Angiotensin I-converting enzyme (ACE) inhibition and nitric oxide (NO)-mediated antihypertensive effect of octaphlorethol A isolated from Ishige sinicola: In vitro molecular mechanism and in vivo SHR model

Angiotensin I-converting enzyme (ACE) inhibition and nitric oxide (NO) production are important factors that regulate blood pressure. In this study, the effects of octaphlorethol A (OPA) isolated from Ishige sinicola on ACE inhibition and NO production, the molecular mechanism underlying ACE inhibition, as well as its antihypertensive effect in spontaneously hypertensive rats (SHRs) were investigated. IC50 value of OPA against ACE was 59 µM. Molecular modelling studies indicated that the compound interacts with Cys370, Glu162, Glu376, Glu403, Glu411, Asp377, His383, His387, Tyr520, Arg522, Tyr523, and Lys511. In human endothelial cells, OPA increased endothelial nitric oxide synthase (eNOS) phosphorylation. We also demonstrated that these OPA-induced effects essentially depended on protein kinase B (Akt) and AMP-activated protein kinase (AMPK) activation. Furthermore, systolic blood pressure was reduced (21.9 mmHg in 6 h) by administration of the compound in SHRs. The results of this study suggested that OPA could be developed as a therapeutic agent for hypertension.