title: Cocaine: cardiovascular effects in relation to inhibition of peripheral neuronal monoamine uptake and central stimulation of the sympathoadrenal system.
abstract: Cocaine (0.03-5.6 mg/kg i.v.) produced a dose-dependent and prolonged increase in mean arterial blood pressure and heart rate in conscious rats. The 0.3 and 1 mg/kg doses of cocaine potentiated the pressor response to exogenous norepinephrine (0.2 microgram/kg), whereas lower (0.03 and 0.1 mg/kg) and higher (3 and 5.6 mg/kg) doses were ineffective. Desipramine (0.03-1 mg/kg), a prototype norepinephrine uptake blocker, did not alter blood pressure or heart rate. Nisoxetine (0.01-1 mg/kg), another norepinephrine selective uptake blocker, produced a small and brief (< 5 min) pressor response, but not tachycardiac response. Unlike cocaine, both desipramine and nisoxetine produced a dose-dependent potentiation of the pressor response to norepinephrine with the maximal potentiation exceeding that of cocaine. Plasma norepinephrine and epinephrine levels were increased by cocaine (3 mg/kg), but not by nisoxetine (1 mg/kg). Chemical sympathectomy by 6-hydroxydopamine selectively antagonized cocaine-induced increases in both blood pressure and plasma norepinephrine levels, but did not alter cocaine-induced increases in heart rate or plasma epinephrine levels; the converse was the case with adrenal demedullation. Both the combination of chemical sympathectomy and adrenal demedullation and pretreatment with chlorisondamine (10 mg/kg) antagonized cocaine-induced pressor and tachycardiac effects and cocaine-induced increases in plasma epinephrine and norepinephrine levels. In the control group, cocaine (3 mg/kg) produced a biphasic increase in blood pressure consisting of an early peak increase of 52 +/- 2.5 mm Hg 15 sec after its injection followed by a quick and partial recovery to an increase of 20.5 +/- 3.3 mm Hg at 1 min which gradually declined to base-line values in about 30 min. Prazosin (1 mg/kg) pretreatment decreased the magnitude of the initial peak pressor response produced by cocaine and reversed the sustained pressor response to cocaine to a depressor response; the reversal of the pressor response to cocaine to a depressor response by prazosin was not seen after erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobuta n-2-ol (ICI 118,551) (3 mg/kg) treatment or adrenal demedullation. Treatment with ICI 118,551 alone enhanced the magnitude of the sustained phase of the pressor response to cocaine. These results indicate that inhibition of peripheral sympathetic neuronal amine uptake mechanism by cocaine is not critical for initiating its pressor, tachycardiac and plasma catecholamine increasing effects in conscious rats and that central stimulation of sympathoadrenal neural axis activity plays an important role in these effects.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Behavioral Pharmacology and Genetics Section, National Institute on Drug Abuse, Baltimore, Maryland.
authors.forename: S R
authors.initials: SR
authors.lastname: Tella
authors.forename: C W
authors.initials: CW
authors.lastname: Schindler
authors.forename: S R
authors.initials: SR
authors.lastname: Goldberg
mesh_terms: D000313:Adrenal Medulla / Q000502:physiology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D002395:Catecholamines / Q000097:blood; D002714:Chlorisondamine / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D016627:Oxidopamine / Q000494:pharmacology; D017933:Peripheral Nervous System / Q000378:metabolism*; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000187:drug effects*; D013997:Time Factors
chemical_list: D002395:Catecholamines; D011412:Propanolamines; D005473:Fluoxetine; C011386:nisoxetine; C026777:ICI 118551; D016627:Oxidopamine; D003042:Cocaine; D002714:Chlorisondamine; D003891:Desipramine; D009638:Norepinephrine