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

• Published in: Cardiovascular research 2010-08, Vol.87 (3), p.569-577
• Main Authors: Bagnost, Teddy, Ma, Ling, da Silva, Rafaela F., Rezakhaniha, Rana, Houdayer, Christophe, Stergiopulos, Nikos, André, Claire, Guillaume, Yves, Berthelot, Alain, Demougeot, Céline
• Format: Article
• Language: English
• Subjects: Animals; Aorta - drug effects; Aorta - enzymology; Aorta - physiopathology; Arginase; Arginase - antagonists & inhibitors; Arginase - metabolism; Arginine - analogs & derivatives; Arginine - pharmacology; Arterial hypertension. Arterial hypotension; Arteries; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Cardiology. Vascular system; Cardiovascular Agents - pharmacology; Carotid Arteries - drug effects; Carotid Arteries - enzymology; Carotid Arteries - physiopathology; Collagen - metabolism; Compliance; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial function; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Endothelium, Vascular - physiopathology; Enzyme Inhibitors - pharmacology; Fibrosis; Heart Diseases - enzymology; Heart Diseases - pathology; Heart Diseases - prevention & control; Hypertension - drug therapy; Hypertension - enzymology; Hypertension - genetics; Hypertension - pathology; Hypertension - physiopathology; Male; Medical sciences; Membrane Proteins - metabolism; Mesenteric Arteries - drug effects; Mesenteric Arteries - enzymology; Mesenteric Arteries - physiopathology; Myocardium - pathology; Nitric Oxide Synthase - metabolism; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Remodelling; Spontaneously hypertensive rat; Time Factors; Vasoconstriction - drug effects; Vasoconstrictor Agents - pharmacology; Vasodilation - drug effects; Vasodilator Agents - pharmacology
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvq081

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.