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Cardiovascular effects of arginase inhibition in spontaneously hypertensive rats with fully developed hypertension

Bagnost, Teddy ; Ma, Ling ; da Silva, Rafaela F. ; Rezakhaniha, Rana ; Houdayer, Christophe ; Stergiopulos, Nikos ; André, Claire ; Guillaume, Yves ; Berthelot, Alain ; Demougeot, Céline

In: Cardiovascular Research, 2010, vol. 87, no. 3, p. 569-577

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    Titre
    • Cardiovascular effects of arginase inhibition in spontaneously hypertensive rats with fully developed hypertension
    Auteur
    • Bagnost, Teddy. Laboratoire de Physiologie - Pharmacologie - Nutrition - Préventive Expérimentale, Equipe Sciences Séparatives Biologiques et Pharmaceutiques, EA-4267, Faculté de Médecine-Pharmacie, Besançon, Place Saint-Jacques, Besançon cedex 25030, France
    • Ma, Ling. Laboratoire de Physiologie - Pharmacologie - Nutrition - Préventive Expérimentale, Equipe Sciences Séparatives Biologiques et Pharmaceutiques, EA-4267, Faculté de Médecine-Pharmacie, Besançon, Place Saint-Jacques, Besançon cedex 25030, France
    • da Silva, Rafaela F.. Institute of Bioengineering, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
    • Rezakhaniha, Rana. Institute of Bioengineering, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
    • Houdayer, Christophe. Laboratoire de Biologie du Développement et de la Reproduction, CHU Jean Minjoz, Besançon, France
    • Stergiopulos, Nikos. Institute of Bioengineering, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
    • André, Claire. Laboratoire de Physiologie - Pharmacologie - Nutrition - Préventive Expérimentale, Equipe Sciences Séparatives Biologiques et Pharmaceutiques, EA-4267, Faculté de Médecine-Pharmacie, Besançon, Place Saint-Jacques, Besançon cedex 25030, France
    • Guillaume, Yves. Laboratoire de Physiologie - Pharmacologie - Nutrition - Préventive Expérimentale, Equipe Sciences Séparatives Biologiques et Pharmaceutiques, EA-4267, Faculté de Médecine-Pharmacie, Besançon, Place Saint-Jacques, Besançon cedex 25030, France
    • Berthelot, Alain. Laboratoire de Physiologie - Pharmacologie - Nutrition - Préventive Expérimentale, Equipe Sciences Séparatives Biologiques et Pharmaceutiques, EA-4267, Faculté de Médecine-Pharmacie, Besançon, Place Saint-Jacques, Besançon cedex 25030, France
    • Demougeot, Céline. Laboratoire de Physiologie - Pharmacologie - Nutrition - Préventive Expérimentale, Equipe Sciences Séparatives Biologiques et Pharmaceutiques, EA-4267, Faculté de Médecine-Pharmacie, Besançon, Place Saint-Jacques, Besançon cedex 25030, France
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Cardiovascular Research, 2010, vol. 87, no. 3, p. 569-577. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:291380
    Summary
    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 Nω-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