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

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.

Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part VI: Treatment

“…24 NO is known to inhibit the synthesis of ET-1. 25 Administration of NO to the transplanted lung theoretically should prevent or attenuate these pathologic processes.…”

Beneficial Effects of Supplemental Nitric Oxide Donor Given during Reperfusion Period in Reperfusion-Induced Lung Injury

“…Our results with other animal studies state that NTG as an NO donor is useful in lung IR [20,23]. Although NTG is available in practice, it was not possible for us to find a human study studying NTG in lung IR, except a case report which used NO by inhalation during lung transplantation [34].…”

“…NTG is thought to act by way of intracellular S-nitrosothiol intermediates to directly stimulate guanylate cyclase or to release NO locally in effector cells and has recently been shown to increase NO in expired air, suggesting that NTG contributes to local levels of NO within the lungs [18,19]. Furthermore, supplementing NTG at the onset of lung preservation maintains vasomotor function through the preservation to early post-transplant periods, and suppresses induction of ET-1 [20].…”

“…Minamoto et al [20] reported that post-transplantation benefits of NTG were restricted to lung grafts which received NTG during the flush perfusion and preservation periods. They were not able to find any benefits of NTG when it is supplemented during ex vivo flush; however, they did not supplement NTG during flush perfusion and continue to give NTG during the reperfusion period.…”

Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation

“…On the other hand, the verdict on the role of NO in animal models of lung transplantation is mixed. Supplementation of the preservation solution with NO donor nitroglycerin in rodents improved recipient survival after lung transplantation (75,77), although NO inhalation in human randomized trials had mixed to no effects (70). Thus the potential benefits or detrimental effect of increased NO generation is not clear.…”