INHIBITION OF NITRIC-OXIDE SYNTHESIS INCREASES THE SECRETION OF ENDOTHELIN-1 IN-VIVO AND IN CULTURED ENDOTHELIAL-CELLS

The aim of this study is to investigate the effects of nitric oxide, f ormed from L-arginine, on the production of endothelin-1 in vivo and i n cultured endothelial cells. In mechanically ventilated abesthetized dogs (n=5), mean pulmonary arterial pressure (PAPm) and pulmonary vasc ular resistance (PVR) during hypoxic ventilation (FIO2=0.10) was 25+/- 3.1 kPa and 68.7+/-10.2 kPa.s/L respectively. N-G-nitro-L-arginine met hylester (L-NAME), an inhibitor of nitric oxide synthase, increased th e peak value of PAPm and PVR during hypoxic ventilation to 36.6+/-4.7 kPa and 158.4+/-25 kPa.s/L and its effect lasted for 2-3 hours. Meanwh ile, plasma endothelin-1 level in the femoral artery increased by 20.9 +/-7.1, 25.6+/-7.7, 28.6+/-7.9 pg/ml at the 60 th, 120th, 180th minute after the injection of L-NAME respectively (P<0.05 vs hypoxic control before the injection). In cultured endothelial cells from umbilical v eins, endothelin-1 level of culture medium in control group was 35.1+/ -5.9 pg/10(5) cells/ml (n=9). L-NAME increased endothelin-1 level to 4 2.8+/-4.9pg / 10(5) cells / ml (n=9, P<0.05) in case of 10(-11) mol / L and to 43.0+/-4.7 pg / 10(5) cells / ml in case of 10(-7) mol/L (n=9 , P<0.05). These findings indicate that endogenous nitric oxide is an inhibitory modulator of hypoxic pulmonary vasoconstriction and that ni tric oxide inhibits the production of endothelin-1 in vivo and in cult ured vascular endothelial cells.