Nitric Oxide Synthesis Inhibition during Cerebral Hypoxemia and Reoxygenation with 100% Oxygen in Newborn Pigs

Abstract

The objective of our study was to evaluate the effects of N_σ-nitro-L-arginine methyl ester (L-NAME), an inhibitor of the nitric oxide (NO) pathway, on cerebral microcirculation during hypoxemia and reoxygenation with 100% oxygen in newborn pigs. Twenty-two pigs were randomized to hypoxemia [inspired fraction of oxygen (FIO₂) 0.08; 20 min] and reoxygenation (FIO₂ 1.0; 60 min) or normoxia. The hypoxemic animals were further randomized to receive either an intravenous bolus injection of 5 mg/kg L-NAME (n = 8) or a corresponding volume of isotonic saline (n = 8) 30 min before the onset of hypoxemia. The normoxemic group (n = 6) received the same pretreatment with L-NAME. Cerebral hemodynamics were assessed by laser Doppler flowmetry and intracranial pressure monitoring. The cerebral NO concentration was continuously measured using an electrochemical sensor. Pretreatment with L-NAME resulted in a more severe systemic hypotension and reduced cerebral microcirculation during the period of hypoxemia compared with the saline/hypoxemia group. NO synthesis inhibition during reoxygenation with 100% oxygen, however, blunted the increase in NO concentration (p < 0.05) without reduction of cerebral blood flow and cerebral perfusion pressure. In conclusion, in this newborn pig model, pretreatment with a bolus infusion of L-NAME induced severe hypotension and reduced cerebral microcirculation during hypoxemia. However, it appears to have no significant adverse effect on cerebral hemodynamics during the period of reoxygenation with 100% oxygen. This deleterious effect during hypoxemia limits the use of L-NAME as a preventive drug but suggests beneficial effects during reoxygenation with 100% oxygen.

Cerebral Blood Flow Regulation by Nitric Oxide: Recent Advances

“…In contrast to the neuroprotective effects of NO donors, there are reports in the literature suggesting that NO synthesis inhibition is beneficial in reducing functional and histological impairments induced by ischemic insult. Pretreatment of newborn pigs with L-NAME induced severe hypotension and reduced cerebral microcirculation during hypoxia, and NO synthesis inhibition during reoxygenation blunted the increase in NO concentration without the undesirable side effect of reducing cerebral blood flow, suggesting a beneficial effect of L-NAME in the reoxygenation phase (Kutzsche et al, 2002). Selective nNOS and iNOS inhibitors may be candidate treatments for acute ischemic stroke (Willmot et al, 2005a).…”

Maternal Nutrient Restriction Reduces Carotid Artery Constriction Without Increasing Nitric Oxide Synthesis in the Late Gestation Rat Fetus

“…During acute hypoxia, the fetal redistribution of cardiac output, and maintenance of brain perfusion has been demonstrated to be caused in part by nitric oxide (12)(13)(14). In both the sheep fetus and newborn pig, inhibition of nitric oxide synthase with N G -nitro-L-arginine methyl ester (L-NAME) during hypoxia has been demonstrated to attenuate changes in blood flow within the cerebral microcirculation (12,13).…”

“…In both the sheep fetus and newborn pig, inhibition of nitric oxide synthase with N G -nitro-L-arginine methyl ester (L-NAME) during hypoxia has been demonstrated to attenuate changes in blood flow within the cerebral microcirculation (12,13). The circulatory adaptations that occur in the cerebral vascular beds of growthrestricted fetuses may involve specific compensatory adaptations in the nitric oxide synthase pathway.…”

Inhaled Gases for Neuroprotection of Neonates: A Review

“…Newborn piglets resuscitated with 100% O 2 improved restoration of mean arterial blood pressure with no difference in amino acid build up in cerebral striatum (glutamate, taurine, and alanine) when compared to those resuscitated with 21% O 2 (63). Reoxygenation of asphyxiated piglets with 100% O 2 did not change cerebral perfusion but restored nitric oxide level in the cortex to a higher level compared to those resuscitated with 21% O 2 (65,66).…”