The effects of cocaine on intracellular Ca²⁺ handling and myofilament Ca²⁺ responsiveness of ferret ventricular myocardium

Abstract

1 When ferret right ventricular papillary muscles were stimulated with threshold punctate pulses (0.33 Hz; 30'C), cocaine, 10-M, increased peak tension development from 815 + 120 to 1125 ± 180mg (P < 0.05) and increased the rate of relaxation from peak tension (time to 80% decline from peak tension decreased from 155 + 11 to 144 + 11 ms; P < 0.05). These changes in the twitch were associated with comparable changes in the amplitude and time course of the calcium transient measured with aequorin (amplitude increased from 62 + 4 to 90 + 7% (P < 0.05) of maximal values; time to 80% decline from peak amplitude decreased from 84 + 8 to 64 + 3 ms; P < 0.05). These effects were markedly attenuated in the presence of the 8-adrenoceptor-blocking agent, propranolol, 6 x 10 7M, or by maximization of catecholamine release from the adrenergic nerve endings with field pulses of supratheshold strength, indicating that catecholamine release from the adrenergic nerve endings is responsible for the positive inotropic and lusitropic responses to low and moderate doses of cocaine (i.e., < 10 -I M). 2 High doses of cocaine (i.e., > 10-M) produced negative inotropic and lusitropic effects that were associated with a decreased amplitude and prolonged duration of the calcium transient. 3 In aequorin-loaded intact fibres, cocaine 10-M did not affect the force-calcium relationship unless catecholamines were present. Cocaine, 10-5M, significantly shifted the force-calcium relationship of saponin-skinned muscles (pCa50 = 6.14 + 0.05 versus 5.92 + 0.07; P < 0.05), indicating reduced responsiveness of the myofflaments to calcium. F. (maximal Ca2+-activated force) was reduced to 58% of control in the presence of 10-M cocaine, while the slope of the calcium-force curve remained unchanged. These data indicate that cocaine may also decrease myofilament calcium sensitivity and maximal calciumactivated force, via mechanisms independent of catecholamines, when cellular diffusion barriers are eliminated.

Differential effects of cocaine and cocaethylene on intracellular Ca24+ and myocardial contraction in cardiac myocytes

“…The present study represents the first direct evidence that cocaine and cocaethylene can alter the Ca2+-dependent steps of excitation-contraction coupling in adult mammalian cardiomyocytes. We previously reported that cocaine produced positive inotropic effects at concentrations of 106 to 10-5M, and negative inotropic effects only at concentrations > 1 x 10-4 M in ferret papillary muscles with intact nerve endings (Perreault et al, 1990). In the present study, we found negative inotropic actions on single myocytes over the entire effective dose-range, indicating that the direct action of cocaine on myocardial cells is to decrease contractility.…”

Triggering of Myocardial Infarction by Cocaine

“…This in turn leads to prolongation of the calcium current and a negative lusitropic effect. 45 The present study has several potential limitations. No data were collected on the method of cocaine exposure, for example, intravenous, intranasal, or inhaled crack cocaine use.…”

“…A possible mechanism for these effects is that cocaine may alter Ca 2ϩ handling by myocytes. For example, Perreault et al 45 demonstrated that cocaine can cause an increase in cytosolic Ca 2ϩ concentration in isolated myocardial tissue. This in turn leads to prolongation of the calcium current and a negative lusitropic effect.…”

Cocaine‐induced microvascular vasoconstriction but differential systemic haemodynamic responses in Yucatan versus Yorkshire varieties of swine

“…It is unlikely, but possible, that this action of the drug could have produced myocardial depression in conjunction with the other anaesthetics utilized in the Yorkshire swine. However, such effects are usually expected in concentrations greater that l0-5 M, which would not have been exceeded except at the higher doses in our experiments (Perreault et al, 1990).…”