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 ETB 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 pressor 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 micrograms 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 pressor 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 micromol 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 30-50s 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 micrograms 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 mumol 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 micrograms kg-1) in these vascular beds. In contrast, hydralazine (0.2-0.3 mumol 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 ETA and constrictor ETB (tentatively termed ETB2) receptors mediating these actions of ET-1 are coupled to calcium influx through dihydropyridine-sensitive calcium channels.
Filep
J G
JG
Research Center, Maisonneuve-Rosemont Hospital, University of Montréal, Canada.
Skrobik
Y
Y
Fournier
A
A
Földes-Filep
E
E
D000418:Albumins / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced; D004562:Electrocardiography / Q000187:drug effects; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D006830:Hydralazine / Q000494:pharmacology; D008297:Male; D017202:Myocardial Ischemia / Q000139:chemically induced; D009543:Nifedipine / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology*
D000418:Albumins; D002121:Calcium Channel Blockers; D019332:Endothelin-1; D016232:Endothelins; D010446:Peptide Fragments; D017466:Receptors, Endothelin; D014665:Vasodilator Agents; C074308:sovateltide; D006830:Hydralazine; D014700:Verapamil; D009543:Nifedipine