Abstract-In the present study, we investigated whether inhaled nitric oxide (NO) was transported by plasma proteins, such as S-nitroso-albumin (SNO-Alb), in the feline circulation and whether this molecule delivers NO to the periphery under conditions of stress, specifically ischemia/reperfusion (I/R). A flow probe was interposed between the femoral and superior mesenteric artery for blood flow measurements, and a branch of the superior mesenteric vein was cannulated for arterial-venous sampling. In animals breathing room air, SNO-Alb was below detection level in arterial or venous blood. NO inhalation resulted in a significant arterial-venous gradient for SNO-Alb. Concomitant with this loss of SNO-Alb across the intestinal vasculature was an increase in nitrite (NO 2 Ϫ ). However, this release of NO was not sufficient to alter intestinal blood flow. I/R during NO inhalation caused a very large increase in arterial SNO-Alb that permitted a 5-fold increase in SNO-Alb consumption and significant generation of NO 2 Ϫ within the postischemic intestinal vasculature. The increased SNO-Alb consumption was sufficient to dramatically improve intestinal blood flow. The very large burst of arterial SNO-Alb during I/R was completely blocked by the administration of superoxide dismutase, suggesting that oxidative stress contributed to the increased SNO-Alb formation. Our data suggest that inhaled NO can increase nitrosothiol production and these molecules may be a functional NO delivery system during cardiovascular disease. Key Words: S-nitroso-albumin Ⅲ oxidative stress Ⅲ postischemic vasculature I n the last 10 years, a significant development in the respiratory field has been the use of inhaled nitric oxide (NO), initially in infants with pulmonary hypertension, but more recently with adults who have respiratory distress as one manifestation of multiple-organ dysfunction syndrome. 1 Experimentally, inhaled NO has been shown to prevent lung injury from hemodialysis, 2 endotoxemia, 3 ischemia/reperfusion (I/R) injury, 4 and even lung allografts. 5 Clinically, inhaled NO is used as a local vasodilator in the pulmonary vasculature. However, because the prevailing view has been that inhaled NO is rapidly inactivated in the pulmonary capillaries by reaction with oxyhemoglobin, 6 most research in this area has been restricted to the lung. Recently, work has focused on the potential effects of inhaled NO on peripheral microvessels. 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.Although NO reacts very quickly with heme groups, thereby allowing for rap...
Background-Intravenous immunoglobulin (IVIg) therapy has been shown to have therapeutic benefit in more than 50 inflammatory and immune-related diseases; however, the potential benefit of IVIg in cardiovascular disease is more limited, in part because our understanding of the mechanisms underlying the effects of IVIg in innate immunity is incomplete. Methods and Results-In this study, a systematic assessment of the role of IVIg in leukocyte recruitment was completed with an in vitro flow-chamber system and in vivo intravital microscopy in a feline ischemia-reperfusion model system. IVIg treatment of blood resulted in a profound decrease in recruitment of either immobilized P-selectin or E-selectin due to direct effects of IVIg on the leukocyte (not substratum). Similar results were observed on endothelium treated with histamine, which induces P-selectin-dependent rolling and  2 -integrin-dependent adhesion. IVIg reduced P-selectin glycoprotein ligand-1 (PSGL-1) antibody binding to PSGL-1 on leukocytes. Use of a  2 -integrin-dependent static assay to bypass selectin-dependent recruitment revealed some inhibitory effectiveness (60%), which suggests that the majority of the effects of IVIg were due to selectin inhibition, with some inhibition of integrin function. In vivo intravital microscopy revealed a potent inhibitory effect of IVIg on P-selectin-dependent rolling and  2 -integrin-dependent adhesion that led to reduced leukocyte recruitment and vascular dysfunction in postischemic microvessels. Conclusions-Our data demonstrate that IVIg has direct inhibitory effects on leukocyte recruitment in vitro and in vivo through inhibition of selectin and integrin function.
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