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

Abstract

1 The effects were investigated of the ETA receptor antagonist, FR 139317, on endothelin-1 (ET-1)-induced coronary vasoconstriction in the isolated perfused heart of the rabbit. In addition, this study examined whether FR 139317 reduced infarct size in a rabbit model of coronary artery occlusion and reperfusion.2 In the rabbit isolated perfused heart, ET-1 (1-100pmol) elicited a dose-dependent increase in coronary perfusion pressure (CPP). For example, 30 pmol ET-1 caused CPP to rise by 22 ± 8 mmHg and 100 pmol ET-1 by 47 ± 10 mmHg (n = 8). Infusion of FR 139317 (1 f.M) significantly attenuated the increase in CPP caused by ET-1 (30 pmol: 3 ± 1 mmHg, 100 pmol: 8 ± 2 mmHg; n = 8). 3 In the anaesthetized rabbit, infarct size (expressed as a percentage of the area at risk) after 45 or 60 min of coronary artery occlusion followed by 2 h of reperfusion was 47 ± 6% (n = 6) and 55 ± 7%(n = 5), respectively. A continuous infusion of FR 139317 (0.2 mg kg-Imin-preceded by a loading dose of 1.0 mg kg-', i.v.; n = 5-6) had no effect on the extent of the myocardial infarct size (45 min: 47 ± 6%; 60 min: 49 ± 7%). Even a three-times higher dose (0.6 mg kg-min-' preceded by a loading dose of 3 mg kg-', i.v.; n = 4) of FR 139317 had no effect on myocardial infarct size (48 ± 5%) after 45 min occlusion of the antero-lateral branch of the left coronary artery (LAL) and 2 h reperfusion. 4 In a separate group of experiments, the LAL was occluded for 60 min and subsequently reperfused for 6 h. FR 139317 (0.6mg kg-Imin' preceded by a loading dose of 3 mg kg', i.v.; n =4) had no significant effect on infarct size even in this long reperfusion model (control: 48 ± 3%, FR 139317: 61 ± 6%). Thus, the vasoconstrictor effects elicited by ET-1 in the coronary vasculature of the rabbit are primarily mediated via the ETA receptor, for they were inhibited by the ETA receptor antagonist, FR 139317. However, an enhanced formation of endogenous ET-1 does not play a major role in ischaemia/ reperfusion injury of the rabbit heart, for FR 139317 had no effect on infarct size.

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

“…However, recent studies with ETA antagonists provided controversial results: continuous i.v. 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.…”

“…These receptor subtypes showed different sensitivities Author for correspondence. to the three endothelin isoforms so that ET-1 and ET-2 had high, almost equal, affinities for both ETA and ETB receptors (Sakurai et al, 1990), whereas ET-3 had a higher affinity for ETB than ETA receptors (Arai et al, 1990). Although ETA and ETB receptors were originally assigned to be responsible for ET-1-induced vasoconstriction and vasorelaxation, respectively (Masaki et al, 1992), it has been demonstrated that both receptor subtypes were involved in ET-1-induced vasoconstriction (Sumner et al, 1992;Clozel et al, 1992) as well as hypertension (McMurdo et al, 1993 antagonists, such as BQ-123 (Ihara et al, 1992), FR139317 (Sogabe et al, 1993), IRL1038 (Urade et al, 1992) and Ro 46-2005 (Clozel et al, 1993) (Mino et al, 1992) and by subarachnoid haemorrhage (Clozel et al, 1993) (Grover et al, 1993), whereas FR139317 did not in rabbits (McMurdo et al, 1994). …”

Effects of the prostanoid EP3‐receptor agonists M&B 28767 and GR 63799X on infarct size caused by regional myocardial ischaemia in the anaesthetized rat

“…This is not entirely surprising, as in rabbits subjected to regional myocardial ischaemia, an increase in the length of the reperfusion period from 2 to 8 h does not result in a signi®cant further increase in infarct site in the rat. This is not entirely surprising as in rabbits subjected to regional myocardial ischaemia, an increase in the length of the reperfusion period from 2 to 8 h does also not result in a signi®cant further increase in infarct size (McMurdo et al, 1994). In addition to measuring myocardial cell necrosis by NBT-staining or histology, the determination of the plasma levels of enzymes which are released by cardiac myocytes may also be used as a reliable indicator of tissue necrosis.…”

Role of ETB receptors in local clearance of endothelin‐1 in rat heart: studies with the antagonists PD 155080 and BQ‐788

“…Thus, the mixed ETA/ETB receptor antagonist TAK-044 showed a limited inhibitory effect on the extension of infarct size in rats [16], whereas BQ-123 (ETA receptor antagonist) was without effect in the same model [17]. Another ETA receptor antagonist, FR 139317 was without effect in a rabbit model of ischemia/reperfusion [18], and led to an increase, rather than a decrease in infarct size in dogs [19]. Our results may be of relevance to these discrepancies.…”