Effect of diltiazem on calcium transport and development of tension in heart muscle

Diltiazem relaxes vascular smooth muscle at concentrations as low as 10^-8 M. These concentrations do not affect either the action potential or the contractile activity of cardiac muscle. In this study the effect of diltiazem on excitation-contraction coupling processes in frog ventricular muscle was investigated. Diltiazem had little effect on the cardiac action potential or tension at concentrations less than 10^-7 M. At higher concentrations (10^-5 M), the action potential shortened, the overshoot potential decreased, twitch tension was reduced, and the resting potential was unaffected. Potassium-chloride induced contractures were reduced by about 60 percent, suggesting that the effect of diltiazem was not due to the alteration in the action potential duration. In chemically skinned myocardium, the sensitivity of the myofilaments to calcium (Ca²⁺) was not altered by diltiazem. The effects of diltiazem could be reversed in part either by increasing extracellular calcium or by adding epinephrine. Diltiazem (2 × 10^-6 M) suppressed the tension-voltage relation under voltage clamp conditions. However, at even higher concentrations, significant tension could still be generated. Diltiazem reduced the slow inward current somewhat, but no direct relation could be found between suppression of the calcium-dependent inward current (I_si) and inhibition of tension. Diltiazem increased the late outward current but had no effect on the inwardly rectifying potassium (K⁺) channel. In sodium (Na⁺)-depleted ventricular preparations, the tension-voltage relation, which reflects the voltage dependence of I_si, is completely suppressed by diltiazem (2 × 10^-5 M). These results suggest that diltiazem in large doses suppresses tension either by inhibition of a slowly inactivating Ca²⁺ current or by modifying an undescribed step in excitation-contraction coupling processes.