Cocaine is a potent central nervous system stimulant and local anesthetic with limited clinical usefulness that has become one of the most widely abused drugs in the U.S. Due to the lack of sufficient scientific data, cocaine is generally considered a """"""""safe"""""""" drug with minimal side effects amongst the estimated 10 to 20 million people who misuse cocaine. Studies describing the cardiovascular effects of cocaine have noted a modest pressor response and tachycardia presumably due to direct potentiation of catecholaminergic activity and indirect (CNS-mediated) sympathoexcitation. Clinical reports suggest that cocaine may cause cardiac myopathies in humans. The incidence of such reports is increasing as is the use of free base cocaine (""""""""crack""""""""), a more potent form of cocaine. We believe this necessitates detailed studies to define the effects of acute and chronic cocaine administration under controlled conditions and to determine the mechanisms by which cocaine elicits its effects on the vasculature and myocardium. The vascular effects of cocaine will be analyzed in awake, freely-moving rats instrumented for measurement of arterial pressure, heart rate and regional blood flows in the mesenteric and hindquarter vascular beds. The mechanisms by which specific cardiovascular effects are caused will be identified using selective receptor antagonists, local anesthetics and adrenalectomy after acute or chronic cocaine. Furthermore, tissue catecholamine turnover will be estimated after chronic cocaine administration to identify sustained alterations in sympathetic nerve activity. The incidence and severity of cardiomyopathies will be determined functionally by measuring cardiac output, levels of myocardial creatine phosphokinase and anatomically by postmortem, light and electron microscopic analysis of the myocardium. The mechanisms by which cardiac ischemia are produced will be deduced using selective antagonists for vasospasm and thrombotic occlusion. The effect of cocaine on baroreflex function will be determined in unanesthetized normal and baro-denervated rats by recording sympathetic nerve activity and heart rate responses to cocaine. CNS sites affecting baroreflex activity will also be examined. Finally, the effect of """"""""free base"""""""" cocaine on cardiovascular function will be compared to that of cocaine hydrochloride. The proposed studies represent a comprehensive approach utilizing the combined expertise of three investigators. This approach will be instrumental in determining mechanisms whereby cocaine affects vascular tone, on the functional and pathological effects of cocaine on the myocardium, on the proposed role of cocaine as a centrally acting sympathoexcitatory agent, on rational drug therapy for toxicity and on the relative dangers of free base cocaine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA005180-01A1
Application #
3211333
Study Section
(SRCD)
Project Start
1989-03-01
Project End
1993-02-28
Budget Start
1989-03-01
Budget End
1990-02-28
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Watanabe, Mari A; Kucenas, Sarah; Bowman, Tamara A et al. (2010) Angiotensin II and CRF receptors in the central nucleus of the amygdala mediate hemodynamic response variability to cocaine in conscious rats. Brain Res 1309:53-65
Schwartz, Julie A; Reilly, Nichole S; Knuepfer, Mark M (2008) Angiotensin and NMDA receptors in the median preoptic nucleus mediate hemodynamic response patterns to stress. Am J Physiol Regul Integr Comp Physiol 295:R155-65
Mueller, P J; Knuepfer, M M (1994) Coronary vascular effects of cocaine in rats. J Pharmacol Exp Ther 268:97-103
Knuepfer, M M; Branch, C A; Wehner, D M et al. (1994) Nonadrenergic mechanisms of cocaine-induced regional vascular responses in rats. Can J Physiol Pharmacol 72:335-43
Branch, C A; Knuepfer, M M (1994) Causes of differential cardiovascular sensitivity to cocaine. I: Studies in conscious rats. J Pharmacol Exp Ther 269:674-83
Branch, C A; Knuepfer, M M (1994) Causes of differential cardiovascular sensitivity to cocaine. II: Sympathetic, metabolic and cardiac effects. J Pharmacol Exp Ther 271:1103-13
Branch, C A; Knuepfer, M M (1993) Dichotomous cardiac and systemic vascular responses to cocaine in conscious rats. Life Sci 52:85-93
Knuepfer, M M; Branch, C A (1993) Calcium channel antagonists reduce the cocaine-induced decrease in cardiac output in a subset of rats. J Cardiovasc Pharmacol 21:390-6
Knuepfer, M M; McCann, R K; Kamalu, L (1993) Effects of cocaine on baroreflex control of heart rate in conscious rats. J Auton Nerv Syst 43:257-66
Knuepfer, M M; Branch, C A; Gan, Q et al. (1993) Cocaine-induced myocardial ultrastructural alterations and cardiac output responses in rats. Exp Mol Pathol 59:155-68

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