oxadiazoles and Pre-Eclampsia

We aimed to determine the effects of sildenafil in human umbilical artery preparation taken from preeclamptic or normal pregnant women, also to investigate underlying mechanisms in these effects.. Eighteen pregnant women with preeclampsia and 18 healthy pregnant women were involved. Relaxation responses of sildenafil in presence and absence of nitric oxide (NO) synthase inhibitor, N-[omega]-nitro-L-arginine methyl ester (L-NAME), and soluble guanylyl cyclase inhibitor, 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), were compared between the preeclampsia group and control group.. Sildenafil-induced relaxation responses were significantly attenuated in the presence of preeclampsia, L-NAME or ODQ, but not totally abolished. Interestingly, except with ODQ incubation, in all set of experiments maximal relaxation response was achieved by sildenafil.. These data indicate that sildenafil might effect vascular responsiveness of human umbilical artery through the involvement of NO/cyclic guanosine monophosphate (cGMP)-dependent and -independent pathways. Further investigations are needed to clarify the exact mechanisms.

Topics: Adolescent; Adult; Case-Control Studies; Endothelium, Vascular; Enzyme Inhibitors; Female; Guanylate Cyclase; Humans; In Vitro Techniques; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Oxadiazoles; Piperazines; Pre-Eclampsia; Pregnancy; Purines; Quinoxalines; Sildenafil Citrate; Sulfones; Umbilical Arteries; Vasodilation; Vasodilator Agents; Young Adult

S-nitrosoalbumin (SNO-Alb) is a major reservoir of releasable nitric oxide (NO) in plasma. In preeclampsia, a pregnancy-specific disorder associated with endothelial dysfunction, we previously found significant elevations in plasma SNO-Alb concentrations and decreased plasma ascorbate (Asc) levels. This increased SNO-Alb may result from low-plasma Asc if Asc, along with transition metals (eg, copper [Cu]) are necessary for release of NO from S-nitrosothiols. We propose that vasodilator effects of SNO-Alb, mediated by release of NO, are fully realized only when Asc/Cu availability is sufficient. Relaxation responses to SNO-Alb or the control reduced human serum albumin (SH-Alb), and responses to pooled plasma from normal or preeclamptic pregnancies were examined in isolated mouse arteries. Arteries preconstricted with phenylephrine were exposed to SNO-Alb or SH-Alb at physiologically relevant concentrations. When free Cu was added in excess (10 mumol/L), NO release was not dependent on Asc. However, when Cu was added at lower (physiological) levels, NO release was dependent on Asc. The addition of Asc and Cu to SNO-Alb stimulated vasodilatory responses in isolated arteries >90%, whereas no change in the SH-Alb (5%) response was observed. Preeclampsia plasma with higher levels of SNO-Alb caused arteries to relax 44.1+/-4.7%, whereas normal pregnancy plasma caused 11.9+/-4.2% relaxation (P=0.007). These data indicate that SNO-Alb alone or in plasma can act as a potent vasodilator, and that sufficient Asc/Cu promotes this action. We suggest that the higher circulating levels of SNO-Alb, in women with preeclampsia, reflect a deficiency in Asc/Cu-mediated release of NO from SNO-Alb.

Topics: Adult; Animals; Ascorbic Acid; Copper; Female; Humans; Mesenteric Arteries; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitroso Compounds; Oxadiazoles; Oxidative Stress; Phenylephrine; Pre-Eclampsia; Pregnancy; Quinoxalines; Serum Albumin, Bovine; Vasodilation

Topics: Benzyl Compounds; Blood Pressure; Diuresis; Edema; Female; Humans; Maternal-Fetal Exchange; Oxadiazoles; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Proteinuria; Uterus