Efficacy of an endothelin-A receptor antagonist in heart transplantation from asphyxiated canine non-heart-beating donors

Objective Hypoxic perfusion before arrest, an indeterminate period of warm ischemia, and subsequent reperfusion are major causes of cardiac allograft dysfunction in non-heart-beating donors (NHBDs). The present study was undertaken to elucidate the cardioprotective effects of ET_A receptor antagonist FR139317 for hearts obtained from asphyxiated NHBDs in a canine transplantation model. Methods Hypoxic cardiac arrest was induced in 17 donor dogs. FR139317 (10 mg/kg) was given to 7 of the dogs over a period of 10 min before disconnecting the ventilator. The hearts were preserved with FR 139317-supplemented cardioplegic solution (FR group). The remaining 10 did not receive FR 139317 at any time during the experiment (control group). Orthotopic transplantation was performed after a mean myocardial ischemic time of 4 h. Results During the agonal period, the highest systolic pulmonary artery pressure in the FR group was lower than that in the control group (47 ± 14 vs. 58 ± 27 mmHg). All animals in the FR group were weaned from cardiopulmonary bypass, whereas only five of the controls were weaned, two of which were identified to have dominant right ventricular failure. After transplantation, recovery rates of the left ventricular end-systolic pressure-volume ratio (Emax) and the maximum first derivative of pressure measured over time (max dP/dt) were not significantly different between the groups, but recovery rates of the cardiac index, left ventricular minimum dP/dt and exponential time constant of LV relaxation (tau) in the FR group were higher than those in the control group. Conclusions The ET_A receptor antagonist FR 139317 reduced pressure overload on the right ventricle by decreasing the peak pulmonary artery pressure before donor arrest. Cardioprotective effects of this agent for heart transplantation from NHBDs are manifested by preserved diastolic properties of the left ventricle.