Differential Effects of Chronic Hypoxia on Basal and Agonist‐Induced NO‐Dependent Pulmonary Vasodilation in Neonatal Rats

Abstract

Endothelial dysfunction contributes to chronic hypoxia (CH)‐induced pulmonary hypertension (PH) in neonates. However, whether basal and stimulated endothelium‐derived nitric oxide (EDNO)‐dependent pulmonary vasodilation are similarly impaired in neonatal PH is unclear. We hypothesized that CH attenuates EDNO‐dependent pulmonary vasodilation both basally and in response to receptor activation in a neonatal rat model of PH. To test this hypothesis, we assessed effects of the NO synthase inhibitor Nω‐nitro‐L‐arginine (L‐NNA; 300 μM) on baseline pulmonary vascular resistance (PVR) in salt‐perfused lungs (in situ) from 2‐wk‐old control and CH (2 wk at 0.5 atm) rats. The contribution of active tone to PVR was assessed by examining responses to exogenous NO (spermine NONOate, 100 μM). Lungs from CH rats showed greater baseline PVR compared to controls (p<0.05) in the absence of L‐NNA. This response to CH reflected active tone, whereas no basal tone was observed in control lungs. Consistent with our hypothesis, L‐NNA modestly increased PVR in the control group (p<0.05 vs. vehicle), but had no effect in lungs from CH neonates. We next examined EDNO‐dependent vasodilatory responses to arginine vasopressin (AVP, 25 nM) in U‐46619‐constricted lungs. Surprisingly, lungs from CH rats showed augmented responses to AVP compared to controls (p<0.05). L‐NNA abolished AVP responses in both groups (p<0.05 vs vehicle). We conclude that CH 1) increases basal PVR in part through vasoconstriction, and 2) impairs EDNO‐dependent pulmonary vasodilation under basal conditions, but paradoxically augments AVP‐induced EDNO‐dependent vasodilation in a neonatal rat model of PH.