The Leaf Aqueous and Ethanolic Extracts of Tricalysia okelensis Hiern. (Rubiaceae) Reverse L-NAME-Induced Hypertension, Cardiac, and Vascular Remodeling in Rats.

Arterial hypertension is a worldwide challenging medical condition that continues to raise havoc despite existing treatments, prompting the need to develop new medicine. In a pilot study, we demonstrated that Tricalysia okelensis exhibits a vasorelaxant effect. This study evaluates the antihypertensive effect of the leaf aqueous (AETO) and ethanolic (EETO) extracts of T. okelensis against L-NAME-induced-hypertension, cardiac, and vascular remodeling. AETO and EETO underwent LC-MS/MS to identify potential metabolites responsible for the activity. Adult male Wistar rats were orally administered L-NAME (30 mg/kg/day) for 3 consecutive weeks. L-NAME administration was continued either alone or with captopril (20 mg/kg/day, p.o.), AETO, or EETO at doses of 85 and 170 mg/kg/day for another 3 consecutive weeks, while the naive group received the vehicle for 6 weeks. Blood pressure (BP) and heart rate were recorded before and weekly after the beginning of each treatment. Plasma angiotensin II (Ang II), serum nitric oxide (NO), lactate dehydrogenase (LDH), cardiac myeloperoxidase (MPO), and NO were assessed at the end of the experiment. Sections from the heart and aorta were analyzed for histological changes and immunohistochemical expression of atrial natriuretic peptide (ANP), endothelial (eNOS), and inducible (iNOS) nitric oxide synthases. AETO and EETO are rich in flavonoids and phenolic compounds. LC-MS/MS-based molecular networking enabled the putative annotation of several polyphenolic metabolites, including chlorogenic acid, neochlorogenic acid, rutin, quercetin derivatives, kaempferol derivatives, isorhamnetin, avicularin, and guaijaverin. L-NAME significantly increased BP and heart rate, Ang II, LDH, cardiac MPO, and heart weight (p < 0.05 - 0.001) while decreasing NO (p > 0.05). AETO and EETO reversed these alterations and also inhibited L-NAME-induced immune cell infiltration, fibrosis, cardiac and vascular eNOS downregulation, and iNOS overexpression, as well as ANP upregulation in heart tissue. AETO and EETO exhibit antihypertensive and anti-remodeling effects probably by modulating the renin-angiotensin system, improving endothelial function, and reducing inflammation and fibrosis.