The prevalence of drug abuse in society, coupled with the higher incidence of hypertension in blacks, has proven to be detrimental to the health and social well being of this segment of the population. The effects of abused substances in females as it relates to mechanism(s) of action of the different agents, has not been adequately explored. The objectives of the proposed studies are; a) to evaluate gender differences on the cardiovascular, metabolic, neuroendocrine, sympathetic and hemodynamic responses to acute and subchronic effects of cocaine in Dahl strain of rats; b) to evaluate gender differences on the neuroendocrine effects of cocaine; c) to evaluate gender differences on the effect of cocaine on release of eicosanoids and endothelium dependent relaxing factor (e.g. nitric oxide); d) to evaluate gender differences on the effect of cocaine on cellular proliferation. These objectives will be addressed by specific experiments in which rats will be treated with cocaine acutely and chronically. Indirect blood pressure (BP) and heart rate (HR) will be measured by tail- plethysmography prior to and every week for six weeks following cocaine administration. Body weights will also be recorded prior to and every week after drug administration. At the end of the experiments, direct measurements of BP, HR and discrete organ flow will be carried out. In addition, sympathetic activity will be assessed by direct measurements of plasma catecholamines. The effects of other pressor systems will be evaluated by injection of different doses of norepinephrine (NE) and angiotensin II (A-ll).
These aims will be achieved as follows; Direct measure of BP, HR will be done in conscious rats; blood flow to discrete organs (renal, mesenteric and hindquarters) will be done using a Transonic flowmeter with microprobes implanted on the respective arteries (microsurgery under anesthesia). Blood samples for eicosanoids and plasma catecholamine assay will be withdrawn from arterial catheters implanted in the femoral arteries. Catecholamines and eicosanoids, will be assayed by the radioenzymatic - TLC method and RIA method respectively. Changes in cardiovascular parameters will be correlated with changes in body weight. The degree of development of tolerance to the cardiovascular and hemodynamic effects of cocaine, if any, will be assessed. The effect of cocaine on endothelial cell injury and motility will be evaluated using an interactive image analysis system and electron microscopy. The data derived from these studies will provide new insights in gender differences on the cardiovascular and discrete hemodynamic and cellular mechanisms involved in the actions of cocaine.
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