PCP abuse is one of the major public health problems in the United States and fatalities resulting from acute PCP intoxication are believed to be the result of either cardiovascular or respiratory failure. The objectives of the proposed studies are: a) to examine the discrete hemodynamic consequences of acute and chronic administration of PCP, b) to evaluate the possibility of development of tolerance to the cardiovascular and hemodynamic effects of PCP, c) to evaluate the effects of acute and prolonged PCP administration on the sympatho-adrenal medullary system, d) to examine the influence of prolonged PCP administration on the pressor responses to other pressor agents [norepinephrine (NE) and angiotensin (A-II), e) to evaluate the effect of prolonged PCP administration on body weights. These objectives will be addressed by specific experiments in which Sprague-Dawley rats will be treated with PCP both acutely and chronically. Indirect blood pressure (BP) and heart rate (HR) will be measured by tailplethysmography prior to and every week for four weeks following PCP administration. Body weights will also be recorded prior to and every week afer PCP 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 plamsa catecholamines. The effects of other pressor systems will be evaluated by injections of different doses of NE and A-II.
These aims will be achieved as follows: Direct measurement of BP, HR will be done in both anesthetized and conscious rats; blood flow to discrete organs (renal, mesenteric and hindquarters) will be done by the directional pulsed Doppler technique using VF-microprobes implanted on the respective arteries (microsurgery under anesthesia). Blood samples for plasma catecholamine assay will be withdrawn from arterial catheters implanted in the femoral arteries. Catecholamines will be assayed by the radioenzymatic - TLC method. 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 PCP, if any, will be assessed. It is hoped that data derived from these studies will provide new insights to the discrete hemodynamic mechanisms involved in the actions of PCP.
