect was not modified by vitamin C. In conclusion, rosiglitazone impairs endothelial function and concurrent therapy with rosiglitazone does not attenuate the adverse effects of transdermal GTN on the vasculature. ii ACKNOWLEDGEMENTS First and foremost, I would like to thank my supervisor Dr. John Parker for his continuous support during my Master’s Program. Dr. Parker has always given me the space, support, and guidance, needed to explore ideas and take on ambitious projects. The successful completion of the current study, the initiation of a pilot project looking at alternative tools to identify and quantify biomarkers, is in part to Dr. Parker’s unrelenting support. He has instilled in me the values and persistence needed in accomplishing goals that are both research and professional oriented. These past years have truly been an informative and exciting time in my life. I’m truly grateful for the opportunity to study under the guidance of Dr. John Parker. I would also like to thank Sue Kelly, Andrew Liuni, Mary Clare DeLuca, Wilson Kwong, Becky Pipes, Diane Locke, Diana Vasiliu, Tom Benson, Wilson Chan, Drs. George Thomas, Gary Newton, Susanna Mak, Alan Barolet, Amar Uxa, Rajesh Dhopeshwarkar, Justin Mariani, and Tommaso Gori, for their support and assistance in completing this study. iii TABLE OF CONTENTS TITLE i ABSTRACT ii ACKNOWLEDGEMENTS iii TABLE OF CONTENTS iv LIST OF TABLES vi LIST OF FIGURES vii ABBREVIATIONS viii CHAPTER 1.0 INTRODUCTION 1 1.1 Problem and Purpose of the Study 2 1.2 Thiazolidinediones 4 1.3 Rationale and Objectives of the Present Study 6 1.3.1 Nitrate-Induced Model of endothelial dysfunction 6 1.3.2 Hypothesis 9 1.4 Literature Review: Fundamentals of Nitrate Tolerance 10 1.4.1 Nitric Oxide Synthesis 10 1.4.2 Nitroglycerin and Organic Nitrates 12 1.4.3 Nitrate Tolerance and Proposed Mechanisms 15 1.4.4 Neurohormonal Activation 16 1.4.5 Plasma Volume Expansion 17 1.4.6 Vascular Free Radical Hypothesis 18 1.4.7 GTN-Induced Abnormalities in the Endothelium 20 1.4.8 Abnormalities in Nitrate Biotransformation 22 1.4.9 Intermittent Nitrate Dosing 25 iv 2.0 METHODOLOGY 27 2.1 Assessment of Endothelial Function 27 2.1.1 Plethysmography 27 2.1.2 Flow-mediated Dilation 29 2.2 Methods 30 2.2.1 Study Population 31 2.2.2 Study Design 32 2.2.3 Vascular Function Procedures 33 2.2.4 Experimental Sessions 36 2.2.5 Side Effects and Risks of the Study 38 2.2.6 Statistical Analysis 39 3.0 RESULTS 40 3.1 Responses to Blood Pressure and Heart Rate 40 3.2 Effect of Acetylcholine on Endothelium-dependent vasodilation 40 3.3 Effect of Vitamin C on Endothelium-dependent vasodilation 41 3.4 Tables and Figures 43 4.0 DISCUSSION 54 4.1 Nitrate-Induced Endothelial dysfunction 55 4.2 Rosiglitazone-Induced Endothelial dysfunction 55 4.3 Limitations of the Current Study 59 5.0 CONCLUSIONS 63 6.0 REFERNCES 65 v LIST OF TABLES 3.0 RESULTS Table 1: The effect of GTN on blood pressure and heart rate on healthy volunteers at baseline, 3 hours, and 7 days after treatment. Table 2: The effect of intra-arterial infusions of acetylcholine and vitamin C after 7 days of treatment with placebo, rosiglitazone, GTN, or both rosiglitazone and GTN. vi LIST OF FIGURES 3.0 RESULTS Figure 1 : Study protocol outlining the sequence of events for this study. Figure 2: Schematic of experimental sessions conducting vasomotor responses using venous occlusion plethysmography. Figure 3: Graphic presentation of plethysmographic curve in response to acetylcholine. Figure 4: Setup of forearm blood flow assessments, including placement of strain-gauge. Figure 5: Baseline (saline infusion) forearm blood flow ratios for subjects randomized to placebo, rosiglitazone, GTN, and both GTN + rosiglitazone Figure 6: The effect of acetylcholine on forearm blood flow in subjects randomized to placebo, rosiglitazone, GTN, and both GTN + rosiglitazone. Figure 7: Saline re-control to ensure forearm blood flows returned to baseline after acetylcholine infusions. Figure 8: The effect of vitamin C (co-infused with acetylcholine) on forearm blood flows in subjects randomized to placebo, rosiglitazone, GTN, and both GTN + rosiglitazone. vii ABBREVIATIONS ADMA Asymmetric Dimethylarginine ANOVA Analysis of Variance GTN Glyceryl trinitrate, Nitroglycerin NOS Nitric Oxide Synthase ISDN Isosorbide dinitrate ISMN Isosorbide Mononitrate NAD/NADPH Nicotinamide Adenine Dinucleotide Phosphate PPAR-γ Peroxisome Proliferator Activated Receptor gamma viii 1.0 INTRODUCTION 1 1.0 INTRODUCTION 1.1 Problem and Purpose of the study The endothelium is a complex organ influencing the delivery of and flow of nutrients that include proteins (growth factors, coagulation and anti-coagulation factors), lipid-transporting particles, metabolites, and hormones.(1-3) While contributions to the regulation of vasomotor tone involve production of mediators such as prostacyclin and endothelium-derived hyperpolarizing factor, the vasodilatory actions of nitric oxide (NO) is believed to be the most potent mediator in regulatory blood flow.(1-3) A healthy endothelium produces NO continuously and is responsible for vascular homeostasis by regulating important physiological functions such as platelet and leukocyte adherence, thrombolysis, inflammation, blood flow, and vascular smooth muscle cell proliferation and migration. (1;3) In contrast, a reduction in the bioavailability of NO results in endothelial dysfunction, which has been implicated in the underlying pathophysiology of several cardiovascular diseases including atherosclerosis, hypertension, heart failure, and stroke.(4-6) Reduced NO bioavailability, brought on by a reduced capability of the endothelium to produce NO or by an increased inactivation of NO, leads to disruption of NO-mediated signaling pathways that regulate homeostasis.(7;8) Organic nitrates such as nitroglycerin (glyceryl trinitrate; GTN) have long been used as a means to improve NO bioavailability by acting as NO donors, and are routinely used in the clinical management of angina pectoris, myocardial 2 infarction, and heart failure.(9;10) When administered acutely, GTN provides rapid hemodynamic and anti-ischemic benefits, but their clinical utility rapidly diminishes with continuous dosing. This is observed as a loss of their hemodynamic and anti-ischemic effects, a phenomenon termed ‘nitrate tolerance.’(10;11) Sustained nitrate therapy has been documented to cause endothelial dysfunction in animals and patients with angina pectoris and heart failure.(12-15) A plethora of evidence has demonstrated that the etiology of nitrate tolerance is multifactorial,(16;17) with an increase in vascular superoxide anions having a prominent role.(17;18) Sources of reactive oxygen species production may include xanthine and nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidases, nitric oxide synthase (NOS), cyclooxygenase, and the mitochondrial respiratory chain.(18) Increased activity of these complexes by GTN may react with nitrate-derived NO, leading to increased NO clearance, dysfunction of the NOS complex, and inhibition of mitochondrial aldehyde dehydrogenase – the enzyme responsible for GTN bioactivation. (16;17) Rosiglitazone is an insulin sensitizing agent that has been demonstrated to improve vascular function in patients with diabetes mellitus and metabolic syndrome.(19-21) Rosiglitazone improves glycemic control by modulating transcription factors involved in the regulation of glucose and lipid metabolism,(22) and has been widely used in the management of type 2 diabetes mellitus.(22;23) Beyond effect on insulin sensitivity, rosiglitazone has been documented to have anti-oxidative properties in cardiovascular animal models, a result that indicates 3 rosiglitazone may act independent of its effect on glycemic control.(24-27) Since oxidative stress have an important role in the development of nitrate tolerance and nitrate-induced endothelial dysfunction,(16;17) we explored whether the potential beneficial effects of rosiglitazone on endothelial function would extend to healthy volunteers randomized to continuous GTN treatment.
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