Nitric Oxide Synthase Inhibition Is Associated With Decreased Survival of Cardiac Allografts in the Rat1

Abstract

Nitric oxide is a biological mediator that regulates blood vessel wall tonus, enhances macrophage cytotoxicity, and inhibits cellular immune reactivity. Primary acute rejection is associated with increased intragraft production of NO but it is unknown whether this delays or enhances the loss of graft function. The aim of the current study was to determine the effect of L-NAME, a nitric oxide synthase inhibitor, on the course and histopathology of rat cardiac allografts with primary acute rejection. L-NAME decreased the graft survival time from 9.4+/-1.5 to 6.9+/-0.3 days; the histopathology at asystole showed predominantly ischemic necrosis. L-NAME combined with antihypertensive drugs restored the rejection time (from 8.6+/-0.4 to 14.2+/-3.2 days) and resulted in an acute rejection pattern. We conclude that blocking of nitric oxide formation during acute rejection of a vascularized cardiac graft results in a decreased graft survival time and ischemic graft necrosis, very likely secondary to unopposed vasoconstriction.

Mechanisms of the protective action of diethyldithiocarbamate-iron complex on acute cardiac allograft rejection

“…The significance of these findings is that the degree of enhancement in graft survival was similar in magnitude to that observed in our laboratory using low-dose cyclosporine (33,37). Enhancement of graft survival is roughly equivalent in magnitude to that seen using specific or nonspecific NOS inhibitors (43,51,53), although some have reported either no benefit or detrimental effects of these agents on graft survival (2,30). The enhanced survival by DETC-Fe is consistent with our findings of improved graft survival using either a ruthenium-based NO scavenger (34) or a water-soluble, dithiocarbamate-based iron complex (33, 37), although the potential mechanisms of action of these other water-soluble derivatives have not been examined in detail previously.…”

“…Also, iNOS is upregulated in rejecting allografts in humans despite immunosuppressant therapy (18,46). Supporting a role of iNOS in acute cardiac allograft rejection, several investigators have used treatments in vivo with nonselective and selective iNOS enzyme inhibitors but with variable findings (2,5,30,43,51). The importance of iNOS was supported as well by studies showing that gene deletion of iNOS decreased histological rejection scores (11).…”

Inducible Nitric Oxide Synthase Inhibition of Weibel-Palade Body Release in Cardiac Transplant Rejection

“…These data confirm the work of others that shows that NOS2 improves long-term cardiac allograft survival. 10,19 …”

The complex role of iNOS in acutely rejecting cardiac transplants

“…Treatment of recipients with these agents either prolonged graft survival [35,36], had no effect on graft survival [37,38] or decreased graft survival [39]. None of these studies provided information on either graft function prior to graft failure or independent evaluation of histological rejection scores.…”

“…Indeed, doses of these agents used may have been in the range that inhibits the constitutive NOS (cNOS) activity; therefore, counteracting any benefits arising from inhibition of iNOS activity. In this context, the study showing decreased graft survival following treatment with L-NAME identified a hypertensive sideeffect of the L-NAME regimen [39]. Antagonizing the hypertensive action of L-NAME with concomitant treatment with the angiotensin converting enzyme inhibitor, cilazapril, resulted in significantly improved graft survival times [39].…”