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

Abstract

1 The effects of the calcium channel blockers, verapamil and nifedipine on myocardial ischaemia and oedema evoked by endothelin-l (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-', i.v.) or IRL 1620 (1 nmol kg-', 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-', i.v.) or nifedipine (200 ,ug kg-', 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-'), respectively, and the accompanying bradycardia. Both verapamil and nifedipine potentiated the magnitude of the depressor action of ET-l and IRL 1620 without affecting the accompanying tachycardia. Decreasing mean arterial blood pressure with hydralazine (0.2-0.3 ymol kg-', 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-') 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-', i.v.) or nifedipine (200 mg kg-', i.v.) inhibited on average by 79 and 76% the ST segment elevation elicited by ET-1 (1 nmol kg-'), respectively. Verapamil and nifedipine also attenuated IRL 1620 (1 nmol kg-')-induced ST segment elevation on average by 71 and 74%, respectively. In contrast, no significant inhibition was observed with hydralazine (0.2-0.3 Mmol kg-').5 Both ET-1 and, to a lesser extent, IRL 1620 (0.1-2 nmol kg-') 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-') 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-') or nifedipine (200 jig kg-') in these vascular beds. In contrast, hydralazine (0.2-0.3 ymol kg-') 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.

Cellular localization of the endothelin receptor subtypes ET A and ET B in the rat heart and their differential expression in coronary arteries, veins, and capillaries

“…In coronary veins, where constrictor ET Breceptors are the sole ET-receptor subtype present on smooth muscle cells, vasoconstriction due to increased ET-1 will be unopposed by ET A -receptor antagonism. In addition, stimulation of vasoconstrictor ET B -receptors on cardiac veins might also take part in the development of cardiac edema by increasing postcapillary resistance and capillary filtration pressure (Filep et al 1996).…”

“…After ischemia/reperfusion the number of patent capillaries is increased by treatment with the ET A -receptor antagonist BQ-123 (Maxwell et al 2000), and myocardial thickening is significantly decreased by the ET A -receptor antagonist LU 135252 (Galiuto 2000). While cardiac edema can be provoked by ET A as well as ET B -receptor agonists (Filep et al 1996), non-specific blockade of both ET-receptor subtypes during endotoxin shock is no more effective than isolated ET A -receptor antagonism in preventing albumin extravasation (Filep 2000). These observations were explained by actions of ET-1 on coronary smooth muscle cells, cardiomyocytes, and polymorphonuclear leukocytes, all of which are known to bind ET-receptor antagonists, but the pathophysiological mechanisms, however, remain unclear partly because of lack of information about ET-receptor subtype distribution in the coronary microcirculation.…”

Plasma ET-1 Concentrations are Elevated in Patients with Hypertension – Meta-Analysis of Clinical Studies

“…RAAS blocking agents thus might influence ET-1 plasma concentrations independent of the actual blood pressure. It was likewise shown that also beta blockers [29, 30] and calcium channel blockers [31-32] alter the paracrine ET-1 system. The majority of the remaining studies reported plasma ET-1 concentrations in treatment naive hypertensive patients, see table 1.…”

Antiischemic Properties of Fasudil in Experimental Models of Vasospastic Angina

“…Endothelin has recently been recognized as one of the key mediators of myocardial ischemia (13). Elevated plasma concentrations of endothelin can be detected in patients exhibiting coronary spasm (14).…”