Endothelin-A and -B antagonists protect myocardial and endothelial function after ischemia/reperfusion in a rat heart transplantation model.
OBJECTIVE
Previous studies suggested that endothelin-1 (ET-1) may play a pathophysiological role in myocardial ischemia/reperfusion injury. This study was designed to investigate the effects of the selective ET-A receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788 on myocardial and endothelial function after reversible deep hypothermic ischemia in a heterotopic rat heart transplantation model.


METHODS
Isogenic intraabdominal heterotopic transplantation was performed in Lewis rats. After 1 h of cold ischemic preservation reperfusion was started either after application of placebo (control), BQ123 (3 mumol/kg/min). BQ788 (3 mumol/kg/min), ET-1 (8 pmol/kg/min) or simultaneous infusion of BQ123 or BQ788 and ET-1, respectively (n = 12 each). An implanted balloon was used to obtain pressure-volume relations of the transplanted heart. Myocardial blood flow (MBF) was assessed by the hydrogen-clearance method. Measurements were taken after 1 and 24 h of reperfusion. Endothelium-dependent vasodilation to acetylcholine (ACH) and endothelium-independent vasodilation to sodium nitroprusside were also determined.


RESULTS
Both BQ123 and BQ788 significantly improved myocardial and endothelial functional recovery during early reperfusion, whereas ET-1 significantly impaired myocardial and endothelial function. Simultaneous infusion of ET-1 diminished the effects of BQ123 and BQ788. Although myocardial function and baseline MBF were similar in all groups after 24 h of reperfusion, endothelium dependent vasodilation to ACH was still significantly higher in the BQ123 and BQ788 groups and lower in the ET-1 groups (p < 0.05).


CONCLUSIONS
These results suggest that endogenous ET release is involved in the pathogenesis of reperfusion injury after heart transplantation. ET-A and ET-B receptor antagonists may be useful to reduce ischemia/reperfusion injury.
Szabó
G
G
Department of Cardiac Surgery, University of Heidelberg, Germany.
Fazekas
L
L
Bährle
S
S
MacDonald
D
D
Stumpf
N
N
Vahl
C F
CF
Hagl
S
S
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D016027:Heart Transplantation; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009599:Nitroprusside / Q000494:pharmacology; D009842:Oligopeptides / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013997:Time Factors; D014665:Vasodilator Agents; D016277:Ventricular Function, Left / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014665:Vasodilator Agents; D009599:Nitroprusside; C086539:BQ 788; D000109:Acetylcholine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)