Treatment with the arginase inhibitor Nω-hydroxy-nor-L-arginine improves vascular function and lowers blood pressure in adult spontaneously hypertensive rat

被引:86
作者
Bagnost, Teddy [4 ]
Berthelot, Alain [4 ]
Bouhaddi, Malika [1 ]
Laurant, Pascal [2 ]
Andre, Claire [3 ]
Guillaume, Yves [3 ]
Demougeot, Celine [4 ]
机构
[1] Besancon Univ Hosp, Minjoz Hosp, Dept Physiol, Besancon, France
[2] Grp Cell Biol & Physiol Sports, EA 3921, Besancon, France
[3] Fac Med & Pharmacie, Lab Separat & Biopharmaceut Sci, EA 3124, Besancon, France
[4] Fac Med & Pharmacie, Physiol Lab, EA 3921, F-25030 Besancon, France
关键词
arginase; endothelial function; hypertension; spontaneously hypertensive rat;
D O I
10.1097/HJH.0b013e3282fcc357
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
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-omega-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-omega-hydroxy-nor-L-arginine treatment decreased arginase activity (30-40%), reduced blood pressure (similar to 35mmHg) 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-omega-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-omega-hydroxy-nor-L-arginine, and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester significantly reduced the effect of N-omega-hydroxy-nor-L-arginine on flow-dependent vasodilation. Conclusion 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.
引用
收藏
页码:1110 / 1118
页数:9
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