Blood pressure and systemic vascular resistance increased during infusion of the NO synthase inhibitor L-NAME, and the dosage of catecholamines was reduced. The vasoconstrictive response to L-NAME most likely was the result of blocking the NO system . In addition to the systemic effects of L-NAME, severe pulmonary vasoconstriction was observed with L-NAME. Analogous to these findings, in patients with Adult Respiratory Distress Syndrome (ARDS), inhalation of NO is reported to be beneficial by causing local vasodilation in bronchial and pulmonary circulation which results in reduced pulmonary vascular resistance and improved oxygenation. This suggests that the pulmonary circulation is sensitive to the vasodilating effects of both endogenous and exogenous NO. Pulmonary vasoconstriction is not, therefore, unexpected with systemic inhibition of NO synthesis. With a continuous infusion of L-NAME, pulmonary vascular resistance increased five-fold, whereas systemic vascular resistance "only" doubled. pulmonary hypertension was reversible after stopping L-NAME infusion. In prior experiments with a lower dose of LNAME, pulmonary vasoconstriction was less pronounced and did not result in pulmonary hypertension.' Thus, pulmonary hypertension is a dose-related effect of L-NAME that can probably be attributed to overdosing of the drug. Reduced cardiac output may have directly resulted from the extreme increase in pulmonary vascular resistance compromising venous return and left ventricular preload and/or a reflex reduction in heart rate by the increase in vascular resistance and blood pressure. S-methyl-isothiourea, a relatively selective inhibitor of iNOS activity, decreased pulmonary leak and improved survival in endotoxemia. However, because of the tissue-protective and antiapoptotic effects of NO, even selective iNOS inhibitors may be detrimental in certain tissues during sepsis.Combining the salutary effects of site-specific local donors that exploit the cytoprotective actions of 'NO with specific agents that combat the deleterious hypotensive and tissue-damaging effects of 'NO overproduction may be needed to treat septic shock. In this regard, inhaled 'NO gas has shown promise as a selective pulmonary vasodilator.

## Role of Nitric Oxide in Inflammation and Tissue Injury

Since the discovery that nitric oxide ('NO) accounts for the biologic activity of endothelial-derived relaxing factor, a torrent of research over the last decade has focused on its role, protective or detrimental, in myriad pathophysiologic conditions. Recently, increasing attention has focused on 'NO as a possible mediator of the severe hypotension and impaired vasoreactivity characteristic of circulatory failure. Experimental and clinical studies have suggested NOS inhibition might have therapeutic potential in circulatory shock, and other studies have demonstrated the beneficial nature of iNOS expression in modulating tissue perfusion and mediating cytotoxicity. However, inhibition of 'NO synthesis in experimental and clinical studies of shock has yielded mixed, sometimes contradictory, results. Overproduction of 'NO in the vasculature may result in systemic vasodilatation, but still 'NO synthesis has a beneficial role in regulating organ perfusion and mediating cytotoxicity.

- • *NO production occurs with hemorrhage • *NO production occurs with hemorrhage

These findings are consistent with those in trauma patients, where nitrite and nitrate levels were reduced for prolonged periods after injury. This impairment of 'NO production in victims of hemorrhagic hypotension may be due to impairment of eNOS, and indeed, several investigators have demonstrated