Increases in placental nitric oxide, but not nitric oxide‐mediated relaxation, underlie the improvement in placental efficiency and antihypertensive effects of hydrogen sulphide donor in hypertensive pregnancy

Abstract

Dysregulation of hydrogen sulphide (H S) producing enzymes has been related to hypertensive pregnancy, and H S donor, sodium hydrosulphide (NaHS) exerts antihypertensive effects, modulates angiogenic factors production and acts as an antioxidant. Moreover, reduction in nitric oxide (NO) bioavailability is related to hypertensive pregnancy and H S may interact with NO, modulating its production. We aimed to investigate the NaHS effects in hypertension-in-pregnancy and also in feto-placental parameters. Female Wistar rats (200-250 g) were mated and desoxycorticosterone acetate injections followed by replacement of water by 0.9% saline solution were used to induce hypertensive pregnancy. Rats were divided into four groups: normal pregnant (Norm-Preg), pregnant + NaHS (Preg+NaHS), hypertensive pregnant (HTN-Preg) and HTN-Preg+NaHS. Systolic blood pressure was increased in HTN-Preg and this increase was blunted in HTN-Preg+NaHS. Fetal and placental weights were decreased in HTN-Preg animals, while fetal growth restriction was improved in HTN-Preg+NaHS. Placental weight was lower in HTN-Preg+NaHS than in HTN-Preg; however, placental efficiency was re-established in HTN-Preg+NaHS rats. We observed that a partial contribution of placental NO, but not changes in anti-angiogenic factors may mediate the increases in placental efficiency in HTN-Preg+NaHS. HTN-Preg presented thoracic aorta hyperreactivity to phenylephrine while NaHS treatment blunted this hyperreactivity, which seems not to be related to NO-mediated relaxation induced by acetylcholine. Therefore, changes in vascular responsiveness promoted by NaHS treatment may underlie the beneficial effects in systolic blood pressure and feto-placental parameters in our study.

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

“…In line with previous findings, foeto‐placental growth restriction with concomitant elevations in systolic blood pressure, in plasma sFlt‐1/PlGF ratio and in oxidative stress was observed here (HTN‐Preg group). Also, we found impaired endothelium‐mediated vasodilation in response to acetylcholine and hyper‐reactivity in the contractile response to phenylephrine in thoracic aorta rings of the HTN‐Preg group, as previously reported . In addition, although KCl‐induced contraction responses suggest that vascular calcium influx through voltage‐gated calcium channels could not be behind hyper‐reactive response to phenylephrine observed in the HTN‐Preg group, it is possible that phenylephrine had further activated calcium influx through receptor and store‐operated calcium channels, and thus, a greater calcium influx could have occurred in HTN‐Preg rats.…”

“…Briefly, conscious rats were first acclimated in a quiet room, conditioned and restrained in a warm‐box (Insight, Ribeirao Preto, Sao Paulo, Brazil, catalogue #EFF‐307) at 40°C for 5‐10 min. Systolic blood pressure was determined as the average of the cuff inflation–deflation (3‐6 cycles) by a trained operator . Measurements on gestational days 14, 16 and 19 were performed 3 hr before drug or saline administrations.…”

“…In order to investigate endothelial function, vascular tissues were pre‐contracted with PHE (10 −6 M) followed by increasing concentrations of acetylcholine (ACh, 10 −9 to 10 −4 M). Participation of endothelium‐dependent NO in vascular relaxation was evaluated in concentration‐response curves to ACh obtained in the presence of Nω‐nitro‐ l ‐arginine methyl ester ( l ‐NAME, 3 × 10 −4 mol/L), added in the last 30‐minutes stabilization period . Concentration‐contraction curves were constructed, and the maximal response to PHE was recorded.…”

Reductions of Circulating Nitric Oxide are Followed by Hypertension during Pregnancy and Increased Activity of Matrix Metalloproteinases-2 and -9 in Rats

“…In addition, we previously showed that L-NAME-induced hypertension in late pregnant rats triggered the increases in MMP-2 and -9 activities in placenta and MMP-2 in uterus and these changes were associated with angiogenic imbalance which was featured by increase in soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PLGF) [77]. Moreover, we also observed in another previous investigation that increases in placental NO levels underlie the improvement in placental efficiency in late hypertensive pregnant rats [86].…”

Potential role of hydrogen sulfide in diabetes-impaired angiogenesis and ischemic tissue repair

“…Several lines of evidence indicate that H 2 S has a role in the regulation of vascular tone. H 2 S induced vascular relaxation in aorta [ [78] , [79] , [80] ], gastric artery [ 81 ], mesenteric artery [ 5 , 82 ], and internal mammary artery [ 83 ]. Accumulative evidence indicate that H 2 S is an EDHF [ 5 , [17] , [18] , [19] , [20] , 82 , [84] , [85] , [86] ].…”