The antihypertensive and cardiovascular effects of lawsone methyl ether in high salt-induced hypertensive rats are...

Lawsone methyl ether (LME), a plant-based naphthoquinone, exhibits remarkable antihyperlipidemic, antioxidant, and anti-inflammatory properties, suggesting its potential evaluation as an antihypertensive drug. Thereby, its antihypertensive effects were assessed via an in vivo invasive procedure, alongside in vitro and in silico investigations, revealing its possible cardiovascular mechanisms. Results revealed that intravenous administration of LME at 0.0001, 0.0003, 0.001, 0.003, and 0.01 mg/kg induced a significant fall (5-42 mmHg) in mean arterial pressure (MAP). This fall in MAP was observed in normotensive as well as hypertensive rats, pre-treated with atropine and Nω-nitro-L-arginine methyl ester (L-NAME), suggesting the association of muscarinic receptors linked to nitric oxide (NO) pathway. Moreover, LME-induced vasorelaxation in the isolated aortic rings was significantly (p < 0.001) reduced by denudation, atropine, or L-NAME pre-treatment. Nonetheless, LME completely reversed the phenylephrine (PE), high K⁺ and angiotensin-II-induced contractions, causing a rightward shift in Ca⁺² concentration response curves, identical to that of verapamil. This vasorelaxant activity was substantially ameliorated by 4-aminopyridine. Aortic rings pre-incubated with LME suppressed the contractions induced by PE in Ca⁺²-free medium, indicating inhibitory effect on internal Ca⁺²-release. In isolated atrial strips, LME induced atenolol-sensitive negative inotropic and chronotropic effects. Molecular docking uncovered cardiovascular targets for LME including NO synthase, muscarinic receptors, voltage-dependent Ca⁺² channels, β-adrenergic receptors, K⁺ channels, and angiotensin-converting enzyme, supporting its potential role as a multi-target antihypertensive agent. In conclusion, LME delivered promising antihypertensive and cardio-suppressive effects by reducing peripheral resistance via muscarinic receptor-linked NO release, Ca⁺² antagonism, inhibiting Ca⁺² efflux, and reducing cardiac output.