Electrophysiological and haemodynamic effects of endothelin ETA and ETB receptors in normal and ischaemic working rabbit hearts

Abstract

The aims of this study were to determine if endothelin-1 (ET-1) under normal and ischaemic conditions exhibits a direct arrhythmogenic effect that is independent of its ability to cause coronary vasoconstriction, and to determine the contribution of the ET(A) and ET(B) receptor subtype. ET(A/B) (with ET-1) and ET(A) (ET-1 in the presence of BQ-788) receptor activation resulted in a significant reduction in both epi- and endocardial monophasic action potential duration (MAPD(90)). ET(A) receptor activation reduced both epi- and endocardial effective refractory period (ERP). This MAPD(90) and ERP shortening were associated with a reduction in coronary flow, myocardial contractility and induction of ventricular fibrillation (VF) during ERP measurement. The ET(B) agonist sarafotoxin (S6c) had no marked, or concentration-dependent, effect on MAPD(90), ERP, myocardial contractility or induction of arrhythmias. Neither ET-1 nor S6c, given prior to coronary artery occlusion, significantly changed the ischaemia-induced dispersion of MAPD(90), ERP or the % incidence of VF. In conclusion, neither ET(A) nor ET(B) receptor stimulation has a direct arrhythmogenic effect in isolated rabbit hearts under normal or ischaemic conditions. The ET-1-induced arrhythmogenic effect observed in nonischaemic hearts is likely to be the result of the associated coronary vasoconstriction caused by ET(A) receptor stimulation resulting in myocardial ischaemia.

Figure 1

Representative MAP recordings from the endocardium (top) and epicardium (bottom) before (baseline) and after 10⁻⁹ M ET-1 in an isolated working rabbit heart.

Figure 2

Effect of cumulative ET-1 (10⁻¹²–10⁻⁹ M) (top), ET-1 in the presence of BQ-788 (3 × 10⁻⁸ M) (middle) and S6c administration (10⁻¹²–10⁻⁸ M) (bottom) on LV epicardial and endocardial monophasic action potential duration (MAPD₉₀) measured at 90% repolarisation (MAPD₉₀, ms) in isolated working rabbit hearts. Dashed line indicates solution change. ^*P<0.05 compared to baseline (15 min) values. n=6, unless otherwise stated.

Figure 3

Effect of cumulative ET-1 (10⁻¹²–10⁻⁹ M) (top), ET-1 in the presence of BQ-788 (3 × 10⁻⁸ M) (middle) and S6c administration (10⁻¹²–10⁻⁸ M) (bottom) on LV epicardial and endocardial ERP (ERP, ms) in isolated working rabbit hearts. Dashed line indicates solution change. ^*P<0.05 compared to baseline (15 min) values. n=6, unless otherwise stated.

Figure 4

Effect of cumulative ET-1 (10⁻¹²–10⁻⁹ M), ET-1 (10⁻¹²–10⁻⁹ M) in the presence of BQ-788 (3 × 10⁻⁸ M) and S6c (10⁻¹²–10⁻⁸ M) administration on coronary flow in isolated working rabbit hearts. Dashed line indicates solution change. ^*P<0.05 compared to baseline (15 min) values. n=6, unless otherwise stated.

Figure 5

Change in MAPD₉₀ in the epicardium (AAR) (top) and endocardium (bottom) of working rabbit hearts treated with 10⁻¹⁰ M ET-1 or vehicle before and during acute regional ischaemia and reperfusion. ^*Significantly different from predrug value. ^**Statistically significant differences from respective preischaemic values (P<0.05 in each case) (n=6–12).

Figure 6

Change in MAPD₉₀ in the epicardium (AAR) (top) and endocardium (bottom) of working rabbit hearts treated with 10⁻⁸ M S6c or vehicle before and during acute regional ischaemia and reperfusion. ^**Statistically significant differences from respective preischaemic values (P<0.05 in each case) (n=6–12).

Figure 7

Coronary flow in working rabbit hearts treated with vehicle, 10⁻¹⁰ M ET-1 (top) or S6c (10⁻⁸ M) (bottom) before and during acute regional ischaemia and reperfusion. ^#Statistically significant difference from control ligation values. ^**Statistically significant difference from respective preischaemic values (P<0.05 in each case) (n=6–12).