Effects of fast versus slow-releasing hydrogen sulfide donors in hypertension in pregnancy and fetoplacental growth restriction.

Hydrogen sulfide (H2S) is a vasorelaxant gas with therapeutic potential in several diseases. However, effects of H2S donors in hypertensive pregnancy complicated by feto-placental growth restriction are unclear. Therefore, we aimed to examine and compare the effects of fast-releasing H2S donor (sodium hydrosulfide-NaHS) and slow-releasing H2S donor (GYY4137) in hypertension-in-pregnancy. Pregnant rats were distributed into four groups: normal pregnancy (Norm-Preg), hypertensive pregnancy (HTN-Preg), hypertensive pregnancy + NaHS (HTN-Preg + NaHS), and hypertensive pregnancy + GYY4137 (HTN-Preg + GYY). Systolic blood pressure, plasma H2S levels, fetal and placental weights, number of viable fetuses, litter size, and endothelium-dependent vasodilation were examined. Also, oxidative stress was assessed in placenta. We found that GYY4137 attenuated hypertension on gestational days 16 and 18, while NaHS presented antihypertensive effect only on gestational day 18. GYY4137, but not NaHS, increased plasma H2S levels. Greater fetal and placental weights were found with GYY4137 than NaHS treatment. Also, HTN-Preg + NaHS presented further reductions in placental weights when compared to HTN-Preg group. Number of viable fetuses and litter size presented no significant changes. GYY4137 reduced placental oxidative stress caused by hypertension, while greater increases in oxidative stress were found in HTN-Preg + NaHS than HTN-Preg group. Hypertensive pregnancy caused impaired endothelium-dependent vasodilation, while GYY4137 and NaHS treatments blunted endothelial dysfunction. Endothelium-dependent vasodilation was completely blocked by the nitric oxide synthase inhibitor. We conclude that slow-releasing H2S donor GYY4137 is advantageous compared with fast-releasing H2S-donor NaHS to attenuate hypertension-in-pregnancy and to protect against feto-placental growth restriction and oxidative stress.

Placental nitric oxide formation and endothelium-dependent vasodilation underlie pravastatin effects against angiogenic imbalance, hypertension in pregnancy and intrauterine growth restriction.

Pre-eclampsia and hypertensive disorders of pregnancy are frequently associated with foeto-placental growth restriction, and that may be triggered by angiogenic imbalance and endothelial dysfunction. Impaired nitric oxide (NO) bioavailability seems to be involved in these pathophysiological changes observed in hypertensive pregnancy. Pravastatin has shown efficacy and to be safe during hypertension in pregnancy. However, NO involvement in pravastatin effects during maternal hypertension and foeto-placental development is unclear. Therefore, we aimed to examine pravastatin effects on placental NO formation, endothelium-dependent vasodilation, systolic blood pressure and foeto-placental development in hypertensive pregnant rats. Biochemical determinants of angiogenesis and oxidative stress were also assessed. Pregnant rats were distributed into four groups: normal pregnancy (Norm-Preg), pregnancy+pravastatin (Preg-Prava), hypertensive pregnancy (HTN-Preg) and hypertensive pregnancy+pravastatin (HTN-Preg+Prava). Our results showed that pravastatin treatment blunts hypertension and foeto-placental growth restriction. Also, increases in placental NO levels were found in the HTN-Preg+Prava group. Pravastatin prevents impaired endothelium-dependent acetylcholine-induced vasodilation, exacerbated contractile response to phenylephrine and increases in oxidative stress in the HTN-Preg+Prava group. Increased soluble fms-like tyrosine kinase-1-to-placental growth factor (sFlt-1/PlGF) ratio is reversed by pravastatin treatment in the HTN-Preg+Prava group. We conclude that NO formation and endothelium-dependent vasodilation underlie pleiotropic effects associated with pravastatin treatment against hypertension in pregnancy, intrauterine growth restriction, vascular dysfunction and angiogenic imbalance.

Clinical and Experimental Evidences of Hydrogen Sulfide Involvement in Lead-Induced Hypertension.

Lead- (Pb-) induced hypertension has been shown in humans and experimental animals and cardiovascular effects of hydrogen sulfide (H2S) have been reported previously. However, no studies examined involvement of H2S in Pb-induced hypertension. We found increases in diastolic blood pressure and mean blood pressure in Pb-intoxicated humans followed by diminished H2S plasmatic levels. In order to expand our findings, male Wistar rats were divided into four groups: Saline, Pb, NaHS, and Pb + NaHS. Pb-intoxicated animals received intraperitoneally (i.p.) 1st dose of 8 µg/100 g of Pb acetate and subsequent doses of 0.1 µg/100 g for seven days and sodium hydrosulfide- (NaHS-) treated animals received i.p. NaHS injections (50 µmol/kg/twice daily) for seven days. NaHS treatment blunted increases in systolic blood pressure, increased H2S plasmatic levels, and diminished whole-blood lead levels. Treatment with NaHS in Pb-induced hypertension seems to induce a protective role in rat aorta which is dependent on endothelium and seems to promote non-NO-mediated relaxation. Pb-intoxication increased oxidative stress in rats, while treatment with NaHS blunted increases in plasmatic MDA levels and increased antioxidant status of plasma. Therefore, H2S pathway may be involved in Pb-induced hypertension and treatment with NaHS exerts antihypertensive effect, promotes non-NO-mediated relaxation, and decreases oxidative stress in rats with Pb-induced hypertension.