INHIBITION OF INDUCIBLE NITRIC-OXIDE SYNTHASE PREVENTS MYOCARDIAL ANDSYSTEMIC VASCULAR BARRIER DYSFUNCTION DURING EARLY CARDIAC ALLOGRAFT-REJECTION

NO is produced during cardiac allograft rejection by expression of ind ucible NO synthase (iNOS) in the rejecting heart. Recent evidence indi cates that NO modulates vascular permeability under both physiological and pathophysiological conditions. The present study explored the eff ects of early acute cardiac allograft rejection, and specifically the effects of NO, on myocardial and systemic vascular barrier function us ing a quantitative double-tracer permeation method in a rat cardiac tr ansplant model. Early allograft rejection increased albumin permeation twofold to fivefold in the allograft heart and systemic vasculature ( brain, lung, sciatic nerve, diaphragm, retina, muscle, kidney, and uve a) compared with isografts and controls. There were no detectable diff erences in regional blood flow or hemodynamics, suggesting that increa sed albumin permeation resulted from increased vascular permeability. iNOS mRNA was expressed in the allograft heart and native lung and was associated with increased serum nitrite/nitrate levels. iNOS inhibiti on with aminoguanidine prevented or attenuated allograft heart and sys temic vascular barrier dysfunction and reduced allograft serum nitrite /nitrate levels to isograft values. Aminoguanidine did not affect the mild histological changes of rejection present in allografts. These da ta demonstrate the novel observations that (1) endothelial barrier fun ction is compromised in the systemic vasculature, particularly in the brain, remote from the site of allograft rejection; (2) allograft vasc ular barrier dysfunction is associated with increased NO production an d iNOS mRNA expression in the affected tissues (eg, native lung and gr afted heart); and (3) inhibition of NO production by iNOS prevents vas cular barrier dysfunction in the allograft heart and systemic vasculat ure.