Treatment with the arginase inhibitor N(omega)-hydroxy-nor-L-arginine improves vascular function and lowers blood pressure in adult spontaneously hypertensive rat.
OBJECTIVE
High vascular arginase activity and subsequent reduction in vascular nitric oxide production were recently reported in animal models of hypertension. The present study investigated the effects of in-vivo arginase inhibition on blood pressure and vascular function in adult spontaneously hypertensive rats.


METHODS
Ten-week-old spontaneously hypertensive rats and normotensive age-matched Wistar-Kyoto rats were treated with or without the selective arginase inhibitor N-hydroxy-nor-L-arginine for 3 weeks (10 or 40 mg/kg per day, intraperitoneally). Systolic blood pressure and cardiac rate were measured before and during treatment. Flow and pressure-dependent reactivity as well as remodeling of mesenteric arteries, acetylcholine-dependent vasodilation of aortic rings, cardiac hypertrophy, arginase activity and nitric oxide production were investigated in 13-week-old spontaneously hypertensive rats.


RESULTS
In spontaneously hypertensive rats, N-hydroxy-nor-L-arginine treatment decreased arginase activity (30-40%), reduced blood pressure ( approximately 35 mmHg) and improved the reactivity of mesenteric vessels. However, vascular and cardiac remodeling was not different between treated and untreated spontaneously hypertensive rats. In Wistar-Kyoto rats, N-hydroxy-nor-L-arginine did not affect blood pressure. Finally, arginase inhibition was associated with increased nitric oxide production. Consistent with this, the response of aortic rings to acetylcholine was fully restored by N-hydroxy-nor-L-arginine, and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester significantly reduced the effect of N-hydroxy-nor-L-arginine on flow-dependent vasodilation.


CONCLUSIONS
Pharmacological inhibition of arginase in adult spontaneously hypertensive rats decreases blood pressure and improves the reactivity of resistance vessels. These data represent in-vivo argument in favor of selective arginase inhibition as a new therapeutic strategy against hypertension.
Bagnost
Teddy
T
Laboratory of Physiology, Pharmacology, Experimental Preventive Nutrition, EA 3921, 'Cellular and Metabolic Optimization', Faculty of Medicine and Pharmacy, Besancon University Hospital, Besancon, France.
Berthelot
Alain
A
Bouhaddi
Malika
M
Laurant
Pascal
P
André
Claire
C
Guillaume
Yves
Y
Demougeot
Céline
C
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014508:Urea / Q000097:blood; D014661:Vasoconstriction / Q000187:drug effects
D001786:Blood Glucose; D007527:Isoenzymes; C404735:N(omega)-hydroxynorarginine; D009569:Nitric Oxide; D014508:Urea; D001120:Arginine; D001119:Arginase