Evidence that oxmetidine inhibits transmembrane-calcium flux in cardiac and vascular tissue.

ABSTRACT

Oxmetidine, at concentrations in excess of 1 X 10(-6)M, caused concentration-dependent negative inotropic and chronotropic responses in guinea-pig isolated heart preparations. Oxmetidine, at concentrations in excess of 1 X 10(-5)M, caused negative inotropic responses in guinea-pig papillary muscle preparations. The negative inotropic responses to oxmetidine were associated with shortening of the plateau phase of the action potential. Verapamil and nifedipine caused similar shortening of the plateau phase of the action potential at equivalent negative inotropic concentrations indicating that oxmetidine may also act as a calcium antagonist. In preparations partially depolarized by raising extracellular K+ concentration, oxmetidine also exhibited negative inotropic activity and reduced the calcium-dependent action potential. However, unlike verapamil and nifedipine, oxmetidine did not show voltage-dependent activity. Oxmetidine, at concentrations in excess of 1 X 10(-5)M, inhibited Ca2+-dependent contractions of dog saphenous vein preparations and inhibited 45Ca2+-uptake into veins depolarized by high extracellular K+. In vivo, these calcium antagonist actions of oxmetidine were demonstrated by vasodilatation, reduction in blood pressure, bradycardia and reduced cardiac output in anaesthetized cats. Oxmetidine, at concentrations of 1 X 10(-5)M and above, shows properties consistent with inhibition of transmembrane Ca2+ flux. This action can be distinguished from other calcium antagonists as the effects of oxmetidine are not voltage-dependent.