Mesenteric Artery Vasoconstriction During Hypoxia is Mediated by a Loss of Basal Nitric Oxide (NO) Production † 983

Abstract

The newborn intestinal circulation is unique in that its intrinsic response to hypoxemia is pronounced vasoconstriction. One mechanism for this unique response might be an acute reduction in endothelial cell NO production, inasmuch as newborn gut vascular tone is highly contingent on the NO/cGMP axis(Am J Physiol 268:G949, '95). To test this hypothesis, mesenteric artery rings from perinatal swine were suspended in buffer-filled myographs and tension recorded continuously; buffer hypoxia (pO2 <10 mmHg) was induced in phenylephrine (PE) precontracted rings by aeration with 95% N2 - 5% CO2 The initial response to hypoxia was brief relaxation(<15sec; -16±2% in both 3- and 35d rings), which was absent in endothelium-denuded rings (E-), but still present following pretreatment with LNMMA (blocks NO production) or indomethacin. Precontraction by depolarization(40 mM KCl) in place of PE significantly blunted this early dilation, suggesting its mediation by an endothelium-derived hyperpolarizing factor. The second, and principal response to hypoxia was pronounced constriction (to 36±4% of maximal KCl-induced constriction in rings from 3d, but only 12±3% in rings from 35d old subjects, p<0.01). Hypoxic vasoconstriction (HVC) was sustained until ATP depletion impaired the contractility of vascular smooth muscle. HVC was absent in E- rings and eliminated by LNMMA, but not by indomethacin, phenidone (lipoxygenase inhibitor), or BQ610 (endothelin ETA receptor antagonist). Addition of superoxide dismutase significantly enhanced HVC (O2- inactivates NO; O2- removal would thus accentuate NO-based responses). Impairment of ATP production with 2,4-dinitrophenol in the presence of adequate O2 did not induce HVC; thus, HVC was initiated by reduced pO2 and not by hypoxia-induced ATP depletion, consistent with the known requirement for molecular O2 in the oxidation of L-arg to L-cit+NO. Speculation: These data support the pivotal role of endothelial NO production in setting basal vascular tone in newborn intestine. Factors which attenuate NO production, such as hypoxia, should thus exert a particularly deleterious effect on newborn gut perfusion. This fact may explain, in part, the unique susceptibility of the newborn intestinal circulation to profound ischemia and the development of necrotizing enterocolitis.