INHIBITION OF NITRIC-OXIDE SYNTHESIS CAUSES MYOCARDIAL-ISCHEMIA IN ENDOTOXEMIC RATS

Inhibitors of nitric oxide (NO) synthesis have been used in the treatm ent of septic and endotoxic shock. However, several studies question t he beneficial effect of inhibiting NO production in sepsis and endotox emia. We have investigated the effect of inhibition of NO synthesis af ter endotoxemia in the isolated perfused rat heart. In hearts from end otoxin-treated animals, coronary flow was elevated 64% and oxygen cons umption was elevated 20% compared with control hearts. NADH fluorescen ce imaging was used as an indicator of regional hypoperfusion. A homog eneous low-surface NADH fluorescence, indicative of adequate tissue pe rfusion, was observed in both control and endotoxin-treated hearts. Th e increase in coronary flow and oxygen consumption could only partiall y be prevented by pretreatment of the animals with dexamethasone. Addi tion of N-omega-nitro-L-arginine (NNLA), an inhibitor of NO synthesis, to the perfusion medium eliminated differences in coronary flow and o xygen consumption between normal and endotoxin-treated hearts. However , NADH sur face fluorescence images of endotoxin-treated hearts after NNLA revealed areas of high fluorescence, indicating local ischemia, w hereas the control hearts remained without signs of ischemia. The isch emic areas were present at various perfusion pressures and disappeared after the infusion of L-arginine, the natural precursor of NO, or the exogenous NO donor sodium nitroprusside. Methylene blue (MB), an inhi bitor of soluble guanylate cyclase, the effector enzyme of NO, also el iminated differences in coronary flow and produced similar areas of lo cal myocardial ischemia in endotoxin-treated hearts but not in control hearts. Reducing coronary flow by direct vasoconstriction with vasopr essin resulted in similar patterns of myocardial ischemia as with NNLA and MB. Our results suggest that the coronary vasodilation in the iso lated rat heart after endotoxemia is caused by an increased release of NO. Coronary flow reduction with NNLA, MB, or direct vasoconstriction with vasopressin causes local areas of myocardial ischemia in endotox in-treated hearts but not in untreated hearts. These data suggest that endotoxemia promotes myocardial ischemia in vulnerable areas of the h eart after inhibition of the NO pathway or direct vasoconstriction.