• A J Nichols, P F Koster, and E H Ohlstein.
• Department of Pharmacology (L-510), SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
• Br. J. Pharmacol. 1990 Mar 1; 99 (3): 597-601.

Abstract1. 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-related 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 ng kg-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 micrograms 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.

24 keywords...

hide…