The rising numbers of sudden cardiac deaths in healthy physically active, athletes and nonathletes after cocaine use is of grave concern. Although the pharmacologic actions of cocaine have been explored with regard to its local anesthetic properties and central nervous system effects, the cellular and subcellular toxic effects of cocaine of the myocardium are as yet unknown. Cocaine prevents the re-uptake of norepinephrine, resulting in higher concentrations of norepinephrine to interact with the physiological receptor site. Catecholamines have the potential to be directly cardiotoxic. Not only does exercise-training alter cellular characteristics of the heart, but during exercise, circulating catecholamine levels are significantly elevated over those values reported for sedentary individuals and as a result, placing them at a significantly higher risk of cocaine-mediated cardiotoxicity. It is possible that cocaine-mediated cardiotoxicity consists of a direct and indirect (catecholamine) component. The direct and indirect components of cocaine-mediated cardiotoxicity will be determined for the first time with isolated intact myocardial cells obtained from chronically cocaine-treated and untreated sedentary and swim-trained Sprague-Dawley rats. Cellular injury to the isolated myocytes from all four animal groups will be measured by assessing alterations in sarcolemmal membrane integrity, composition, and ability to mediate a physiological response. Specifically , morphological alterations, cytoplasmic enzyme release, beta-adrenergic receptor number and affinity, slow calcium channel number and affinity, transmembrane cellular calcium exchange, cellular high energy phosphate concentrations, and phospholipid composition and lipid peroxidation of the myocytes will be evaluated in response to treatment with cocaine alone and cocaine plus norepinephrine. It has been demonstrated that exercise-induced myocardial adaptations are retained and expressed na an isolated whole myocardial cell model. Furthermore, these myocardial cells respond differently to drug-mediated actions. The preliminary data demonstrate that cocaine has direct toxic potential to neonatal prima myocardial cells in culture. Never before has this novel isolated myocardial cell system been used to delineate cellular and subcellular mechanisms of cocaine toxicity in the exercise-trained and untrained myocardium. This toxicologic mechanistic information would provide a basis for future delineation of pharmacologic agents that could be used for the prevention, protection, and treatment of cocaine related cardiac events. The recent highly publicized cardiac-cocaine-induced deaths of All-American athletes has initiated national concern as to the cardiotoxic potential of cocaine for any individual who exercises on a regular basis. As the numbers of both cocaine abusers and individuals who participate in regular exercise increases, so may the number of cocaine and exercise-influenced cardiac associated sudden deaths.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29DA005699-01A1
Application #
3461154
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
1989-08-01
Project End
1994-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Type
Schools of Pharmacy
DUNS #
937727907
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
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Welder, A A; Melchert, R B (1993) Cardiotoxic effects of cocaine and anabolic-androgenic steroids in the athlete. J Pharmacol Toxicol Methods 29:61-8
Welder, A A; Grammas, P; Melchert, R B (1993) Cellular mechanisms of cocaine cardiotoxicity. Toxicol Lett 69:227-38
Welder, A A; Eselin, J A; Melchert, R B et al. (1992) Effects of cocaine and norepinephrine on primary cultures of neonatal rat myocardial cells. J Toxicol Environ Health 36:75-90
Melchert, R B; Welder, A A (1992) The combined effects of cocaine and amphetamine on primary postnatal rat heart cell cultures. Reprod Toxicol 6:467-73
Melchert, R B; Herron, T J; Welder, A A (1992) The effect of anabolic-androgenic steroids on primary myocardial cell cultures. Med Sci Sports Exerc 24:206-12
Welder, A A (1992) A primary culture system of adult rat heart cells for the evaluation of cocaine toxicity. Toxicology 72:175-87
Melchert, R B; Eselin, J A; O'Dell, J F et al. (1991) Effects of nitrendipine on cocaine-induced toxicity evaluated in primary myocardial cell cultures. J Pharm Sci 80:700-4