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 administered as a gas at low concentrations shares this effect, decreasing 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 report the effects of NO and cGMP upon DNA synthesis and proliferation of passaged pulmonary vascular smooth muscle cells from fetal rats. Smooth muscle cells from rat fetal pulmonary artery (RFPASM; 18-19 day gestation; term 21 days) were treated in culture with sodium nitroprusside (SNP), isosorbide dinitrite (ISDN)--both NO-generating vasodilators--or 8-bromo-cGMP, a cell-permeant cGMP analog. All agents inhibited thymidine uptake at concentrations of 10(-3)-10(-2) M. Lower concentrations (10(-5)-10(-4) M) of SNP and ISDN increased [3H]-thymidine ([3H]TdR) uptake, an effect not seen with cGMP at similar concentrations. Exposing RFPASM to authentic NO gas in a deoxygenated medium inhibited [3H]TdR uptake only. NO appears to have a biphasic effect on DNA synthesis in passaged RFPASM, with stimulation at micromolar concentrations and inhibition at higher levels. NO may thus alter vascular smooth muscle growth and pulmonary vascular remodeling in conditions complicated by pulmonary hypertension and treated with inhaled NO.
Thomae
K R
KR
Department of Surgery, University of North Carolina at Chapel Hill 27599-7210, USA.
Nakayama
D K
DK
Billiar
T R
TR
Simmons
R L
RL
Pitt
B R
BR
Davies
P
P
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000187:drug effects*; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000196:embryology; D009569:Nitric Oxide / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D011247:Pregnancy; D011651:Pulmonary Artery / Q000166:cytology / Q000196:embryology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
D014316:Tritium; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D004247:DNA; D006152:Cyclic GMP; D007548:Isosorbide Dinitrate; D013936:Thymidine