nNOS Inhibitors(AKAVA)

The regulation of vascular tone plays a fundamental role in blood pressure homeostasis and still represents a significant challenge in clinical practice. Boldine, a naturally occurring alkaloid from Peumus boldus , has emerged as a compound of interest due to its therapeutic potential. This study explored boldine's vasorelaxant effects on aortas of normotensive (NTR) and spontaneously hypertensive (SHR) rats. N ω‐Nitro‐ l ‐arginine methyl ester (l ‐NAME) (a nitric oxide synthase inhibitor), ODQ (a soluble guanylate cyclase inhibitor), and tetraethylammonium (TEA) (a nonselective K⁺ channel blocker) exerted a modest inhibitory effect, causing a rightward shift in the boldine‐induced relaxation curves without significantly affecting the maximal relaxation. Boldine affected both endoplasmic reticulum‐based IP 3 and ryanodine receptors (RyRs) and transmembrane calcium channels in NTR aortas, whereas in SHR aortas, its actions were linked to IP 3 and RyRs receptors. These findings indicate that boldine's vasorelaxant effects may contribute to vascular tone regulation through modulation of Ca 2 ⁺ channels.

Preeclampsia (PE) represents a severe gestational disorder defined by the development of hypertension accompanied by systemic organ dysfunction during pregnancy, affecting 3 %-5 % of pregnancies globally and contributing markedly to maternal-perinatal mortality. Placental oxidative stress (OS) is a key pathophysiological driver. A well-known antidiabetic drug metformin (MET) possesses anti-inflammatory and antioxidant properties, suggesting its therapeutic potential for PE; however, its molecular mechanisms remain unclear.

A PE-like rat model was established using N(ω)-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor. Pregnant Sprague-Dawley rats (n = 30) were divided into the control, l-NAME, and l-NAME + MET groups. We evaluated clinical parameters (blood pressure, proteinuria, placental, and renal histopathology), angiogenic factors (soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF)), and OS markers (malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT)). Nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch Like ECH Associated Protein 1 (Keap1) signaling analysis employed western blotting, immunohistochemistry, immunofluorescence and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Molecular docking and dynamics simulations explored MET's interaction with the Nrf2-Keap1 complex.

Significant reductions in systolic blood pressure, proteinuria, and placental-renal histopathological damage, along with improved fetal weight, were observed with MET treatment. It normalized the sFlt-1/PlGF ratio and boosted antioxidant enzyme activities. MET promoted nuclear Nrf2 translocation, upregulated NAD(P)H:quinone oxidoreductase 1 (NQO1), and suppressed Keap1. Molecular modeling suggests that MET-induced destabilization of the Nrf2-Keap1 complex facilitates Nrf2 dissociation.

MET mitigates l-NAME induced oxidative stress by activating the Nrf2 signaling pathway, highlighting its potential as a novel therapeutic target for PE management.