Timing of Nitric Oxide Donor Supplementation Determines Endothelin-1 Regulation and Quality of Lung Preservation for Transplantation

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Abstract
Nitroglycerin (NTG) given to donor lungs improves lung preservation for transplantation, but the mechanism(s) underlying this therapeutic benefit remain incompletely understood. Furthermore, it is not known whether the therapeutic window of opportunity for NTG administration is temporally-restricted. Because endothelin-1 (ET-1), a potent vasoconstrictor, and nitric oxide (NO) are reciprocally regulated in vitro, we hypothesized that early administration of the NO donor NTG may suppress ET-1 and thereby improve lung preservation. Using an isogeneic rat left lung transplantation model, four groups were studied (n = 12 transplant/group): (1) NTG given during flush/ preservation (Early NTG); (2) NTG given in the ex vivo flush (Late NTG); (3) No NTG; and (4) a nonselective ET-receptor antagonist (PD156252) given during flush/preservation. Early NTG decreased vascular tone in lung grafts measured ex vivo as well as in vivo following lung transplantation, and resulted in improved survival (100%) and gas exchange (pO2 209 ± 19 mm Hg) compared with Late (17%, 62 ± 16 mm Hg) or No NTG (25%, 59 ± 9 mm Hg) (P < 0.05 for Early NTG versus all other groups for both survival and pO2). PD156252 was associated with an intermediate level of survival (50%) and function (104 ± 23 mm Hg). Transplanted lung graft ET-1 mRNA, measured by Northern blotting and in situ hybridization, and protein, measured by Western blotting and immunohistochemistry, were suppressed only with Early NTG (P < 0.05 versus all other groups). Post-transplantation benefits of NTG are restricted to lung grafts which received NTG during the early harvest and immersion periods, and are coincident with suppression of graft ET-1 expression. When viewed in the context of improved graft survival and function with ET-1 receptor blockade, these data suggest that early administration of NTG to donor lungs improves primary graft function, in part, by suppressing graft ET-1 expression.