REGULATION OF LEFT-VENTRICULAR RELAXATION IN THE ISOLATED GUINEA-PIG HEART BY ENDOGENOUS ENDOTHELIN

Objective: To examine the effects of endogenous endothelin-1 on cardia c contraction in the isolated heart using endothelin receptor antagoni sts. Methods: Isolated ejecting guinea-pig hearts were perfused with K rebs buffer (1 mu M indomethacin) at 37 degrees C, constant loading an d heart rate, and high-fidelity left ventricular pressure was monitore d by an apical 2F Millar catheter. The effects of the following interv entions on left ventricular performance and coronary flow were determi ned: (a) no treatment (i.e., time controls) (n = 8); (b) the specific ET(A) receptor antagonist, BQ123 (1 mu M, n = 8); (c) the specific ET( B) receptor antagonist, IRL1038 (0.1 mu M, n = 4; 1 mu M, n = 6); (d) exogenous endothelin-1 (0.01 nM, n = 6; 0.1 nM, n = 6; 1 nM, n = 6); ( e) the specific ET(B) receptor agonist, BQ3020 (5 nM, n = 8). Results: All parameters were stable in control (untreated) hearts. BQ123 induc ed progressive acceleration of early left ventricular pressure decline and a fall in left ventricular end-diastolic pressure with no effect on peak left ventricular pressure, dP/dt(max), stroke Volume or corona ry flow. IRL1038 had no effect on any of these parameters. In contrast , exogenous endothelin-1 exerted potent vasoconstrictor effects associ ated with a fall in peak left ventricular pressure, dP/dt(max) and str oke volume. Similar changes were observed with BQ3020. Concentrations of endothelin-1 <0.1 nM, which had no vasoconstrictor effect, produced no change in LV function. Conclusions: These data indicate that basal intracardiac release of endothelin-1 significantly delays LV relaxati on in the isolated guinea-pig heart, but has no effect on coronary flo w. The contrasting effects of endogenous endothelin-1 (elicited by BQ1 23) and exogenous endothelin-1 are likely to reflect differences in th eir site of action and in their effective concentrations at these site s.