Effects of cocaine on intracellular calcium handling in cardiac and vascular smooth muscle.
The inotropic and lusitropic (i.e., relaxant) actions of cocaine on the heart appear to be caused primarily by changes in intracellular calcium handling. The positive inotropic and lusitropic effects of low and moderate concentrations (i.e., less than or equal to 10(-5)M) are mediated by catecholamines; the negative inotropic effects of higher concentrations appear to be due to the direct local anesthetic effects of cocaine on excitation-contraction coupling mechanisms. The relevance of these findings to humans is suggested by the fact that blood levels of cocaine in excess of 10(-5) M have been described in patients abusing this drug (Van Dyke et al. 1976; Paly et al. 1982). Blood vessels from certain vascular beds, including the epicardial coronary arteries of humans and swine, show little or no constrictor response to low concentrations of cocaine and relax at higher concentrations. In contrast to the effects on the heart, the relaxant effects of cocaine on vascular smooth muscle appear to be related to marked changes in myofilament calcium responsiveness, which may be mediated by the protein kinase-C system. These results at least indicate that the depressant effects of cocaine on cardiac vs. vascular smooth muscle occur by different mechanisms and suggest the need for specific therapeutic approaches to managing cardiac depression vs. vasodilatation when they occur in cocaine-intoxicated individuals. Moreover, these data provide evidence supporting the hypothesis that the net effects of cocaine in the intact organism are highly dependent on the underlying level of sympathetic adrenergic activity.
Perreault
C L
CL
Harvard-Thorndike Laboratory, Cardiovascular Division, Beth Israel Hospital, Boston, MA 02215.
Morgan
K G
KG
Morgan
J P
JP
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D004558:Electric Stimulation; D005289:Ferrets / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D013552:Swine
D003042:Cocaine; D002118:Calcium; D009638:Norepinephrine