Role of endogenous endothelin in myocardial and coronary endothelial injury after ischaemia and reperfusion in rats: studies with bosentan, a mixed ET_A‐ET_B antagonist

Abstract

1Previous studies suggested that endothelin-l (ET-1) may play a role in myocardial ischaemia and reperfusion. This study was designed to test the effect of a new nonpeptide antagonist of endothelin ETA and ETB receptors, bosentan, on myocardial infarct size, ventricular arrhythmias, and coronary endothelial dysfunction after ischaemia and reperfusion. 2 Anaesthetized male Wistar rats were subjected to 20 min ischaemia (left coronary artery occlusion) followed by 1 h (for the evaluation of coronary endothelial dysfunction) or 2 h (for the evaluation of infarct size) reperfusion, or 5 min ischaemia followed by 15 min reperfusion (for the evaluation of reperfusion arrhythmias). Vascular studies were performed on 1.5-2 mm coronary segments (internal diameter 250-300 ftm) removed distal to the site of occlusion and mounted in wire myographs for isometric tension recording. Area at risk and infarct size were determined by Indian ink injection and triphenyl tetrazolium staining, using computerized analysis of enlarged sections after colour video acquisition.3 Bosentan, administered at a dose which virtually abolished the pressor response to big ET-1 (3 mg kg-', i.v. before ischaemia) did not affect heart rate, arterial pressure or the rate pressure product before ischaemia, during ischaemia and during reperfusion. Bosentan did not affect the incidence of reperfusion-induced ventricular fibrillation (controls: 86%, n = 14; bosentan: 93%, n = 15), and did not modify infarct size (% of area at risk: controls: 63 ± 4, n = 10; bosentan: 60 ± 6, n = 8). Ischaemia followed by reperfusion markedly reduced the endothelium-dependent relaxations to acetylcholine (maximal response: sham: 59 + 4%, n = 9; ischaemia-reperfusion: 26± 6%, n = 8; P<0.01), characteristic of reperfusion-induced endothelial dysfunction, and this dysfunction was not prevented by bosentan (maximal response to acetylcholine: 25 ± 5%, n = 9; P<0.01 vs sham; P = NS vs ischaemia/ reperfusion). 4 These experiments suggest that endogenous endothelin does not contribute to myocyte or coronary endothelial injury in this rat model of ischaemia and reperfusion.

Characterization of the endothelin receptor selective agonist, BQ3020 and antagonists BQ123, FR139317, BQ788, 50235, Ro462005 and bosentan in the heart

“…This was similar to that reported for bosentan in human smooth muscle (ETA) and human placenta (ETB): Ki of 4.7 nM and 95 nM, respectively (Clozel et al, 1994). Although oral administration of bosentan decreased mean arterial blood pressure in a conscious rat coronary heart failure model (Teerlink et al, 1994), and reduced elevated blood pressure, vascular hypertrophy and remodelling in DOCA-salt (deoxycorticosterone acetate-salt) hypertensive rats (Li et al, 1994), bosentan did not affect myocyte or coronary endothelial injury in a rat model of ischaemia and reperfusion (Richard et al, 1994). We have previously characterized the mRNA encoding the ET receptors present in human left ventricle using molecular biology techniques .…”

Coronary vasoregulation in health and disease

“…Few studies have shown a positive influence of IPC on restoration of cardiac contractile function (49). Protection against vascular dysfunction by IPC also remains controversial (50)(51)(52)(53), but several studies have shown that preconditioning pretreatment protects blood vessels and possibly the microcirculation against vascular stunning (54,55). The mechanisms that are responsible for cytoprotection against infarction and contractile or vascular stunning are not the same, and many of these mechanisms are believed to be shared.…”

Chronic Endothelin-1 Improves Nitric Oxide–Dependent Flow-Induced Dilation in Resistance Arteries From Normotensive and Hypertensive Rats

“…In deoxycorticosterone acetate salt-hypertensive rats, ET-1 is a determinant of hypertension. 26,29 Angiotensin II-induced hypertension 30 as well as the hypertension due to the chronic inhibition of NO synthesis 31 is counteracted by the blockade of ET A receptors. Nevertheless, no study has yet clearly determined the consequences of a chronic increase in ET-1 on vascular reactivity.…”