Billman G E
Department of Physiology, Ohio State University, Columbus 43210.
FASEB J. 1990 May;4(8):2469-75. doi: 10.1096/fasebj.4.8.2185973.
Cocaine can induce lethal cardiovascular events, including myocardial infarction and ventricular fibrillation. The mechanisms responsible for these cardiotoxic effects of cocaine remain largely to be determined. Cocaine has both sympathomimetic (inhibition of neuronal uptake of norepinephrine) and local anesthetic (Na+ channel blockade) properties. Neurotransmitters released from cardiac sympathetic nerves bind to both alpha- and beta-adrenergic receptors eliciting a cascade of intracellular responses. Stimulation of beta-adrenergic receptors activates adenylate cyclase, increasing cyclic AMP levels, whereas alpha-adrenergic receptor stimulation activates phospholipase C, increasing inositol trisphosphate. These second messengers, in turn, elicit increases in cystolic calcium. Elevations in cystolic calcium can provoke oscillatory depolarizations of the cardiac membrane, triggering sustained action potential generation and extrasystoles. Cocaine also acts as a local anesthetic by inhibiting sodium influx into cardiac cells, which impairs impulse conduction and creates an ideal substrate for reentrant circuits. Thus, the adrenergic and anesthetic properties of cocaine could act synergistically to elicit and maintain ventricular fibrillation. Adrenergic receptor activation would trigger the event whereas sodium channel blockade would create the reentrant substrate to perpetuate the malignant arrhythmias.
可卡因可诱发致命的心血管事件，包括心肌梗死和心室颤动。可卡因产生这些心脏毒性作用的机制在很大程度上仍有待确定。可卡因具有拟交感神经作用（抑制去甲肾上腺素的神经元摄取）和局部麻醉作用（钠通道阻滞）。从心脏交感神经释放的神经递质与α和β肾上腺素能受体结合，引发一系列细胞内反应。刺激β肾上腺素能受体激活腺苷酸环化酶，增加环磷酸腺苷水平，而刺激α肾上腺素能受体激活磷脂酶C，增加肌醇三磷酸。这些第二信使继而引起胞质钙增加。胞质钙升高可引发心脏膜的振荡性去极化，触发持续动作电位的产生和期前收缩。可卡因还通过抑制钠流入心脏细胞而起到局部麻醉作用，这会损害冲动传导并为折返环路创造理想的底物。因此，可卡因的肾上腺素能和麻醉特性可能协同作用，引发并维持心室颤动。肾上腺素能受体激活会触发该事件，而钠通道阻滞会产生折返底物，使恶性心律失常持续存在。
