Regulation of left ventricular relaxation in the isolated guinea-pig heart by endogenous endothelin.
OBJECTIVE
TO examine the effects of endogenous endothelin-1 on cardiac contraction in the isolated heart using endothelin receptor antagonists.


METHODS
Isolated ejecting guinea-pig hearts were perfused with Krebs buffer (1 microM indomethacin) at 37 degrees C, constant loading and heart rate, and high-fidelity left ventricular pressure was monitored by an apical 2F Millar catheter. The effects of the following interventions on left ventricular performance and coronary flow were determined: (a) no treatment (i.e., time controls) (n = 8); (b) the specific ETA receptor antagonist, BQ123 (1 microM, n = 8); (c) the specific ETB receptor antagonist, IRL 1038 (0.1 microM, n = 4; 1 microM, n = 6); (d) exogenous endothelin-1 (0.01 nM, n = 6; 0.1 nM, n = 6); (e) the specific ETB receptor agonist, BQ3020 (5 nM, n = 8).


RESULTS
All parameters were stable in control (untreated) hearts. BQ123 induced 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/dtmax, stroke volume or coronary flow. IRL 1038 had no effect on any of these parameters. In contrast, exogenous endothelin-1 exerted potent vasoconstrictor effects associated with a fall in peak left ventricular pressure, dP/dtmax and stroke 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 relaxation in the isolated guinea-pig heart, but has no effect on coronary flow. The contrasting effects of endogenous endothelin-1 (elicited by BQ123) and exogenous endothelin-1 are likely to reflect differences in their site of action and in their effective concentrations at these sites.
Prendergast
B D
BD
Department of Cardiology, University of Wales College of Medicine, Cardiff, UK.
Anning
P B
PB
Lewis
M J
MJ
Shah
A M
AM
D000818:Animals; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology*; D016232:Endothelins / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010477:Perfusion; D017466:Receptors, Endothelin / Q000819:agonists; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C075771:BQ 3020; C077420:Cys(11)-Cys(15)-endothelin-1 (11-21); C072247:cyclo(Trp-Asp-Pro-Val-Leu)