Key result
Losartan reversed endothelial vasodilator dysfunction and reduced systolic blood pressure in L-NAME-induced hypertensive rats, an effect that was blunted by co-administration of icatibant.
Why the study?
Does losartan improve endothelial vasodilator function in L-NAME-induced hypertensive rats, and is this effect mediated by bradykinin B2-receptor activation?
Does losartan improve endothelial vasodilator function in L-NAME-induced hypertensive rats, and is this effect mediated by bradykinin B2-receptor activation?
Losartan reverses endothelial dysfunction in L-NAME-induced hypertensive rats through a mechanism dependent on bradykinin B2-receptor activation.
Supports bradykinin B2 mediation of losartan's effects in hypertensive rats; leaves open translation to clinical practice.
OBJECTIVE: This study was designed to investigate the ability of a chronic blockade of angiotensin II type 1 receptors with losartan to reverse the endothelial dysfunction present in N-nitro-L-arginine methyl ester (L-NAME)-treated hypertensive rats and the possible dependence of this effect on bradykinin B2-receptor activation. METHODS: Rats treated with L-NAME alone (60 mg/kg per day for 8 weeks) or with L-NAME + losartan, L-NAME + icatibant (a bradykinin B2-receptor antagonist) and L-NAME + losartan + icatibant were studied. Losartan, icatibant or losartan + icatibant were co-administered with L-NAME during the last 4 weeks of the experiment. Endothelial nitric oxide synthase gene expression in aortic tissues, plasma nitrite/nitrate concentrations, the relaxant effect of acetylcholine on norepinephrine-precontracted aortic rings and 6-keto-PGF1alpha release from aortic rings were used as markers of the endothelial function. RESULTS: Rats treated with L-NAME alone and L-NAME + icatibant showed, as compared with untreated animals, a clear-cut increase in systolic blood pressure and a decrease of all the markers of endothelial function evaluated. In L-NAME-rats, administration of losartan reduced the systolic blood pressure and restored endothelial nitric oxide synthase gene expression, plasma nitrite/nitrate levels, the relaxant activity of acetylcholine on aortic rings and the generation of 6-keto-PGF1alpha from the aortic tissues. Co-administration of icatibant with losartan blunted the stimulatory effect of losartan on the markers of endothelial function evaluated. CONCLUSION: These results demonstrated that losartan is capable of reversing the endothelial vasodilator dysfunction in L-NAME-induced hypertensive rats, and that the beneficial effect of losartan is mediated by bradykinin B2-receptor activation.
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Colonna et al. (2005) studied L-NAME-induced hypertension. Losartan vs. L-NAME alone, L-NAME + icatibant, or L-NAME + losartan + icatibant was evaluated on Endothelial function markers (eNOS gene expression, plasma nitrite/nitrate, relaxant effect of acetylcholine, 6-keto-PGF1alpha release) and systolic blood pressure. Losartan reversed endothelial vasodilator dysfunction and reduced systolic blood pressure in L-NAME-induced hypertensive rats, an effect that was blunted by co-administration of icatibant.
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