EFFECT OF INHIBITION OF NITRIC-OXIDE SYNTHASE AND GUANYLATE-CYCLASE ON HYDRALAZINE-INDUCED VASODILATATION OF THE HUMAN FETAL-PLACENTAL CIRCULATION

1. The vasodilator effects of hydralazine in vitro, using the Krebs' p erfused human placental lobule was studied. Single placental lobules w ere bilaterally perfused (maternal and fetal sides 5 mL/min each, 95% O-2, 5% CO2, 37 degrees C) and changes in fetal arterial pressure (FAP ) and venous outflow (VO) were recorded. 2. Submaximal vasoconstrictio n was induced by KCl (20-50 mmol/L), which increased basal FAP from 22 .8 +/- 1.7 to 91.3 +/- 3.9 mmHg (n = 9, P < 0.001), and decreased VO f rom 4.1 +/- 0.6 to 0.2 +/- 0.1 mL/min (n = 6, P < 0.01). 3. Hydralazin e caused vasodilatation (IC50 1.9 mmol/L, n = 9) and increased VO in t he presence of KCl-induced vasoconstriction. 4. Infusion of N-omega-ni tro-L-arginine (100 mu mol/L) to block nitric oxide synthase caused th e basal FAP to increase from 30.9 +/- 5.9 to 47.4 +/- 6.7 (n = 6, P < 0.05) and significantly potentiated hydralazine-induced vasodilatation (n = 7, P < 0.05). 5. The soluble guanylate cyclase inhibitor LY 8358 3 (6-anilino-5,8-quinolinedione) (1 mu mol/L) significantly antagonize d the vasodilatation produced by hydralazine (n = 5, P < 0.05). 6. Thu s, hydralazine appears to activate guanylate cyclase, leading to incre ased cyclic GMP in fetal arterial vascular smooth muscle to cause vaso relaxation. No evidence was obtained to suggest that hydralazine exert ed its action by either releasing nitric oxide from endothelial cells in the placenta or acting as a nitric oxide donor.