Cyclic guanosine 3′3′ monophosphate concentrations in pre‐eclampsia: effects of hydralazine

Abstract

Objective To elucidate the role of the L-arginine:nitric oxide pathway in pregnancy and preeclampsia.Participants Pregnant women (nulliparous, age < 25 years). Normotensive pregnancy (n = 22) was defined when blood pressure remained at levels of < 120/80mmHg and there was no proteinuria. Women with pre-eclampsia (n = 22) had blood pressure measurements of > 140/90 mmHg and proteinuria of > 300 mg/l. Nonpregnant normotensive women (n = 22) were studied as controls. Study Design Blood samples were taken for measurements of ionised calcium, atrial natriuretic factor, cyclic guanosine 3'5' monophophate (GMP), arginine and asymmetric dimethylarginine. Urine samples were collected for determination of cyclic GMP excretion. Cyclic GMP concentrations were also determined in 12 women with severe pre-eclampsia before and after treatment with hydralazine.Results L-arginine, asymmetric dimethylarginine and atrial natriuretic factor were not different in any group. Cyclic GMP concentrations in plasma [0.94 (SD 0-23) nM] as well as in urine [ 5 0 1 (SD 15.7) pM] were increased significantly ( P < 0.05) in normal pregnancy compared to nonpregnant controls [plasma mean 0.46 (SD 0.12) nM and urine mean 18.4 (SD 10.3) pM], but not in the pre-eclampsia group [plasma mean 0.48 (SD 0.10) nM and urine mean 24.1 (SD 14.5) pM]. Concentrations of cyclic GMP in plasma and urine increased significantly ( P < 0.05) in women treated with hydralazine. Conclusions The differences in cyclic GMP concentrations may reflect differences in nitric oxide production. Hydralazine increases cyclic GMP concentrations in severely pre-eclamptic women. This action could explain the antihypertensive effect of hydralazine.Recently it was proposed4 that an increased

eNOS haplotypes affect the responsiveness to antihypertensive therapy in preeclampsia but not in gestational hypertension

“…32,33 In addition, hydralazine, which is widely used in the treatment of PE, enhanced cyclic guanosine 3 0 5 0 monophosphate concentrations in preeclamptic pregnant women, thus suggesting that this drug produces its effects by activating NO synthesis. 34 Therefore, it is possible that the drugs used to treat hypertensive disorders of pregnancy produce their effects by enhancing NO bioavailability, thus counteracting the impaired NO formation that has been reported in these hypertensive conditions. [12][13][14] Our findings reported here are consistent with this suggestion and also indicate that combinations of eNOS polymorphisms (haplotypes) affect the responsiveness to drugs used in the therapy of PE patients.…”

Endothelial NO Synthase Genotype and Risk of Preeclampsia

“…26 This increase in NO availability is thought to be responsible for maternal vasodilation required to accommodate the increased circulating volume during pregnancy without a rise in blood pressure. In preeclampsia, this adaptation fails, endothelial dysfunction occurs, 27 blood pressure rises, and proteinuria develops.…”

Impact of Pregnancy on Underlying Renal Disease

“…Both plasma and urinary levels of inorganic nitrite and nitrate (NO x ; oxidation products of NO) and cyclic guanosine monophosphate (cGMP) (a major second messenger of NO) increase during pregnancy in rats, [13][14][15] suggesting an increase in total systemic NO production is occurring. In women, 24-hour urinary excretions of cGMP and plasma cGMP increase in normal pregnancy, 16,17 although the persistence of this increased cGMP excretion long after delivery 16 may reflect the prolonged postpartum rise in plasma atrial natriuretic peptide, 18 rather than stimulation by NO. The findings with plasma and urinary NO x excretions have been more variable, 19 and the only study conducted using a controlled low NO x intake (a requirement for interpretation of NO x values in the context of NO activity 20 ) reported no elevation in plasma or 24-hour urinary NO x excretion in late pregnancy versus the nonpregnant state.…”