Effects of calcium antagonists on endothelin-1-induced myocardial ischaemia and oedema in the rat

1 The effects of the calcium channel blockers, verapamil and nifedipine on myocardial ischaemia and oedema evoked by endothelin-1 (ET-1) or IRL 1620, an ET(B) receptor-selective agonist were studied in anaesthetized and conscious rats. 2 Bolus injection of ET-1 (1 nmol kg(-1), i.v.) or IRL 1620 (1 nmol kg(-1), i.v.) to conscious chronically catheterized rats evoked a transient depressor response followed by a prolonged presser effect. Corresponding to changes in blood pressure, a transient tachycardia and a sustained bradycardia were observed. Pretreatment of the animals with verapamil (1 mg kg(-1), i.v.) or nifedipine (200 mu g kg(-1), i.v.) produced on average 5 mmHg decrease in mean arterial blood pressure. Both verapamil and nifedipine inhibited by 63 and 44% the presser actions of ET-1 or IRL 1620 (1 nmol kg(-1)), respectively, and the accompanying bradycardia. Both verapamil and nifedipine potentiated the magnitude of the depressor action of ET-1 and IRL 1620 without affecting the accompanying tachycardia. Decreasing mean arterial blood pressure with hydralazine (0.2-0.3 mu mol kg(-1), i.v.) to levels comparable to those observed after verapamil or nifedipine had no significant effects on the haemodynamic responses to ET-1 or IRL-1620. 3 Intravenous bolus injection of ET-1 or IRL 1620 (0.1-2 nmol kg(-1)) into anaesthetized rats produced dose-dependent ST segment elevation of the electrocardiogram without causing arrhythmias. ST segment elevation developed within 30-50 s and persisted for at least 10-20 min following injection of the peptides. 4 Pretreatment of the animals with verapamil (1 mg kg(-1), i.v.) or nifedipine (200 mu g kg(-1), i.v.) inhibited on average by 79 and 76% the ST segment elevation elicited by ET-1 (1 nmol kg(-1)), respectively. Verapamil and nifedipine also attenuated IRL 1620 (1 nmol kg(-1))-induced ST segment elevation on average by 71 and 74%, respectively. In contrast, no significant inhibition was observed with hydralazine (0.2-0.3 mu mol kg(-1)). 5 Both ET-1 and, to a lesser extent, IRL 1620 (0.1-2 nmol kg(-1)) evoked albumin accumulation in cardiac tissues in a dose-dependent fashion as measured by the local extravascular accumulation of Evans blue dye in conscious rats. ET-1 and IRL 1620 (1 nmol kg(-1)) enhanced albumin extravasation by 109 and 82%, and 34 and 44% in the left ventricle and right atrium, respectively. ET-1 or IRL 1620-induced albumin extravasation was completely prevented by verapamil (1 mg kg(-1)) or nifedipine (200 mu g kg(-1)) in these vascular beds. In contrast, hydralazine (0.2-0.3 mu mol kg(-1)) failed to modify the effects of ET-1 or IRL 1620 on albumin extravasation. 6 These results show that verapamil and nifedipine are highly effective in protecting the myocardium against the pro-ischaemic and microvascular permeability enhancing effects of ET-1 and suggest that ET(A) and constrictor ET(B) (tentatively termed ET(B2)) receptors mediating these actions of ET-1 are coupled to calcium influx through dihydropyridine-sensitive calcium channels.