[Direct negative inotropic effect of cocaine in rat ventricle strip]

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.