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


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.


CONCLUSIONS
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.
Bagnost
Teddy
T
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
L
da Silva
Rafaela F
RF
Rezakhaniha
Rana
R
Houdayer
Christophe
C
Stergiopulos
Nikos
N
André
Claire
C
Guillaume
Yves
Y
Berthelot
Alain
A
Demougeot
Céline
C
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D003094:Collagen / Q000378:metabolism; D003187:Compliance; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005355:Fibrosis; D006331:Heart Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008638:Mesenteric Arteries / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; C404735:N(omega)-hydroxynorarginine; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D003094:Collagen; D001120:Arginine; D019001:Nitric Oxide Synthase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D001119:Arginase