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Abstract
The cardiovascular effects of cocaine are numerous and complex. Despite recent reports of pulmonary complications following cocaine abuse, very little is known concerning the effects of cocaine on the pulmonary circulation. This dissertation provides insight into possible mechanisms by which cocaine affects pulmonary blood flow. Pulmonary blood flow responses were highly variable, altered by anesthesia, dependent on $\alpha\sb1$- and $\beta\sb1$-adrenergic receptor activation, and mimicked by air jet stress. Collectively these experiments suggest that cardiovascular responses to cocaine are mediated in part by central nervous system sympathoexcitation producing catecholamine-mediated $\alpha\sb1$- and $\beta\sb1$-adrenergic receptor activation. The variable pulmonary blood flow responses may be related to susceptibility to adverse cardiovascular effects of cocaine demonstrated in human and animal studies.
Clinical and experimental data provide evidence that cocaine produces deleterious effects on the cardiovascular system resulting in impaired cardiac function, diminished cardiovascular reflexes, myocardial damage, and possibly sudden death. The second portion of this dissertation examines hemodynamic, anatomical and biochemical alterations in the cardiovascular system after repeated cocaine administration. Acute repeated cocaine administration (0.5 mg/kg, twelve times at ten minute intervals) resulted in tolerance to the initial pressor response and sensitization to the initial bradycardic response. Two weeks of cocaine treatment resulted in similar pressor responses to the first daily doses of cocaine, but diminished pressor responses occurred to a cocaine challenge (5 mg/kg) on the fifteenth day. There was diminished reflex bradycardia, direct depressor responses, and vascular heat shock protein expression in cocaine treated animals. These results suggest that chronic administration of cocaine produces adverse effects on cardiovascular structure and regulation.
In summary, the pulmonary vascular effects of cocaine have important clinical implications related to emergency room complications and susceptibility to cardiac toxicity. Chronic cocaine administration also may reveal varying sensitivities to cocaine manifested by cardiac pathology and diminished cardiovascular function.
