Maturational changes in the regulation of pulmonary vascular tone by nitric oxide in neonatal rats

1 Centers for Gene Therapy, Perinatal Research, and Cardiovascular Medicine, Columbus Children's Research Institute, and Department of Pediatrics, The Ohio State University, Columbus, Ohio; and 2 Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, New Mexico Submitted 22 June 2006 ; accepted in final form 5 September 2007 Nitric oxide (NO) is an important regulator of vasomotor tone in the pulmonary circulation. We tested the hypothesis that the role NO plays in regulating vascular tone changes during early postnatal development. Isolated, perfused lungs from 7- and 14-day-old Sprague-Dawley rats were studied. Baseline total pulmonary vascular resistance (PVR) was not different between age groups. The addition of KCl to the perfusate caused a concentration-dependent increase in PVR that did not differ between age groups. However, the nitric oxide synthase (NOS) inhibitor N -nitro- L -arginine augmented the K + -induced increase in PVR in both groups, and the effect was greater in lungs from 14-day-old rats vs. 7-day-old rats. Lung levels of total endothelial, inducible, and neuronal NOS proteins were not different between groups; however, the production rate of exhaled NO was greater in lungs from 14-day-old rats compared with those of 7-day-old rats. Vasodilation to 0.1 µM of the NO donor spermine NONOate was greater in 14-day lungs than in 7-day lungs, and lung levels of both soluble guanylyl cyclase and cGMP were greater at 14 days than at 7 days. Vasodilation to 100 µM of the cGMP analog 8-(4-chlorophenylthio)guanosine-3',5'-cyclic monophosphate was greater in 7-day lungs than in 14-day lungs. Our results demonstrate that the pulmonary vascular bed depends more on NO production to modulate vascular tone at 14 days than at 7 days of age. The observed differences in NO sensitivity may be due to maturational increases in soluble guanylyl cyclase protein levels. nitric oxide synthase; pulmonary vascular resistance; isolated perfused lungs; soluble guanylyl cyclase; guanosine-3',5'-cyclic monophosphate Address for reprint requests and other correspondence: L. G. Chicoine, Center for Gene Therapy, Columbus Children's Research Institute, 700 Children's Drive, Rm. WA3021, Columbus, OH 43205 (e-mail: Louis.Chicoine{at}nationwidechildrens.org )