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The effect of diltiazem on the coronary haemodynamic and cardiac functional effects produced by intracoronary administration of endothelin‐1 in the anaesthetized dog

1 We have studied the effect of the calcium channel antagonist, diltiazem, on the coronary haemodynamic and cardiac functional responses produced by intracoronary (i.c.) administration of endothelin‐1 (ET‐1) in anaesthetized dogs. 2 ET‐1, 1, 3 and 10 ng kg−1 i.c., produced dose‐delated increases in coronary blood flow with no cardiac functional or systemic haemodynamic changes. ET‐1, 30, 100 and 300 ng kg−1 i.c., produced dose‐related reductions in coronary artery blood flow. The reduction in coronary blood flow was accompanied by dose‐related falls in cardiac output, mean arterial pressure, +dP/dt and –dP/dt and increases in left ventricular end‐diastolic pressure. However, there was no reflex tachycardia in response to the fall in blood pressure and at 300 ngkg−1, ET‐1 produced a 22% reduction in heart rate. 3 Following a series of abnormal ECG changes, four out of five dogs died of ventricular fibrillation at 13 ± 2 min after 300 ng kg−1 ET‐1. 4 The administration of diltiazem (15 μg kg−1 min−1, i.v.) reduced mean arterial pressure by 10% and heart rate by 15%, and increased coronary blood flow by 39%. Diltiazem did not have any significant effect on the coronary dilator response to low doses of ET‐1. Although there was a general trend for diltiazem to inhibit the coronary vasoconstrictor responses to ET‐1, diltiazem significantly attenuated only the reduction in coronary blood flow produced by 100 ng kg−1 ET‐1 by 60% but not the response to 30 or 300 ng kg−1 ET‐1. Two out of five diltiazem‐treated dogs died of ventricular fibrillation with a mean time to death of 20 min following treatment with ET‐1 (300 kg−1). 5 ET‐1 is a very potent coronary vasodilator. At slightly higher doses ET‐1 is also a coronary vasoconstrictor. ET‐1 also appears to have direct cardiotoxicity independent of myocardial ischaemia. The vasoconstrictor activity and direct cardiotoxicity are only weakly inhibited by diltiazem.