Endothelium-dependent and -independent mechanisms of vasorelaxation by corticotropin-releasing factor in pregnant rat uterine artery

Corticotropin-releasing factor (CRF), a potent vasorelaxant, is increased t remendously during human pregnancy. Placenta is the main source for this in crease. CRF is thought to be important in modulating vascular resistance an d uteroplacental blood flow during pregnancy. Here we investigated pathways mediating a vasorelaxant effect of CRF in the uterine artery. Two-millimet er segments of uterine artery (o.d. 300-400 mu m) from day 18 pregnant rats were mounted in a small vessel myograph and precontracted with norepinephr ine, and relaxation responses to CRF were studied. CRF relaxed the uterine artery in a concentration-dependent manner. Relaxation of uterine artery by GRF was abolished completely by alpha-helical CRF 9-41 (CRF antagonist, 1 mu mol) and partially by removal of endothelium, N omega-nitro-L-arginine m ethyl eater (nitric oxide synthase inhibitor, 0.1 mmol), 6-anilino-5,8-quin olinedione (guanylate cyclase inhibitor, 10 mu mol), or thiopental/miconazo le (cytochrome P-450 inhibitors, 0.3 mmol/30 mu mol), but remained unaffect ed by indomethacin (cyclo-oxygenase inhibitor, 10 mu mol). Relaxation was a lso inhibited when depolarizing solution (K+, 120 mmol) was used for precon traction. In deendothelized preparations, relaxation was not inhibited by 9 -tetrahydro-2-furanyl-9H-purin-6-amine (adenylate cyclase inhibitor, 0.2 mm ol), glibenclamide (adenosine triphosphate-dependent K+ channel blocker, 10 mu mol), tetrabutyl ammonium (nonspecific K+ channel blocker, 1 mmol), nit rendipine (voltage-gated Ca++ channel blocker, 1 mu mol), or when vessels w ere precontracted with depolarizing solution. CRF causes vasorelaxation by receptor-operated, endothelium-dependent and -independent pathways. The end othelium-dependent relaxation is mediated by nitric oxide-cyclic guanosine monophosphate pathway and endothelium-derived hyperpolarizing factor but no t prostacyclin. However, cyclic adenosine monophosphate, K+ channels, or Ca ++ channels are not involved in endothelium-independent vasorelaxation by C RF.