Effects of cocaine on excitation-contraction coupling of aortic smooth muscle from the ferret.

Abstract

The mechanism by which cocaine alters vascular tone is not fully understood. We determined the effects of cocaine on excitation-contraction coupling of isolated ferret aorta. Cocaine in concentrations < 10-4 M caused a contractile response in a dose-dependent manner. The response of control muscle was significantly larger than that in muscle from ferrets pretreated with reserpine. Cocaine-induced contraction was not affected by endothelial factors, but was significantly inhibited by prazosin 10-7 M pretreatment. The intracellular calcium ([Ca"],), as measured with aequorin, rose in conjunction with cocaine-induced contraction. The degree of contraction generated by 10-4 M cocaine decreased after higher concentrations of cocaine 2 10-M, while aequorin luminescence remained elevated above the levels before 10-6 M cocaine. The dose-response relationships of norepinephrine and sympathetic nerve stimulation were enhanced by 10-M cocaine in control muscles; this did not occur in muscles from reserpine pretreated ferrets. In conclusion, (a) cocaine in concentrations 10-4 M caused vascular contraction presumably by its presynaptic action with consequent alpha-i adrenoceptor activation and consequent ICa++I, rise; (b) high concentrations of cocaine 2 10-3 M reduced muscle tone by decreasing the Ca++ sensitivity of the contractile proteins; and (c) supersensitivity to norepinephrine was mediated by cocaine's action on adrenergic nerve endings. (J. Clin.

Ethanol, Morphine and Barbiturate Alter the Hemodynamic and Cerebral Response to Cocaine in Newborn Pigs

“…Several mechanisms contribute to the hemodynamic response to cocaine in adults. On the one hand, cocaine increases central sympathetic transmission and blocks the reuptake of norepinephrine, potentiating the myocardial contractile and vasoconstrictor ef fect of this catecholamine, which increases arterial pressure [26][27][28][29]. On the other hand, cocaine, as a local anesthetic, inhibits intracel lular calcium availability, resulting in de pressed myocardial contractility, vasodila tion, and decreased arterial pressure [28,29], In adults, the pressor response dominates over the depressor response because the sym pathetic nervous system is fully functional.…”

“…On the one hand, cocaine increases central sympathetic transmission and blocks the reuptake of norepinephrine, potentiating the myocardial contractile and vasoconstrictor ef fect of this catecholamine, which increases arterial pressure [26][27][28][29]. On the other hand, cocaine, as a local anesthetic, inhibits intracel lular calcium availability, resulting in de pressed myocardial contractility, vasodila tion, and decreased arterial pressure [28,29], In adults, the pressor response dominates over the depressor response because the sym pathetic nervous system is fully functional. We speculate that the pressor effect in the newborn is less than in the adult because the sympathetic nervous system is immature, in that less catecholamine is present in the syn aptic cleft and peripheral vascular receptors are less sensitive to the neurotransmitter [19].…”

Cardiovascular consequences of cocaine use

“…In contrast to sympathomimetic effects, blockade of cardiomyocyte sodium channels acts as a class I antiarrhythmic agent or local anesthetic [13], and blockade of both the cardiomyocyte sodium and potassium channels has been shown to depress cardiovascular parameters by decreasing myocardial contractility, causing arrhythmia, and decreasing left ventricular ejection fraction [10,[14][15][16]. Recent research also suggests the potential for cocaine to disrupt excitationcontraction coupling via prevention of calsequestrin polymerization in the sarcoplasmic reticulum and altered storage and release of calcium with arrhythmogenic effects [17].…”

Vascular Toxicity of Cocaine

“…We have shown that the contractile response of ferret muscles is inhibited when they are pretreated with reserpine ( Fig. (1)) [34]. This happens because reserpine depletes the synaptic vesicles of norepinephrine.…”