The overall purpose of this proposal is to determine the cellular mechanisms responsible for the cardiac and vascular toxicity of cocaine, the nature of coexisting conditions which can predispose users to toxicity, and approaches for preventing and treating the cardiovascular complications of cocaine exposure. First, we will test the hypothesis that the acute cardiovascular toxicity of cocaine is caused by abnormal intracellular calcium ((Ca++)i) handling and production of a (Ca++)i overload state. Electrical and mechanical studies will be performed with cardiac and vascular tissue from swine and ferrets that has been loaded with the calcium indicator aequorin to directly measure intracellular levels of free, ionized Ca++. Second, we will determine how chronic treatment with cocaine modifies its acute cardiac and vascular effects. Third, we will determine the degree to which the cardiovascular effects and toxicity of cocaine are caused by indirect actions of the drug; in particular, blockage of catecholamine uptake by the adrenergic nerve endings. Studies will be performed before and after the addition of propranolol and phentolamine to block post - synaptic adrenoceptors, nortriptyline to block adrenergic neuronal UPTAKE I mechanisms, or reserpine, to deplete adrenergic neurons of catecholamines. Fourth, we will determine the degree to which the cardiovascular effects and toxicity of cocaine are due to its direct effects on muscle, including actions on the sarcolemma (i.e., local anesthetic, calcium channel blockade, effects on Na+/Ca++ exchange), sarcoplasmic reticulum (i.e., Ca++ uptake and release processes) and myofilaments (i.e., altered Ca++ sensitivity and cross-bridge cycling rates). Fifth, we will identify factors that predispose to, and prevent or reverse, cocaine's cardiovascular toxicity. Experiments will be designed to identify factors that may predispose (i.e., hypertrophy, atherosclerosis, sex, aging, exercise training, hypoxia, body temperature, caffeine, alcohol, nicotine, tyramine) and that may prevent or reverse (i.e., blockade of neuronal uptake of cocaine, adrenergic neuron blockade, alpha and beta adrenoceptor blockade, calcium channel blockade) cocaine's toxicity. Sixth, we will evaluate the toxic effects of cocaine on human cardiac and vascular smooth muscle isolated from patients undergoing cardiac surgery, cardiac transplantation or organ donation. We anticipate that the results of these studies will not only clarify the pathophysiologic basis of cocaine's cardiovascular toxicity but will provide a rational basis for preventative measures and therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA005171-04
Application #
3211314
Study Section
Special Emphasis Panel (SRCD (03))
Project Start
1987-09-30
Project End
1992-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Nunez, B D; Miao, L; Wang, Y et al. (1994) Cocaine-induced microvascular spasm in Yucatan miniature swine. In vivo and in vitro evidence of spasm. Circ Res 74:281-90
Paik, G Y; Wang, J; Perreault, C L et al. (1994) Endothelin-1 does not alter Ca2+ responsiveness in saponin-skinned ferret papillary muscles. Eur J Pharmacol 264:437-43
Perreault, C L; Hague, N L; Morgan, K G et al. (1993) Negative inotropic and relaxant effects of cocaine on myopathic human ventricular myocardium and epicardial coronary arteries in vitro. Cardiovasc Res 27:262-8
Wang, J; Flemal, K; Morgan, J P (1993) Endothelin-1 enhances cross-bridge function of ferret myocardium: role of second messengers. Am J Physiol 265:H2168-74
Litwin, S E; Morgan, J P (1992) Captopril enhances intracellular calcium handling and beta-adrenergic responsiveness of myocardium from rats with postinfarction failure. Circ Res 71:797-807
Meuse, A J; Perreault, C L; Morgan, J P (1992) Pathophysiology of cardiac hypertrophy and failure of human working myocardium: abnormalities in calcium handling. Basic Res Cardiol 87 Suppl 1:223-33
Perreault, C L; Gonzalez-Serratos, H; Litwin, S E et al. (1992) A chemical method for intracellular loading of the calcium indicator aequorin in mammalian skeletal muscle. Proc Soc Exp Biol Med 199:178-82
Wang, J; Morgan, J P (1992) Endothelin reverses the effects of acidosis on the intracellular Ca2+ transient and contractility in ferret myocardium. Circ Res 71:631-9
Wang, J; Morgan, J P (1992) Endocardial endothelium modulates myofilament Ca2+ responsiveness in aequorin-loaded ferret myocardium. Circ Res 70:754-60
Qiu, Z; Wang, J; Perreault, C L et al. (1992) Effects of endothelin on intracellular Ca2+ and contractility in single ventricular myocytes from the ferret and human. Eur J Pharmacol 214:293-6

Showing the most recent 10 out of 21 publications