THE EFFECT OF NITRIC-OXIDE ON FETAL PULMONARY-ARTERY SMOOTH-MUSCLE GROWTH

Endothelium-derived nitric oxide (NO) relaxes fetal pulmonary arterial vessels through activation of guanylate cyclase and increasing smooth muscle cyclic guanosine 3', 5'-monophosphate (cGMP). Exogenous NO adm inistered as a gas at low concentrations shares this effect, decreasin g pulmonary artery resistance and increasing in pulmonary blood flow. NO, endogenously synthesized or inhaled as a gas, may affect cellular growth in the underlying pulmonary vascular smooth muscle media. We re port the effects of NO and cGMP upon DNA synthesis and proliferation o lf passaged pulmonary vascular smooth muscle cells from fetal rats. Sm ooth muscle cells from rat fetal pulmonary artery (RFPASM; 18-19 day g estation; term 21 days) were treated in culture with sodium nitropruss ide (SNP), isosorbide dinitrite (ISDN)-both NO-generating vasodilators -or 8-bromo-cGMP, a cell-permeant cGMP analog. All agents inhibited th ymidine uptake at concentrations of 10(-3)-10(-2) M. Lower concentrati ons (10(-5)-10(-4) M) of SNP and ISDN increased [H-3]- thymidine ([H-3 ]TdR) uptake, an effect not seen with cGMP at similar concentrations. Exposing RFPASM to authentic NO gas in a deoxygenated medium inhibited [H-3]TdR uptake only. NO appears to have a biphasic effect on DNA syn thesis in passaged RFPASM, with stimulation at micromolar concentratio ns and inhibition at higher levels. NO may thus alter vascular smooth muscle growth and pulmonary vascular remodeling in conditions complica ted by pulmonary hypertension and treated with inhaled NO. (C) 1995 Ac ademic Press,Inc.