Chronic hypoxia increases the NO contribution of acetylcholine vasodilation of the fetal guinea pig heart

To investigate the effect of chronic hypoxia (HPX) on vasodilation of the f etal heart, we exposed pregnant guinea pigs to room air or 12% O-2 for 4, 7 , or 10 days. We excised hearts from anesthetized fetuses (60 +/- 3 days; 6 5-day gestation = term) and measured changes in both the coronary artery pr essure of the isolated constant-flow preparation and endothelial nitric oxi de synthase (eNOS) mRNA of fetal ventricles. Dilator responses to cumulativ e addition (10(-9) -10(-5) M) of acetylcholine and sodium nitroprusside in prostaglandin F-2 alpha (5 x 10(-6) M)-constricted hearts were similar amon g normoxia (NMX), 4-, 7-, and 10-day HPX (control). Nitro-L-arginine (L-NA, 10(-4) M), a NOS inhibitor, inhibited maximal acetylcholine dilation of he arts exposed to 10-day HPX greater than NMX, 4-, and 7- day HPX. Hypoxia (a fter 7 and 10 days) increased eNOS mRNA of fetal ventricles compared with N MX and 4- day HPX. 4- Aminopyridine (3 mM), a voltage-dependent K+-channel inhibitor, inhibited acetylcholine- but not sodium nitroprusside-induced di lation of NMX and 10-day HPX hearts to a similar magnitude. Glibenclamide ( 10(-5) M), an ATP-sensitive K+-channel inhibitor, had no effect on vasodila tion. We conclude that chronic HPX increases the contribution of NO but doe s not alter K+-channel activation in response to acetylcholine- stimulated coronary dilation. Thus increases in NO production via upregulation of eNOS gene expression may be an adaptive response to chronic HPX in the fetal co ronary circulation.