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

1. When ferret right ventricular papillary muscles were stimulated with threshold punctate pulses (0.33 Hz; 30 degrees C), cocaine, 10(-5) M, increased peak tension development from 815 +/- 120 to 1125 +/- 180 mg (P less than 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 less than 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 less than 0.05) of maximal values; time to 80% decline from peak amplitude decreased from 84 +/- 8 to 64 +/- 3 ms; P less than 0.05). These effects were markedly attenuated in the presence of the beta-adrenoceptor-blocking agent, propranolol, 6 x 10(-7) M, or by maximization of catecholamine release from the adrenergic nerve endings with field pulses of suprathreshold 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., less than or equal to 10(-5) M). 2. High doses of cocaine (i.e., greater than 10(-5) 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(-5) M did not affect the force-calcium relationship unless catecholamines were present. Cocaine, 10(-5) M, significantly shifted the force-calcium relationship of saponin-skinned muscles (pCa50 = 6.14 +/- 0.05 versus 5.92 +/- 0.07; P less than 0.05), indicating reduced responsiveness of the myofilaments 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.