Endothelin-A and -B antagonists protect myocardial and endothelial function after ischemia/reperfusion in a rat heart transplantation model

Abstract

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 mmol / kg / min), BQ788 (3 mmol / kg / min), ET-1 (8 pmol / kg / min) or simultaneous infusion of BQ123 or BQ788 and ET-1, respectively (n512 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.

Poly(ADP-Ribose) Polymerase Inhibition Reduces Reperfusion Injury After Heart Transplantation

“…On the other hand, the control group showed a recovery after 24 hours with similar values to the PJ34 group, suggesting that that the applied cardiac preservation time and reperfusion lead to only reversible changes of functional status of the heart. 16,17 Although no differences were found between the groups in systolic and diastolic function and baseline coronary blood flow after 24 hours of reperfusion, endothelial function was still depressed in the control group as indicated by the lower CBF response to acetylcholine and bradykinin. The fact that after 24 hours reperfusion the histological specimens from both control and PJ34 showed only little PARP activation suggested that delayed endothelial dysfunction in the control animals may be a late consequence of a transient, earlier burst of PARP activation and subsequent cellular alterations.…”

“…16,17 Briefly, donor hearts were explanted from Lewis rats. After 1 hour of ischemic preservation at 4°C, the hearts were implanted intraabdominally anastomosing the aorta and the pulmonary artery of the donor heart with the abdominal aorta or the vena cava of the recipient rat, respectively.…”

“…16,17 Total coronary blood flow (CBF) was measured by a perivascular ultrasonic flow probe on the donor aorta. After baseline measurement, the endothelium-dependent vasodilator acetylcholine (ACH, 1 nmol/L, 0.2 mL) and bradykinin (BK 0.1 nmol/L, 0.2 mL) as well as the endothelium-independent vasodilator sodiumnitroprusside (SNP, 10 nmol/L, 0.2 mL) were administered directly into the coronary arteries of the graft via the donor aorta.…”

Patterns of Myocardial Endothelin-1 Expression and Outcome After Cardiac Transplantation

“…The present study addresses the importance of the interstitium, where ET-1 expression may have a prognostic role as well. Animal models of myocardial ischemia have shown that endogenous ET release is involved in the pathogenesis of ischemia/ reperfusion injury, 12 and that ET-1 stimulates cardiac fibroblast proliferation. 13 The negative interstitial ET-1 expression in 2 patients with post-transplantation ischemic injury might be related to sampling error, a problem inherent in biopsy studies.…”

Protective effect of carbon monoxide in transplantation

“…During I/R injury, damaged VECs release a variety of vasoconstructive proteins such as endothelin (ET)-1, which is the most powerful natural mammalian vasoconstrictive agent [76]. For instance, an elevation of ET-1 has been reported in renal I/R injury [77], and the blockade of ET A receptor prevents I/R injury in rat cardiac transplantation model [78]. CO inhalation at 250 ppm prevents ET-1 activation after cardiac transplantation and improves graft outcome [79].…”