Cardiovascular effects of cocaine in conscious rats: relative significance of central sympathetic stimulation and peripheral neuronal monoamine uptake and release mechanisms

Abstract

Cocaine (0.03-3 mg/kg, i.v.) produced a dose-dependent increase in mean arterial blood pressure and heart rate in conscious Sprague-Dawley rats. Pretreatment with the competitive ganglionic blockers pentolinium or hexamethonium attenuated cocaine's pressor effect, whereas noncompetitive (chlorisondamine) or mixed (mecamylamine) type blockers not only abolished, but also reversed it to a depressor effect. Cocaine's tachycardiac effect was attenuated by all four ganglionic blockers. The relative effectiveness of the four ganglionic blockers in antagonizing cocaine-induced cardiovascular effects was similar to that of antagonism of phenylephrine-induced, centrally mediated reflex bradycardia. All four ganglionic blockers at all the doses tested produced similar reductions in base-line BP, thereby suggesting that these agents produced similar degrees of maximal reduction of basal sympathetic tone. The pressor responses to norepinephrine (0.2 micrograms/kg) were potentiated, whereas those to tyramine (0.3 mg/kg) were inhibited by cocaine (0.3-3 mg/kg); the former effect was not dose dependent (bell-shaped dose-response curve), whereas the latter effect was dose-dependent. The amine uptake inhibitory potency (ED50, 0.85 mg/kg) of cocaine is about 10 times less than its potency to produce pressor (ED50, 0.075 mg/kg) and tachycardiac (ED50, 0.083 mg/kg) effects. Chlorisondamine did not antagonize the pressor effects of the indirect sympathomimetic agent, tyramine. These results suggest that the blockade of cocaine's pressor and tachycardiac effects by ganglionic blockers is not related to their ability to eliminate basal sympathetic tone and, thereby, indirectly blunt cocaine's inhibitory effect on sympathetic neuronal uptake of norepinephrine. Rather, the results indicate that these effects are mainly due to their antagonistic actions on cocaine-induced central stimulation of sympathetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)