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

Bagnost, Teddy; Berthelot, Alain; Bouhaddi, Malika; Laurant, Pascal; André, Carl; Guillaume, Yves Claude; Demougeot, Céline

doi:10.1097/hjh.0b013e3282fcc357

Cited by 87 publications

(80 citation statements)

References 41 publications

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“…34,35 AHeFT suggested that chronic HISDN mediated positive effects on the myocardium. 17,23 NO exerts beneficial effects on the vasculature, 15,36 lowers SBP, 37 and also has direct effects on cardiac remodeling, 11 partly by increasing endothelial NO synthase and inhibiting LVH. [11][12][13] In our study, aldosterone induced LVH and diastolic HF, 18 and NO given in the form of ISDN was ineffective in reducing LVH or cardiomyocyte size despite SBP reduction.…”

Section: Hisdn and Cardiac Remodelingmentioning

confidence: 99%

Effects of Fixed-Dose Isosorbide Dinitrate/Hydralazine on Diastolic Function and Exercise Capacity in Hypertension-Induced Diastolic Heart Failure

et al. 2009

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Abstract-Hypertension-induced diastolic heart failure accounts for a large proportion of all heart failure presentations.Hypertension also induces left ventricular (LV) hypertrophy. Fixed-dose isosorbide dinitrate/hydralazine (HISDN) decreased mortality in human systolic heart failure but it is unknown whether it improves maladaptive myocardial remodeling. We sought to test the hypothesis that chronic HISDN modulates LV hypertrophy and myocardial remodeling in hypertension-induced diastolic heart failure. FVB mice underwent either saline (nϭ18) or aldosterone (nϭ28) infusion. All underwent uninephrectomy and drank 1% salt water for 4 weeks. Mice were randomized after surgery to regular chow or chow containing HISDN (isosorbide dinitrate: 26 mg/kg per day; hydralazine: 50 mg/kg per day) for 4 weeks. Aldosterone infusion increased tail-cuff blood pressure (161Ϯ3 mm Hg) versus saline-infused mice (129Ϯ2 mm Hg). Aldosterone induced LV hypertrophy versus saline-infused mice (LV:body weight ratio: 4.2Ϯ0.1 versus 3.6Ϯ0.1 mg/g). HISDN attenuated the aldosterone-induced increased in systolic blood pressure (137Ϯ5 mm Hg) and also lowered blood pressure in saline-infused mice (114Ϯ2 mm Hg). However, HISDN did not cause LV hypertrophy regression in aldosterone-infused mice. Aldosterone increased LV end-diastolic dimensions that were not attenuated by HISDN. Similarly, neither aldosterone infusion nor HISDN affected LV end-systolic dimensions. LV ejection fraction and wet:dry lung ratio were not different between aldosterone-untreated and aldosterone-HISDN mice. However, mitral Doppler E/A ratio (a measure of diastolic function), exercise capacity, and plasma soluble vascular cell adhesion molecule 1 levels were improved in aldosterone-HISDN hearts. In conclusion, fixed-dose HISDN improved hypertension, diastolic function, and exercise capacity and reduced soluble vascular cell adhesion molecule 1 levels. There were no reductions in LV hypertrophy, cardiac fibrosis, or pulmonary congestion. These functional improvements are likely related to extracardiac effects, such as effects on the vasculature. Key Words: diastolic heart failure Ⅲ hydralazine Ⅲ nitrates Ⅲ hypertension Ⅲ exercise capacity H ypertension induces left ventricular (LV) hypertrophy (LVH) and is a major cause of both diastolic and systolic heart failures (HF). 1 Diastolic HF accounts for up to Յ50% of all HF presentations 2 and is associated with increasing morbidity and mortality. 3 Diastolic HF refers to the clinical syndrome of pulmonary congestion in the presence of a normal LV ejection fraction, whereas diastolic dysfunction denotes an abnormality of mechanical properties that exist during LV relaxation and filling. 4,5 Diastolic dysfunction may be an intermediary between hypertension and HF. 6 In the setting of hypertension, diastolic HF represents a diverse clinical syndrome with various associated comorbidities (eg, age and sex) and manifests a spectrum of symptoms ranging from exercise intolerance to acute pulmonary edema. In addition to LVH, cardiac...

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Section: Hisdn and Cardiac Remodelingmentioning

confidence: 99%

Effects of Fixed-Dose Isosorbide Dinitrate/Hydralazine on Diastolic Function and Exercise Capacity in Hypertension-Induced Diastolic Heart Failure

et al. 2009

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“…In accordance with this hypothesis, we recently showed that in vivo pharmacological blockade of arginase decreased endothelial dysfunction and prevented blood pressure rising in prehypertensive spontaneously hypertensive rats (SHRs) and young adult SHRs. 10,12 These latter studies only focused interest on the role of arginase in aortic and mesenteric endothelial dysfunction in SHRs, and as yet no study investigated the arginase pathway in tissues that encompass those implicated in the pathogenesis and pathophysiology of genetic hypertension, such as the heart, brain and kidney. However, hypertension-related damage to these target organs is a major cause of morbidity and mortality, and future antihypertensive therapy is expected to prevent or reduce it.…”

Section: Introductionmentioning

confidence: 99%

Misregulation of the arginase pathway in tissues of spontaneously hypertensive rats

Bagnost¹,

Berthelot²,

Alvergnas³

et al. 2009

Hypertens Res

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There is a growing evidence that arginase has a role in the pathophysiology of cardiovascular diseases including hypertension. We recently reported arginase upregulation in aortas from hypertensive spontaneously hypertensive rats (SHRs). The aim of this study was to determine whether arginase abnormalities occur in other tissues of SHR, including the target organs of hypertension. Experiments were conducted on 5-, 10-, 19-and 26-week-old SHRs and Wistar-Kyoto (WKY) rats. Arginase activity and expression were evaluated in heart, kidney, liver, lung and brain tissue extracts. To investigate the role of blood pressure by itself in arginase abnormalities, arginase activity was determined in 10-week-old SHRs previously treated with hydralazine (20 mg kg À1 per day, for 5 weeks). Compared with WKY rats, cardiac arginase activity was higher in hypertensive SHRs aged 10 weeks (+46%, Po0.05), 19 weeks (+29%, Po0.05) and 26 weeks (+23%, NS). Similar results were found in lungs in which arginase activity was increased in SHRs aged 10 weeks (+39%, Po0.05), 19 weeks (+49%, Po0.05) and 26 weeks (+36%, Po0.05) compared with WKY rats. The changes in arginase activity in these tissues were not associated with changes in enzyme expression. The prevention of hypertension by hydralazine blunted the increase in arginase activity in the hearts but not in the lungs. No change in arginase activity/expression was found in the kidney, liver or brain. In conclusion, this study shows that increased arginase activity is not restricted to large vessels in SHRs and suggests that cardiac arginase activity is hemodynamic sensitive.

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“…Pre clinical trial in adult spontaneously hypertensive rats showed that Nor-NOHA decreases blood pressure and improves the reactivity of resistance vessels. 23 Small scale clinical trial showed that nor-NOHA infusion increased endothelium-dependent vasodilatation in patients with coronary artery disease and diabetes mellitus type 2. 24 Arginase inhibition test on four samples showed that highest inhibitory effect was on Melastoma malabathricum leaf extract.…”

Section: Figure 1: Melastoma Malabathricum Leavesmentioning

confidence: 99%

Inhibitory Effect on Arginase and Total Phenolic Content Determination of Extracts from Different parts of Melastoma malabathricum L.

Sembiring

Elya²,

Sauriasari³

2018

JYP

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The part of the plant were collected and cleaned, dried at room temperature, and then powdered and stored in an air tight glass container. 50 g of each plant part was extracted by maceration with 500 mL of 70% ethanol ABSTRACTBackground: Some phenolic compounds are potential source for arginase inhibitor that can be used in management of disease associated with endothelial dysfunction. Objective: The aim of this study was to investigate the inhibitory effect on arginase and to determine total phenolic content of extracts from different parts of Melastoma malabathricum L. Methods: Each part were extracted with 70% ethanol by maceration. The extracts were mixed with bovine liver arginase and L-arginine as a substrate. The inhibitory effect of extracts were determined in vitro, by measuring its absorbance on 430 nm. Total phenolic content were determined with Folin-Ciocalteu 25% on 750 nm. Results: The 70% ethanol extract of M. malabathricum leaves at 100 µg/mL was found to have highest inhibition (81.26 ± 5.27 %) followed by flower 73.39 ± 9.39%, fruit 67.63 ± 7.61 and stem 61.61 ± 4.56%. The IC 50 value of the most active extract was 62.43 µg/mL while the IC 50 value of N-hidroksi-nor-L-arginin (nor-NOHA) acetate, an arginase inhibitor was found to be 3.91 µg/mL. Total phenolic content of 70% ethanolic extracts of M. malabathricum leaves, flower, fruit and stem was 15.9, 20.7, 6.44, and 6.29%. Conclusion: The 70% ethanol extract of M. malabathricum leaves exhibited the highest inhibition on arginase but highest total phenolic content was from flower part. Pearson correlation test showed no correlation p>0.05 between arginase inhibition and total phenolic content of the samples.

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

Abstract: 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.

Cited by 87 publications

References 41 publications

Effects of Fixed-Dose Isosorbide Dinitrate/Hydralazine on Diastolic Function and Exercise Capacity in Hypertension-Induced Diastolic Heart Failure

Effects of Fixed-Dose Isosorbide Dinitrate/Hydralazine on Diastolic Function and Exercise Capacity in Hypertension-Induced Diastolic Heart Failure

Misregulation of the arginase pathway in tissues of spontaneously hypertensive rats

Inhibitory Effect on Arginase and Total Phenolic Content Determination of Extracts from Different parts of Melastoma malabathricum L.

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