The Effects of Acidosis on eNOS in the Systemic Vasculature: A Focus on Early Postnatal Ontogenesis

Abstract

The activity of many vasomotor signaling pathways strongly depends on extracellular/intracellular pH. Nitric oxide (NO) is one of the most important vasodilators produced by the endothelium. In this review, we present evidence that in most vascular beds of mature mammalian organisms metabolic or respiratory acidosis increases functional endothelial NO-synthase (eNOS) activity, despite the observation that direct effects of low pH on eNOS enzymatic activity are inhibitory. This can be explained by the fact that acidosis increases the activity of signaling pathways that positively regulate eNOS activity. The role of NO in the regulation of vascular tone is greater in early postnatal ontogenesis compared to adulthood. Importantly, in early postnatal ontogenesis acidosis also augments functional eNOS activity and its contribution to the regulation of arterial contractility. Therefore, the effect of acidosis on total peripheral resistance in neonates may be stronger than in adults and can be one of the reasons for an undesirable decrease in blood pressure during neonatal asphyxia. The latter, however, should be proven in future studies.

Keywords: acidosis; anticontractile influence; eNOS; early postnatal development; endothelium; nitric oxide; pH; vasculature.

Figure 1

Acidosis potentiates the functional contribution of eNOS to the regulation of vascular tone in the early postnatal period. In 10–15-day old rat pups, extracellular acidosis (pH 6.8) reduces contractile responses of saphenous arteries to the α₁-adrenoceptor agonist methoxamine by increasing the anticontractile influence of NO. (a) Concentration-response relationships to methoxamine in the presence of the NO-synthase inhibitor L-NNA (100 µM) or its vehicle (H₂O, 50 µL) at pH 7.4 and pH 6.8. The numbers in brackets indicate the number of animals. * p < 0.05 (two-way ANOVA with Tukey’s multiple comparisons test). (b) Contractile effect of L-NNA at pH 7.4 and pH 6.8. # p < 0.05 (unpaired Student’s t-test).