ENDOTHELIUM-DERIVED RELAXING FACTOR - EVIDENCE THAT IT REGULATES PULMONARY VASCULAR-RESISTANCE IN THE ISOLATED NEONATAL GUINEA-PIG LUNG

Endothelium-derived relaxing factor (EDRF), believed to be nitric oxide or a compound that releases nitric oxide, has been previously identified in the pulmonary and systemic vasculature of the newborn guinea pig using isolated arterial rings. The aim of our study was to determine if EDRF regulates vasomotor tone at the level of resistance vessels in the neonatal pulmonary circulation. Isolated lungs from guinea pigs (1-3 d old, n = 4-8/protocol) were ventilated with room air and perfused with a Krebs-Henseleit solution containing albumin at a constant flow. Angiotensin II (AII, 6 nM) was added to the perfusate to give a stable elevation in mean pulmonary artery pressure (PAP) from 7.0 +/- 1.1 to 19.7 +/- 1.5 torr, a 182 +/- 32% (mean +/- SEM) increase above baseline. Addition of bradykinin (BK, 10 nM) or L-arginine (2 mM) markedly reduced the AII-induced elevation in PAP. At the steady state response to BK (33% above baseline), addition of Hb (10-mu-M, binds EDRF), N(G)-monomethyl-L-arginine (NMA, 100-mu-M, blocks EDRF production), NMA (200-mu-M), or NMA + Hb, reversed the effect of BK to the following levels of PAP above baseline: 77 +/- 5, 94 +/- 24, 163 +/- 20, or 246 +/- 25%, respectively (p < 0.05). Indomethacin had no effect on BK-induced vasodilation. In separate studies, NMA (200-mu-M) increased baseline PAP by 46 +/- 13% and NMA pretreatment raised the AII-pressor response (AII 6 nM) from 133 +/- 49 to 306 +/- 65% above baseline PAP. NMA (200-mu-M) pretreatment also inhibited the dilator action of submaximal doses of BK on the AII-induced elevation of PAP. We conclude that, in the isolated neonatal guinea pig lung, EDRF plays an important role in the: 1) control of baseline PAP, 2) vasoreactivity of AII, and 3) dilator mechanism of BK, EDRF may play an important role in the pulmonary hemodynamic adjustments at birth.