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

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 hypertensio

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

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

Intérêt de l'arginase comme nouvelle cible thérapeutique dans le traitement de la dysfonction endothéliale associée à l'hypertension artérielle

BESANCON-BU Médecine pharmacie (250562102) / SudocSudocFranceF

Testimony of the Correlation Between the Reactive Histidine Residue and the Arginase Catalytic Mechanism Using a Biochromatographic Concept and Mutagenesis Experiments

International audienceIn a previous paper (Bagnost et al., J Chromatogr B Analyt Technol Biomed Life Sci 853:38-46, 2007), an arginase chromatographic support was developed to study the association mechanism of arginase (an enzyme which can reduce endothelial dysfunction and blood pressure rising in spontaneously hypertensive rats) with nor-NOHA a potential inhibitor of its activity. In this report mutagenesis experiments associated with this biochromatographic approach confirmed that the active-site residue Hist 141 is protonated as imidazolium cation. Hist 141 could function as a general acid to protonate the leaving amino group of L-ornithine during catalysis

Biochromatographic framework for analyzing magnesium chloride salt dependence on nor-NOHA binding to arginase enzyme

International audienc

A molecular chromatographic approach to analyze the cell diffusion of arginase inhibitors.

International audienceOur group demonstrated that arginase inhibition reduces endothelial dysfunction in spontaneously hypertensive rats [C. Demougeot, A. Prigent-Tessier, C. Marie, A. Berthelot, J. Hypertens. 23 (2005) 971; C. Demougeot, A. Prigent-Tessier, T. Bagnost, C. Andre, Y. Guillaume, M. Bouhaddi, C. Marie, A. Berthelot, Life Sci. 80 (2007) 1128] which opens perspectives in the development of drugs against hypertension. In previous papers [T. Bagnost, Y.C. Guillaume, M. Thomassin, J.F. Robert, A. Berthelot, A. Xicluna, C. Andre, J. Chromatogr. B: Analyt. Technol. Biomed. Life Sci. 856 (2007) 113; T. Bagnost, Y.C. Guillaume, M. Thomassin, A. Berthelot, C. Demougeot, C. Andre, J. Chromatogr. B: Analyt. Technol. Biomed. Life Sci. 873 (2008) 37], we developed a biochromatographic column for studying the binding of an arginase inhibitor with this enzyme and the effect of magnesium on this binding. In this paper, the interaction of arginase inhibitors with an immobilized artificial membrane (IAM) has been studied using a biochromatographic approach. This IAM provided a biophysical model system to study the inhibitor passive transport across cells. It was demonstrated that more the inhibitor cross the cell membrane by passive diffusion more it is potent. As well, an analysis of the thermodynamics of the interaction of the arginase inhibitors with the IAM showed that van der Waals, hydrogen and ionic bonds were the main forces between the arginase inhibitors and the polar head groups of the IAM surface

Treatment with the arginase inhibitor N(omega)-hydroxy-nor-L-arginine improves vascular function and lowers blood pressure in adult spontaneously hypertensive rat.

International audienceOBJECTIVE: 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. 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

Time course of vascular arginase expression and activity in spontaneously hypertensive rats.

International audienceThere is growing evidence that vascular arginase plays a role in pathophysiology of vascular diseases. We recently reported high arginase activity/expression in young adult hypertensive spontaneously hypertensive rats (SHR). The aim of the present study was to characterize the time course of arginase pathway abnormalities in SHR and to explore the contributing role of hemodynamics and inflammation. Experiments were conducted on 5, 10, 19 and 26-week-old SHR and their age-matched control Wistar Kyoto (WKY) rats. Arginase activity as well as expression of arginase I, arginase II, endothelial and inducible NOS were determined in aortic tissue extracts. Levels of L-arginine, NO catabolites and IL-6 (a marker of inflammation) were measured in plasma. Arginase activity/expression was also measured in 10-week-old SHR previously treated with hydralazine (20 mg/kg/day, per os, for 5 weeks). As compared to WKY, SHR exhibited high vascular arginase I and II expression from prehypertensive to established stages of hypertension. However, a mismatch between expression and activity was observed at the prehypertensive stage. Arginase expression was not related either to plasma IL-6 levels or to expression of NOS. Prevention of hypertension by hydralazine significantly blunted arginase upregulation and restored arginase activity. Importantly, arginase activity and blood pressure (BP) correlated in SHR. In conclusion, our results demonstrate that arginase upregulation precedes blood pressure rising and identify elevated blood pressure as a contributing factor of arginase dysregulation in genetic hypertension. They also demonstrated a close relationship between arginase activity and BP, thus making arginase a promising target for antihypertensive therapy