Pretreatment of brain dead rabbits with pinacidil before prolonged cold-storage with an extracellular solution alters aortic endothelial function

Objective: Endothelial injury occurs during heart transplantation and contr ibutes to the development of cardiac allograft vasculopathy. We have evalua ted in a brain death model in the rabbit whether pre-treatment with the pot assium channel opener (PCO) pinacidil before prolonged hypothermic storage with an extracellular solution would improve vascular endothelial recovery. Methods: Rabbits were randomized into 4 experimental groups (n = 8 per grou p). In the control group (CTRL), abdominal aortic rings were assessed immed iately after 90 minutes of anesthesia. In the brain death group (BD), aorti c rings were assessed immediately after 90 minutes of brain death. In the S TH group, aortic rings taken from brain dead rabbits were stored for 24 hou rs at 4 degrees C with the extracellular preservation solution of St. Thoma s Hospital (STH) before assessment. In the STH + PCO group, the potassium c hannel opener pinacidil, 1 mg/kg, was administered intravenously to brain d ead rabbits 10 minutes before explantation. Aortic rings were then stored f or 24 hours at 4 degrees C with the STH solution before evaluation. Brain d eath was induced by rapid inflation of a sub-durally placed balloon and val idated by clinical and electroencephalographic data. Concentration-response curves to acetylcholine (ACH, 10(-9) to 10(-4) mol/liter) and nitroglyceri n (NGL, 10(-9) to 10(-5) mol/liter) were constructed in phenylephrinepre-co ntracted rings. Results: ACH evoked a similar concentration-dependent relaxation in the CTR L (E-max: 95.8 +/- 2.9%; EC50: -6.86 +/- 0.13 log M) and BD groups (E-max: 90.8 +/- 3.8%; EC50: -6.75 +/- 0.15 log M). The concentration-relaxation cu rve was shifted rightward in the STH group (E-max: 76.7 +/- 7.1%; EC50: -6. 75 +/- 0.16 log M) in comparison with the CTRL and ED groups, but there wer e no significant differences in either E-max or EC50 values. After pinacidi l pre-treatment, there was a further significant shift to the right of the concentration-relaxation curve to ACH (E-max: 77.4 +/- 5.0%; EC50: -6.14 +/ - 0.19 log M, p < 0.05 vs CTRL, ED and STH). There were no significant diff erences between groups in the concentration-relaxation curves to NGL in end othelium-intact and endothelium-denuded vascular rings (either E-max or EC5 0). Conclusion: Pre-treatment of brain dead rabbits with pinacidil before prolo nged cold-storage with STH solution significantly impaired endothelium-depe ndent vasorelaxation in comparison to storage with STH solution. The role o f PCO pre-treatment in the context of cardiac transplantation needs to be r econsidered.