Effect of spironolactone on endothelial dysfunction in rheumatoid arthritis

Syngle, Ashit; Vohra, Kanchan; Kaur, Ladbans; Sharma, Sanjeev

doi:10.1080/03009740802279709

Cited by 34 publications

(23 citation statements)

References 32 publications

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“…To confirm that the abnormal response of vessels from AIA rats to ACh was not due to decreased response of vascular smooth muscle cells to NO, we demonstrated that the relaxing effect of the NO donor SNP was not impaired in the AIA rats. This result is in accordance with recent study findings in AIA rats (12,14,36) as well as in RA patients (37)(38)(39)(40). Likewise, we verified that the contractile response of vessels from AIA rats to NE was not different from that of control rats.…”

Section: Discussionsupporting

confidence: 93%

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Prati¹,

Berthelot²,

Wendling³

et al. 2011

Arthritis & Rheumatism

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Objective. To investigate whether arginase pathway abnormalities occur in vessels from rats with adjuvant-induced arthritis (AIA), and to determine whether the up-regulation of arginase, which reciprocally regulates nitric oxide synthase (NOS) by competing for the same substrate, L-arginine, contributes to endothelial dysfunction in AIA.Methods. We performed vascular reactivity experiments on thoracic aortic rings from AIA rats and control rats, and we investigated the response of rings to norepinephrine (NE), sodium nitroprusside (SNP), and acetylcholine (ACh). ACh-induced relaxation was evaluated in the presence (or not in the presence) of the NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME), the arginase inhibitor N -hydroxy-nor-Larginine (nor-NOHA), or both. Aortic arginase activity was measured using a spectrophotometric method, and the expression of arginase and endothelial NOS (eNOS) was evaluated by Western blotting.Results. ACh-induced vasodilation was significantly impaired in AIA rats, while the responses to NE and to SNP did not differ from those in control rats. L-NAME reduced ACh-induced vasodilation to a lesser extent in AIA rats than in control rats. Incubation of aortic rings with nor-NOHA enhanced the vascular response to ACh in AIA rats and reversed the effects of L-NAME. Compared with control rats, AIA rats exhibited increased vascular expression of arginase II (by 22%) (P < 0.05) as well as increased arginase activity (by 49%) (P < 0.05), whereas eNOS expression was unchanged. Finally, arginase activity and expression correlated positively with arthritis severity.Conclusion. Our results are consistent with the notion that arginase up-regulation plays a role in AIAassociated endothelial dysfunction. They suggest that arginase might be an attractive new target for treating endothelial dysfunction in arthritis.

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Section: Discussionsupporting

confidence: 93%

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Prati¹,

Berthelot²,

Wendling³

et al. 2011

Arthritis & Rheumatism

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“…62 Treatment with spironolactone has been shown to improve the endothelial dysfunction and inflammatory disease activity in rheumatoid arthritis. 63 Although the beneficial effects of spironolactone in attenuating neuropathic pain have been described as being due to its aldosterone receptor blockade activity, some studies have suggested that the suppressive effect of spironolactone on immune-reactive and inflammatory cytokines is independent of mineralocorticoid receptor blockade. Furthermore, the direct role of pro-renin receptors in decreasing inflammatory cytokines and producing beneficial effects in neuropathic pain may not be completely ruled out in aliskerin-mediated beneficial effects.…”

Section: Possible Mechanismsmentioning

confidence: 99%

Renin–angiotensin system in pain: Existing in a double life?

Bali

Singh

Jaggi

2014

J Renin Angiotensin Aldosterone Syst

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Apart from the well-documented role of the renin-angiotensin-aldosterone system (RAAS) in regulating the blood pressure and other related parameters, its role in modulating different physiological/pathological functions, including pain, has also been described. Like its dual role in regulating stress-related anxiety and cognitive functions, its dual role has also been documented in pain modulation in different disease states. Drugs blocking the RAAS activation, viz., renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, AT 1 receptor antagonists and aldosterone antagonists, have been shown to produce beneficial effects in migraine and neuropathic and nociceptive pain. Their beneficial effects have been mainly attributed to inhibition of the inflammatory cascade of reactions by inhibiting the generation of key cytokines, including tumor necrosis factor (TNF)-α. On the contrary, clinical as well as preclinical studies have also shown the paininducing actions of renin-angiotensin system (RAS) blocking drugs. Furthermore, the pain-relieving actions of angiotensin II (AngII) and pain-inducing actions of AT 1 blockers have also been described. The pain-inducing actions of ACE inhibitors have been mainly attributed to interference with metabolism of bradykinin and substance P, while the analgesic actions of AngII have been mainly related to activation of brain localized AT 2 receptors and release of endogenous opioids. The present review describes the dual role of the RAAS in different states of pain.

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“…In clinical trials, markers of chronic low-grade inflammation and endothelial dysfunction were shown to be reduced by spironolactone in rheumatoid arthritis 15 and by eplerenone in essential hypertension. 16 From previous long-term prospective studies we have seen that in type 1 2 and type 2 diabetes, 4 lower levels of markers of endothelial dysfunction and inflammation are associated with a better outcome regarding cardiovascular morbidity, renal disease and all-cause mortality.…”

Section: Introductionmentioning

confidence: 99%

Levels of NT-proBNP, markers of low-grade inflammation, and endothelial dysfunction during spironolactone treatment in patients with diabetic kidney disease

Nielsen

Schjoedt

Rossing

et al. 2012

J Renin Angiotensin Aldosterone Syst

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Renin-angiotensin-aldosterone system (RAAS) blockade may reduce levels of biomarkers of chronic low-grade inflammation and endothelial dysfunction. We investigated the effect of spironolactone added to standard RAAS blockade on these biomarkers in an analysis of four original studies. Materials and methods:The studies were double-blind, randomised, placebo-controlled studies in 46 type 1 and 23 type 2 diabetic patients with micro-or macroalbuminuria treated with angiotensin-converting enzyme inhibitor (ACE inhibitor) or angiotensin receptor blocker (ARB), and randomised to additional treatment with spironolactone 25 mg and placebo daily for 60 days. Outcome measures: Changes in inflammatory (hsCRP, s-ICAM, TNFα, IL-6, IL-8, Serum amyloid A, IL1β), endothelial dysfunction (sE-selectin, s-ICAM1, s-VCAM1, VWF, p-selectin, s-thrombomodulin) and NT-proBNP after each treatment period. Results: During spironolactone treatment, u-albumin excretion rate was reduced from 605 (411-890) to 433 (295-636) mg/24 h, as previously reported. Markers of inflammation and endothelial dysfunction did not change; only changes in NT-proBNP (reduced by 14%, p=0.05) and serum amyloid A (reduced by 62%, p=0.10) were borderline significant. Discussions: Our results indicate that the renoprotective effect of spironolactone when added to RAAS blockade is not mediated through anti-inflammatory pathways since markers of inflammation and endothelial dysfunction are not affected during treatment.

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Effect of spironolactone on endothelial dysfunction in rheumatoid arthritis

Abstract: The study suggests that, in RA, endothelial dysfunction is part of the disease process and treatment with spironolactone improves both endothelial dysfunction and inflammatory disease activity in RA.

Cited by 34 publications

References 32 publications

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Renin–angiotensin system in pain: Existing in a double life?

Levels of NT-proBNP, markers of low-grade inflammation, and endothelial dysfunction during spironolactone treatment in patients with diabetic kidney disease

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