Umans [9; 10; 11; 12]. Mammals produce haptoglobin (Hp) to neutralize cell-free Hb and, thereby
Umans [9; ten; 11; 12]. Mammals CXCR6 review generate haptoglobin (Hp) to neutralize cell-free Hb and, thereby, protect against inflammatory damage and systemic vasoconstriction. Information from Hp knockout mice recommend that Hp also attenuates Hb-mediated oxidative organ harm [13; 14]. However, mice have low baseline Hp levels [15], which could easily be depleted by cell-free Hb challenge. The vascular endothelium modulates pulmonary artery tone by making numerous vasoactive mediators, which includes the potent vasodilators prostacyclin (PGI2) and NO. Synthesis and release of NO from pulmonary endothelial cells results in pulmonary vasodilation [16]. Uncoupling of nitric oxide synthase 3 (NOS3) by lowered co-factors (NADPH, tetrahydrobiopterin) or low levels of L-arginine benefits in formation of superoxide rather of NO [17]. In humans, impaired NO production or availability can lead to pulmonary hypertension [18]. Systemic endothelial dysfunction is frequently related with metabolic disorders which include diabetes [19] and is characterized by impaired generation of NO by endothelial cells [20]. We have previously reported that endothelial dysfunction in diabetic (db/db) mice augments the systemic vasoconstrictor response to infusion of cell-free Hb [21]. NO made by pulmonary endothelium also modulates hypoxic pulmonary vasoconstriction (HPV) a physiological mechanism exclusive to the pulmonary vasculature making certain the optimal oxygenation of arterial blood. The precise mechanisms involved within the control of pulmonary vascular tone are 5-HT3 Receptor Storage & Stability complex, incompletely understood, and vary substantially involving species [22]. Studies of NOS inhibition in rats [23], rabbits [24], dogs [25] and cats [26] all demonstrate that pharmacological NOS inhibition with NG-nitro-Larginine methylester (L-NAME) enhances HPV. Having said that, we did not know irrespective of whether scavenging of NO by Hb affects pulmonary vascular tone in mice. Mice are widely studied in different experimental models, due to the excellent possibilities of altering their genetic composition. The interaction among Hb, NO and pulmonary vasculature is crucial to our understanding on the effects of NO scavenging on pulmonary blood flow distribution, gas exchange and oxygen delivery through regional lung hypoxia. The aim of this study was to elucidate the effects of plasma Hb on the pulmonary vascular tone of anesthetized and ventilated mice. As a way to precisely assess pulmonary vascular resistance [27], we obtained dynamic simultaneous measurements of pulmonary arterial pressure and blood flow at thoracotomy. As in other species we hypothesized that i.v. infusion of Hb would generate pulmonary vasoconstriction in wild-type (WT) mice. We also hypothesized that the endothelial dysfunction of diabetic (db/db) mice [21], which sensitizesNitric Oxide. Author manuscript; available in PMC 2014 April 01.Beloiartsev et al.Pagethese mice to Hb-produced systemic vasoconstriction could possibly improve Hb-induced pulmonary vasoconstriction. Furthermore, we hypothesized that i.v. infusion of cell-free Hb, by scavenging NO and reducing NO-mediated vasodilation, would enhance the vasoconstrictor response on the pulmonary vasculature to regional hypoxia, thereby augmenting HPV. Surprisingly, we discovered that scavenging of NO by cell-free oxyHb in mice didn’t alter either the basal pulmonary vascular tone or the degree of HPV.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptMethodsAll animal experiments were approved by the Subcommittee on Rese.