Inhaled NO as a viable antiadhesive therapy for ischemia/reperfusion injury of distal microvascular beds.

Abstract

Inhaled nitric oxide (NO) is being used more and more in intensive care units as a modality to improve the outcome of patients with pulmonary complications. Our objective was to demonstrate that inhaled NO could impact upon a distally inflamed microvasculature-improving perfusion, leukocyte adhesive interactions, and endothelial dysfunction. Using intravital microscopy to visualize ischemia/reperfusion of postcapillary venules, we were able to demonstrate that the reduction in perfusion, the dramatic increase in leukocyte rolling, adhesion, and emigration, and the endothelial dysfunction could all be significantly abrogated with 80 ppm, but not 20 ppm inhaled NO. Perfusing whole blood directly over an inert P-selectin and CD18 ligand substratum incorporated in a flow chamber recruited the same number of rolling and adhering leukocytes from NO-ventilated and non-NO-ventilated animals, suggesting that inhaled NO was not directly affecting leukocytes. To demonstrate that inhaled NO was actually reaching the peripheral microvasculature in vivo, we applied a NO synthase inhibitor locally to the feline mesentery and demonstrated that the vasoconstriction, as well as leukocyte recruitment, were essentially abolished by inhaled NO, suggesting that a NOdepleted peripheral microvasculature could be replenished with inhaled NO in vivo. Finally, inhaled NO at the same concentration that was effective in ischemia/reperfusion did not affect vascular alterations, leukocyte recruitment, and endothelial dysfunction associated with endotoxemia in the feline mesentery. In conclusion, our data for the first time demonstrate a role for inhaled NO as a therapeutic delivery system to the peripheral microvasculature, showing tremendous efficacy as an antiadhesive, antivasoconstrictive, and antipermeabilizing molecule in NO-depleted tissues, but not normal microvessels or vessels that have an abundance of NO (LPS-treated). The notion that blood borne molecules have NO carrying capacity is conceptually consistent with our observations. ( J. Clin. Invest. 1998. 101:2497-2505.)

Inhaled nitric oxide augments nitric oxide transport on sickle cell hemoglobin without affecting oxygen affinity

“…Although it is expected that higher levels of modified cysteine 93 are needed to inhibit hemoglobin S polymerization and improve oxygen affinity, it is possible that small quantities of SNOhemoglobin would have significant peripheral physiological effects. NO, carried as SNO-hemoglobin to the microvasculature, may modulate vascular tone (6), inhibit platelet activation (18), and inhibit leukocyte Pselectin-dependent adhesion and migration (19). These actions could potentially have a favorable impact on the pathophysiology of sickle cell anemia, a disease characterized by major abnormalities in microvascular perfusion; hypercoagulability; and increased expression of erythrocyte, endothelial, and leukocyte adhesion molecules (20).…”

Inhaled Nitric Oxide

“…Inhaled NO has been shown to attenuate ischemia-reperfusion injury in the lung and other organs in preclinical 55 and in clinical studies. 56,57 However, a recent randomized, placebo-controlled study demonstrated that inhaling 20 ppm NO beginning 10 minutes after reperfusion does not affect the physiological or clinical outcome of patients after lung transplantation.…”

“…For example, inhaled NO appears to modestly inhibit platelet activation in some species 89,90 and to attenuate neutrophil-mediated ischemia-reperfusion injury. 55 Decreased bioavailability of NO may contribute to the pathogenesis of sickle cell disease, and inhaled NO has been suggested to modulate the course of this disease. 91 In this regard, the treatment of vaso-occlusive crises with inhaled NO in patients with sickle cell disease may become a promising therapy.…”

Chimeric SOD2/3 inhibits at the endothelial-neutrophil interface to limit vascular dysfunction in ischemia-reperfusion

“…The surgical preparation used in this study is the same as that described previously (7,19). Briefly, age-matched cats (1.2-2.4 kg) were fasted for 12 h and initially anesthetized with ketamine hydrochloride (75 mg im).…”

“…The mesentery was prepared for in vivo microscopic observation as previously described (7,19). The mesentery was draped over an optically clear viewing pedestal that allowed for transillumination of a 3-cm segment of tissue.…”