Effets d’un extrait aqueux de Fagara tessmannii Engl. (Rutaceae) sur quelques altérations cardiovasculaires chez le rat.

Abstract

Cardiovascular disease remains the leading cause of early death and disability worldwide. The pandemic increase and the difficulties in the management of risk factors such as arterial hypertension, dyslipidemia, insulin resistance and obesity, and / or their cardiovascular complications constitute one of the millennium health problems and a heavy burden for lowincome countries. However, these countries use traditional medicine. F. tessmannii is a Rutaceae used in folk medicine in Cameroon to treat several conditions including tumors, inflammation, heart disease and high blood pressure. The aim of this work was to evaluate the hypotensive and vasorelaxant activities of the stem bark aqueous extract of F. tessmannii and the effects of this extract on some cardiovascular risk alterations linked to arterial hypertension and obesity. In the first part of this work, the hypotensive effects of the plant extract (5, 10, 20, 30, and 40 mg.kg-1, iv) in acute administration were evaluated by the invasive method in anesthetized rats. The effect of the dose of 30 mg.kg-1 was evaluated in the presence of some pharmacological antagonists. In vitro, the effects of the plant extract on isolated rat aorta rings with and without endothelium were also evaluated in the absence and then in the presence of some antagonists. In the second part of this work, two animal models were used to explore the effects of the plant extract on high BP and some metabolic alterations with cardiovascular risks. The extract was administered for 21 days during (preventive study) or after (curative study) the essential hypertension-induced by the inhibition of NO - Synthase by L - NAME (25 mg.kg- 1, ip). Hemodynamic parameters were recorded. An analysis of lipid profile, levels of protein, albumin, activities of lactate dehydrogenase, alkaline phosphatase, ALT, AST and gamma- GT, levels of creatinine, uric acid and K+ and Na+ ions were assessed. Target organ homogenates were used to measure catalase activity, the concentration of reduced glutathione, malonyl dialdehyde and nitrites. Histomorphometry of the aorta was performed using H&E staining. An examination of the microarchitecture of the aorta and heart was performed using H&E and AFOG - Trichrome stains. Metabolic alterations (obesity, insulin resistance and dyslipidemia) were obtained after 21 weeks follow the administration of monosodium glutamate (4 mg.g-1, sc) in neonatal rats on the first four days after parturition, then on days 6, 8 and 10. These obese rats were subjected to 6 weeks of pharmacological treatment. In addition to adiposity, body mass index, Lee's index, insulin sensitivity and glucose tolerance, blood pressure and vascular reactivity of isolated thoracic aortic rings of rats were assessed. The activities of ALT and AST, ionogram, creatinine level, and oxidative status were also assessed. The acute toxicity (2000 mg.kg-1) of the aqueous extract was conducted. Subacute toxicity (28 days) was explored using doses of 100, 200 and 400 mg.kg-1 of the extract. The extract showed better hypotensive activity at a dose of 30 mg.kg-1. This activity, linked to the bioactive compounds (alkaloids, polyphenols and terpenoids) demonstrated, would be mediated at least in part by a sympatholytic action via the inhibition of the presynaptic release of catecholamines, the blocking of the α2 and β - adrenergic receptors, and decrease in peripheral resistance via activation of muscarinic receptors, NOS and / or prostacyclin production. Endotheliumdependent vasorelaxant effects were observed on isolated rat aortic rings, involving cyclic guanosine monophosphate signaling pathways and muscarinic receptors. Chronic oral treatment of the plant extract at the doses of 100 and 200 mg.kg-1 prevents the occurrence of hypertension (preventive effect) and reduces blood pressure (curative effect) in rats treated with L - NAME. These beneficial effects are associated with an improvement in dyslipidemia and oxidative status and with protection against functional cardiovascular changes by decreasing transaminases, lactate dehydrogenase and cardiac fibrosis. At the same doses, F. tessmannii extract reduced general adiposity, android fat accumulation, body mass index, Lee index, coronary risk dyslipidemia, insulin resistance, intolerance to glucose, ionic imbalance and increased blood pressure and arterial remodeling induced by monosodium glutamate; and decreased the vascular contractile response associated with obesity. The extract was shown to be of low toxicity, with an LD50 greater than 2000 mg.kg-1 in acute treatment. Reversible leukopenia two weeks after stopping treatment was observed at a dose of 400 mg.kg-1 in the subacute toxicity study. The results showed that this plant extract would have hypotensive, antihypertensive, vasorelaxant, anti-lipid-lowering, and antiobese effects resulting in part from the presence of certain secondary metabolites and antioxidant activities. This would in part justify the empirical use of this plant for the management of cardiovascular diseases.