Role of nitric oxide in regulating neonatal porcine pulmonary artery smooth muscle cell proliferation

Nitric oxide (NO), which is known to inhibit systemic vascular smooth muscl e cell proliferation, is used in the management of neonatal pulmonary hyper tension. Our objectives were to determine: (1) if endogenous NO production by neonatal porcine pulmonary artery smooth muscle cells (PASMCs) varied wi th oxygen tension in vitro, and (2) the effect of exogenous NO and inducibl e NO synthase (iNOS) stimulators and inhibitors on PASMC proliferation and apoptosis. PASMCs were exposed to different conditions (varying PO2, NO don ors and scavengers, iNOS stimulators and inhibitors) and proliferation, apo ptosis, and cyclic guanosine 5 '-monophosphate (cGMP) assessed. PASMCs prol iferated best between 5 and 10% O-2 but cGMP levels were similar at all oxy gen levels. NO donors (S-nitroso-N-acetyl-penicillamine, NOC-12, NOC-18) in hibited PASMC proliferation in a dose-dependent manner with associated cGMP increases, while NO scavengers (carboxy-PTIO), iNOS stimulators (interleuk in-1 beta, lipopolysaccharide), and iNOS inhibitors (aminoethylisothiourea) did not affect proliferation or cGMP. No changes in apoptosis were found a t the concentrations of NO donors or iNOS stimulators used. These results s uggest that while exogenous NO inhibits PASMC proliferation, endogenous NO may not regulate proliferation during changes in oxygen tension or cytokine levels. Endothelial derived and inhaled NO may attenuate smooth muscle hyp erplasia and vascular remodeling. Inducible NOS in porcine PASMCs appears r esistant to stimulation with interleukin-1 beta or lipopolysaccharide. The mechanisms underlying hypoxia-mediated changes in PASMC proliferation requi re investigation.