Role of Endogenous Endothelin in Extension of Rabbit Myocardial Infarction

The effects of the endothelin ETA receptor antagonist, FR 139317, on infarct size in a rabbit model of acute myocardial ischaemia and reperfusion

“…Furthermore, pretreatment of rabbits with an antibody to ET-1 reduced infarct size caused by 30 min occlusion of the first branch of the left circumflex coronary artery followed by 24 h of reperfusion from 61 ± 5% (control) to 37 ± 5% (treatment, n = 5). In this study, the areas at risk in control and treated animals were 43 ± 5% and 44 ± 3%, respectively (Kusumoto et al, 1993). Why then, does the ETA receptor antagonist, FR 139317, not reduce infarct size in this study?…”

“…In anaesthetized rabbits subjected to coronary artery occlusion (30 min) and reperfusion (24 h), plasma levels of ET-1 are maximally elevated (approximately 2.5 fold) at 3 h after reperfusion (Kusumoto et al, 1993). Thus, ET-l may play a pathophysiological role after longer periods of reperfusion and hence, 2 h of reperfusion may not have been long enough to see a potential beneficial action of FR 139317.…”

“…Enhanced plasma levels of ET-1 in man are associated with a variety of cardiovascular disorders including acute myocardial infarction (Miyauchi et al, 1989;Salminen et al, 1989), angina pectoris (Nakao et al, 1989), coronary artery vasospasm (Matsuyama et al, 1990) and congestive heart failure (Grenier et al, 1990). The hypothesis that endogenous ET-1 plays a role in the extension of ischaemia/reperfusion injury of the heart is supported by the findings that (i) intravenous administration of a monoclonal antibody against ET-1 reduces infarct size in a model of coronary artery occlusion and reperfusion in the anaesthetized rat (Watanabe et al, 1991) or anaesthetized rabbit (Kusumoto et al, 1993) and (ii) infusion of the endothelinconverting enzyme inhibitor, phosphoramidon, results in a substantial reduction in infarct size in the anaesthetized rat (Grover et al, 1992).…”

Pharmacology of a non‐selective ETA and ETB receptor antagonist, TAK‐044 and the inhibition of myocardial infarct size in rats

“…injection of BQ-123 reduced the infarct size in dogs (Grover et al, 1993), while that of FR139317 showed no effects in rabbits (McMurdo et al, 1994). Since monoclonal antibody for ET-1 reduced the infarct size in rats (Watanabe et al, 1991), rabbits (Kusumoto et al, 1993) and dogs (unpublished observations), species-dependency is not likely to be the explanation. One of the possible explanations is, thus, organ-selectivity of the endothelin antagonist: TAK-044 was demonstrated to inhibit ET-i-induced vasoconstriction of the coronary artery more than the basilar, femoral, renal or mesenteric artery .…”

“…Alternatively, it is possible that ETA/ETB receptor antagonists show stronger inhibitory effects over ETA receptor antagonists for limiting myocardial infarct size extension. Since increases in ET-I play an important role in it (Watanabe et al, 1991;Kusumoto et al, 1993) and ET-1 has been reported to activate both ETA and ETB receptors (Arai et al, 1990;Sakurai et al, 1990), it is reasonable to assume that both receptor subtypes are involved in the extension of infarct size. The existence of ETA and ETB receptors in smooth muscle of artery and vein (e.g.…”