Benidipine reduces ischemia reperfusion-induced systemic oxidative stress through suppression of aldosterone production in mice

Ohtani, Kazuhiro; Usui, Soichiro; Kaneko, Shuichi; Takashima, Shinya; Kitano, Katsunori; Yamamoto, Kanako; Okajima, Masaki; Furusho, Hiroshi; Takamura, Masayuki

doi:10.1038/hr.2011.183

Cited by 12 publications

(10 citation statements)

References 41 publications

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“…The mice were subjected to I/R or sham operation as described elsewhere [16]. Briefly, a lateral thoracotomy was performed in the anesthetized and ventilated mice, and a 7-0 suture was looped under the left descending coronary artery for the induction of a coronary artery occlusion for 30 min, followed by 24 h of reperfusion.…”

Section: Methodsmentioning

confidence: 99%

Rho-Kinase Activation in Leukocytes Plays a Pivotal Role in Myocardial Ischemia/Reperfusion Injury

et al. 2014

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The Rho/Rho-kinase pathway plays an important role in many cardiovascular diseases such as hypertension, atherosclerosis, heart failure, and myocardial infarction. Although previous studies have shown that Rho-kinase inhibitors reduce ischemia/reperfusion (I/R) injury and cytokine production, the role of Rho-kinase in leukocytes during I/R injury is not well understood. Mice were subjected to 30-min ischemia and reperfusion. Rho-kinase activity was significantly greater in leukocytes subjected to myocardial I/R compared to the sham-operated mice. Administration of fasudil, a Rho-kinase inhibitor, significantly reduced the I/R-induced expression of the proinflammatory cytokines interleukin (IL)-6, C-C motif chemoattractant ligand 2 (CCL2), and tumor necrosis factor (TNF)-α, in leukocytes, compared with saline as the vehicle. Furthermore, fasudil decreased I/R-induced myocardial infarction/area at risk (IA) and I/R-induced leukocyte infiltration in the myocardium. Interestingly, IA in fasudil-administered mice with leukocyte depletion was similar to that in fasudil-administered mice. I/R also resulted in remarkable increases in the mRNA expression levels of the proinflammatory cytokines TNF-α, IL-6, and CCL2 in the heart. Inhibition of Rho-kinase activation in leukocytes has an important role in fasudil-induced cardioprotective effects. Hence, inhibition of Rho-kinase may be an additional therapeutic intervention for the treatment of acute coronary syndrome.

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Section: Methodsmentioning

confidence: 99%

Rho-Kinase Activation in Leukocytes Plays a Pivotal Role in Myocardial Ischemia/Reperfusion Injury

et al. 2014

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“…According to Sato and Fukuda (), eplerenone, when given with amlodipine or the ACE inhibitor imidapril, causes a beneficial antihypertensive effect in Japanese patients with essential hypertension. Benidipine, as a T‐type Ca 2+ channel blocker, has benefits in reducing ischaemia/reperfusion‐induced systemic oxidative stress through suppression of aldosterone production and increase in eNOS phosphorylation in mice (Ohtani et al ., ).…”

Section: Therapeutic Measuresmentioning

confidence: 97%

Aldosterone affects blood flow and vascular tone regulated by endothelium‐derived NO: therapeutic implications

Toda¹,

Nakanishi

Tanabe³

2013

British J Pharmacology

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Aldosterone, in doses inappropriate to the salt status, plays an important role in the development of cardiovascular injury, including endothelial dysfunction, independent of its hypertensive effects. Acute non-genomic effects of aldosterone acting on mineralocorticoid receptors are inconsistent in healthy humans: vasoconstriction or forearm blood flow decrease via endothelial dysfunction, vasodilatation mediated by increased NO actions, or no effects. However, in studies with experimental animals, aldosterone mostly enhances vasodilatation mediated by endothelium-derived NO. Chronic exposure to aldosterone, which induces genomic responses, results in impairments of endothelial function through decreased NO synthesis and action in healthy individuals, experimental animals and isolated endothelial cells. Chronic aldosterone reduces NO release from isolated human endothelial cells only when extracellular sodium is raised. Oxidative stress is involved in the impairment of endothelial function by promoting NO degradation. Aldosterone liberates endothelin-1 (ET-1) from endothelial cells, which elicits ETA receptor-mediated vasoconstriction by inhibiting endothelial NO synthesis and action and through its own direct vasoconstrictor action. Ca 2+ flux through T-type Ca 2+ channels activates aldosterone synthesis and thus enhances unwanted effects of aldosterone on the endothelium. Mineralocorticoid receptor inhibitors, ETA receptor antagonists and T-type Ca 2 + channel blockers appear to diminish the pathophysiological participation of aldosterone in cardiovascular disease and exert beneficial actions on bioavailability of endothelium-derived NO, particularly in resistant hypertension and aldosteronism. AbbreviationsACE, angiotensin-converting enzyme; BH4, tetrahydrobiopterin; eNOS, endothelial NOS; ET, endothelin; G6PD, glucose-6-phosphate dehydrogenase; L-NMMA, N G -monomethyl-L-arginine; MR, mineralocorticoid receptor; PMA, phorbol 12-myristate 13-acetate; ROS, reactive oxygen species; SHRSP, stroke-prone spontaneously-hypertensive rat; SNP, sodium nitroprusside IntroductionThe mineralocorticoid aldosterone is synthesized from cholesterol in the zona glomerulosa of the adrenal gland and extra-adrenal tissues. In blood vessels, it is produced in both endothelial and smooth muscle cells (Schiffrin, 2006;Skøtt et al., 2006). The main role of aldosterone is to maintain body sodium homeostasis. In normal physiological situations, aldosterone is regulated inversely with salt (NaCl) status. If aldosterone becomes inappropriately high for the salt status, elevated plasma aldosterone results in endothelial dysfunction, vasculopathy, vascular and ventricular remodelling and renal injury. Most of these effects are mediated via mineralocorticoid receptors (MR) (Brown, 2005; receptor nomenclature follows Alexander et al., 2011). Substantial evidence has emerged to show that aldosterone plays an independent role in the development of cardiovascular tissue damage. The Randomized Aldactone Evaluation Study (RALES) has demonstrated ...

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“…In this way, in vivo studies with benidipine and cilnidipine were found to reduce the plasma aldosterone concentration (PAC) in stroke-prone spontaneously hypertensive rats [35], in the ischemia reperfusion mouse model [36], and in male SHR/Izm rats [37]. In clinical studies, azelnidipine, benidipine, and efonidipine were shown to exert suppressive actions on PAC in hypertensive patients with type 2 diabetes mellitus [38], in patients with mild-to-moderate stage chronic kidney disease with albuminuria [39], in patients with chronic glomerulonephritis [40], and in patients with essential hypertension [41].…”

Section: Actions Of Dihydropyridine Ccbs On Adrenal Steroid Synthesismentioning

confidence: 99%

Suppression of Aldosterone Synthesis and Secretion by Channel Antagonists

Ikeda

Isaka

Fujioka

et al. 2012

International Journal of Endocrinology

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Aldosterone, a specific mineralocorticoid receptor (MR) agonist and a key player in the development of hypertension, is synthesized as a final product of renin-angiotensin-aldosterone system. Hypertension can be generally treated by negating the effects of angiotensin II through the use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin II type 1 receptor antagonists (ARBs). However, the efficacy of angiotensin II blockade by such drugs is sometimes diminished by the so-called “aldosterone breakthrough” effect, by which ACE-Is or ARBs (renin-angiotensin system (RAS) inhibitors) gradually lose their effectiveness against hypertension due to the overproduction of aldosterone, known as primary aldosteronism. Although MR antagonists are used to antagonize the effects of aldosterone, these drugs may, however, give rise to life-threatening adverse actions, such as hyperkalemia, particularly when used in conjunction with RAS inhibitors. Recently, several groups have reported that some dihydropyridine Ca2+ channel blockers (CCBs) have inhibitory actions on aldosterone production in in vitro and in the clinical setting. Therefore, the use of such dihydropyridine CCBs to treat aldosterone-related hypertension may prove beneficial to circumvent such therapeutic problems. In this paper, we discuss the mechanism of action of CCBs on aldosterone production and clinical perspectives for CCB use to inhibit MR activity in hypertensive patients.

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Benidipine reduces ischemia reperfusion-induced systemic oxidative stress through suppression of aldosterone production in mice

Cited by 12 publications

References 41 publications

Rho-Kinase Activation in Leukocytes Plays a Pivotal Role in Myocardial Ischemia/Reperfusion Injury

Rho-Kinase Activation in Leukocytes Plays a Pivotal Role in Myocardial Ischemia/Reperfusion Injury

Aldosterone affects blood flow and vascular tone regulated by endothelium‐derived NO: therapeutic implications

Suppression of Aldosterone Synthesis and Secretion by Channel Antagonists

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