Romero-Vecchione E, Vasquez J, Rosa F
Laboratorio de Estudios Cardiovasculares, Escuela de Medicina José María Vargas, UCV, Caracas, Venezuela.
Acta Cient Venez. 1996;47(1):17-23.
Cocaine, when used as a recreative drug, can induce cardiovascular toxic effects such as acute reduction of left ventricle ejection fraction, which indicates a negative inotropic effect of the drug. The purpose of this study was to clarify the direct negative inotropic effect of cocaine in in vitro conditions. Rat right ventricle strips were incubated in Krebs solution gassed with 95% O2 and 5% CO2 at 37 degrees, and electrically driven with 2 ms square pulses, 17 mA, at 110 systoles/min. Separate experiments were conducted to study cocaine effect at 210 and 310 systoles/min. The contractile force was recorded through a strain-gauge isometric transducer. Cocaine increased contractile force at doses of 0.3-10.0 micrograms/ml, up to 53% over basal contraction. In the presence of 4 x 10(-8) M atenolol, low doses of cocaine did not increase contractile force and at doses between 3.0-10.0 micrograms/ml revealed a depressant activity on heart muscle contractions. Doxazosin (1.0 microM) and yohimbine (0.1 microM) did not modify the positive inotropic effect of cocaine, showing that alpha 1 and alpha 2 adrenergic receptors were not involved in this cocaine ventricle action. Increasing ventricle strip stimulation rate to 210 and 310 systoles/min for 30 seconds, the contractile force was risen by 55% and 95%, respectively. Cocaine at doses 1.0-3.0 micrograms/ml did not modify the physiological increase of contractile force seen upon ventricle rate increase. The mechanism involved in the contractile force increment after ventricle rate increase is a transient rise of cytosolic Ca2+, mainly derived from the sarcoplasmic reticulum and from extracellular fluid. Atenolol (4 x 10(-8) M) exposure of the right ventricle strip intensified the negative inotropic effect of cocaine (3.0-10 micrograms/ml) seen by ventricle stimulation at 210 and 310 systoles/min. The myocardial direct depressant effect of cocaine, in the presence of atenolol, was gradually reversed by extracelular Ca2+ increase at 3.2 and 5.0 mM, respectively. In conclusion, the mechanism of myocardial direct depressant effect of cocaine is related to the beating frequency of the ventricle, which may be associated to interference with the Ca2+ release process from the myocite sarcoplasmic reticulum, and not to calcium entry blockade from extracellular fluid. However, a dpressant effect of cocaine on phase "0" of depolarization, related to its local anesthetic properties can not be ruled out.
可卡因作为一种消遣性药物使用时，可诱发心血管毒性作用，如左心室射血分数急性降低，这表明该药物具有负性肌力作用。本研究的目的是阐明可卡因在体外条件下的直接负性肌力作用。将大鼠右心室肌条置于含95% O₂和5% CO₂的Krebs溶液中，于37℃孵育，并用2 ms方波脉冲、17 mA、110次收缩/分钟进行电驱动。进行单独实验以研究可卡因在210次和310次收缩/分钟时的作用。通过应变片等长换能器记录收缩力。可卡因在0.3 - 10.0微克/毫升的剂量下可增加收缩力，比基础收缩力增加高达53%。在存在4×10⁻⁸ M阿替洛尔的情况下，低剂量可卡因不会增加收缩力，而在3.0 - 10.0微克/毫升的剂量下显示出对心肌收缩的抑制活性。多沙唑嗪（1.0微摩尔）和育亨宾（0.1微摩尔）不会改变可卡因的正性肌力作用，表明α1和α2肾上腺素能受体不参与可卡因对心室的这种作用。将心室肌条刺激频率增加到210次和310次收缩/分钟持续30秒，收缩力分别增加55%和95%。1.0 - 3.0微克/毫升剂量的可卡因不会改变心室率增加时所见的收缩力的生理性增加。心室率增加后收缩力增加所涉及的机制是胞质Ca²⁺的短暂升高，主要来源于肌浆网和细胞外液。右心室肌条暴露于阿替洛尔（4×10⁻⁸ M）会增强在210次和310次收缩/分钟时心室刺激所见的可卡因（3.0 - 10微克/毫升）的负性肌力作用。在存在阿替洛尔的情况下，可卡因对心肌的直接抑制作用分别通过将细胞外Ca²⁺增加到3.2 mM和5.0 mM而逐渐逆转。总之，可卡因对心肌的直接抑制作用机制与心室的搏动频率有关，这可能与干扰肌细胞肌浆网的Ca²⁺释放过程有关，而不是与细胞外液的钙内流阻断有关。然而，不能排除可卡因因其局部麻醉特性对去极化“0”期的抑制作用。
