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  • Title: Cardiovascular effects of arginase inhibition in spontaneously hypertensive rats with fully developed hypertension.
    Author: Bagnost T, Ma L, da Silva RF, Rezakhaniha R, Houdayer C, Stergiopulos N, André C, Guillaume Y, Berthelot A, Demougeot C.
    Journal: Cardiovasc Res; 2010 Aug 01; 87(3):569-77. PubMed ID: 20219858.
    Abstract:
    AIMS: Growing evidence suggests that arginase misregulation plays a key role in the pathophysiology of essential hypertension. In the present study, we investigated the potential cardiovascular therapeutic effects of a long-term treatment with an arginase inhibitor in adult spontaneously hypertensive rats (SHR) with fully developed hypertension. METHODS AND RESULTS: Treatment of 25-week-old SHR with the arginase inhibitor N(omega)-hydroxy-nor-L-arginine (nor-NOHA, 40 mg/day for 10 weeks) sustainably reduced systolic blood pressure (-30 mmHg, P < 0.05). The antihypertensive effect of nor-NOHA was associated with changes on mesenteric artery reactivity including the restoration of angiotensin-II-induced contraction and acetylcholine-induced vasodilation to the values of normotensive Wistar Kyoto rats. Both nitric oxide synthase and cyclooxygenase-dependent mechanisms account for the improvement of endothelial function afforded by the arginase inhibitor, which in addition blunted hypertension-induced endothelial arginase I overexpression in mesenteric arteries. Nor-NOHA also prevented the remodelling of aorta as measured by collagen content and media/lumen ratio, and improved the compliance of carotid artery in SHR. Cardiac fibrosis assessed by collagen content of left heart ventricle was reduced by nor-NOHA, with no significant effect on cardiac hypertrophy. CONCLUSION: Our results report that a long-term treatment with an arginase inhibitor reduced blood pressure, improved vascular function, and reduced cardiac fibrosis in SHR with fully developed hypertension. These data suggest that arginase represents a promising novel target for pharmacological intervention in essential hypertension.
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