Inhaled NO impacts vascular but not extravascular compartments in postischemic peripheral organs

Abstract

Inhaled nitric oxide (NO) reduces pulmonary hypertension and dampens various aspects of lung inflammation; however, its effects are thought to be restricted to the lung because of its short half-life in biological systems. More recently, however, NO was shown to nitrosylate hemoglobin, albumin, and other plasma molecules to form stable nitrosothiol derivatives and could have an impact on the periphery. We examined whether inhaled NO could have an impact on the two compartments of distal organs, namely, the intravascular and extravascular spaces. The feline intestine was exposed to 1 h of ischemia and 1 h of reperfusion, and intestinal blood flow and mucosal dysfunction were measured in animals ventilated with room air and inhaling 0 or 80 ppm NO. A decrease in intestinal blood flow and an increase in mucosal barrier leakiness were noted in animals not exposed to inhaled NO. The intestinal blood flow impairment was entirely reversed in animals breathing 80 ppm NO, but the mucosal dysfunction was not affected. We further examined whether inhaled NO could reach the extravascular space by simply inhibiting NO in the intestine with the NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME) that causes an increase in mucosal permeability that is rapidly reversed with NO donors. However, inhaled NO had no effect on the rise in mucosal permeability. l-NAME reduced lymph nitrosothiol concentrations, but inhaled NO could not replenish these levels. To further explore the intravascular impact of inhaled NO, we used intravital microscopy to visualize the microvasculature and demonstrated that inhaled NO could be initiated after reperfusion and still reduced microvascular disturbances, including reversing the impairment in blood flow and increasing leukocyte adhesion. The effects of inhaled NO persisted for an additional hour after termination of NO inhalation, consistent with a dramatic increase in nitrate within 1 h of NO inhalation, which persisted for 1 h after the termination of NO inhalation. These data suggest that inhaled NO can reach distal organs to dramatically improve reperfusion-induced microvascular but not extravascular dysfunction.

Functional Coupling of Oxygen Binding and Vasoactivity inS-Nitrosohemoglobin

“…We have also demonstrated that SNO-Hb can sense the physiological O 2 gradient in resistance vessels (small arterioles that control blood flow), thereby coupling the release of vasodilator SNO with regional metabolic needs of the tissue (5). Additional work that supports the importance of SNO-Hb includes the myriad studies of the systemic effects of inhaled NO (25)(26)(27)(28)(29), which raises the levels of endogenous SNO-Hb (16). It is tempting to suggest, moreover, that the hypoxia-increased tissue levels of NO in kidneys of animals that had been treated with NO synthase inhibitors (30) implicate SNO-Hb as the source of the elevated NO.…”

Nitric oxide promotes distant organ protection: Evidence for an endocrine role of nitric oxide

“…Recent observations that the inhalation of NO gas at moderate to high levels (80 ppm) can result in systemic effects have begun to challenge the notion of NO being restricted to paracrine actions. NO gas has been shown to modulate a number of remote physiological and pathophysiological processes including systemic vascular resistance, intestinal blood flow, urinary flow, gastrointestinal I/R injury, and myocardial I/R injury (23)(24)(25)(26). Additionally, it has been reported that modifications of dietary NOx (nitrate and/or nitrite) results in the alteration of systemic NO metabolite levels, and thus impacts physiological processes (11,18,27,28).…”

Enhanced S -Nitroso-Albumin Formation From Inhaled NO During Ischemia/Reperfusion

“…Interestingly, inhaled NO has been reported to reduce systemic vascular resistance, 7 increase kidney filtration rates, 8 increase aortic cGMP levels, 9 and improve blood flow in intestine after NO synthase inhibitors. 10,11 The latter work has been extended by Cannon and colleagues 12 who reported that after blockade of forearm NO production followed by forearm exercise, NO inhalation greatly improved blood flow. Clearly, the bulk of evidence would support the view that inhaled NO can be transported to peripheral vasculatures.…”