Effects of Vasodilatory Antihypertensive Agents on Endothelial Dysfunction in Rats with Ischemic Acute Renal Failure.

Kakoki, Masao; Hirata, Yasunobu; Hayakawa, Hiroshi; Suzuki, Emiko; Nagata, Daisuke; Nishimatsu, Hiroaki; Kimura, Kenjiro; Goto, Atsuo; Omata, Masao

doi:10.1291/hypres.23.527

Cited by 55 publications

(61 citation statements)

References 31 publications

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“…12,13 Briefly, cell lysates were extracted with Nonidet P-40lysis buffer (50 mmol/L of Tris-HCl [pH 8.0], 150 mmol/L of NaCl, 1% [NP-40], 2 g/mL of aprotinin, 2 g/mL of leupeptin, 1 mmol/L of PMSF, and 1 mmol/L of sodium orthovanadate) followed by SDS-PAGE (25 g of protein per lane). For immunoblot analysis of the dimeric form of eNOS, samples were subjected to 6% to 9% gradient polyacrylamide gels without preheating, and the temperature of the gels was maintained at 4°C during electrophoresis (low-temperature SDS-PAGE).…”

Section: Western Blot Analysismentioning

confidence: 99%

Molecular Mechanism of the Inhibitory Effect of Aldosterone on Endothelial NO Synthase Activity

et al. 2006

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Abstract-Although the proinflammatory and profibrotic actions of aldosterone (Aldo) on the vasculature have been reported, the effects and molecular mechanisms of Aldo on endothelial function are yet to be determined. We investigated how Aldo regulates endothelial NO synthase (eNOS) function in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated for 16 hours with Aldo 10 Ϫ7 mol/L. The concentration of reactive oxygen species was estimated by measuring 2Ј,7Ј-dichlorodihydrofluorescein diacetate chemiluminescence. Signal transduction was estimated by Western immunoblots. Real-time RT-PCR was performed to measure expression of transcripts of endogenous GTP cyclohydrolase-1 and components of reduced nicotinamide-adenine dinucleotide phosphate oxidase. To eliminate the possible effect of the glucocorticoid receptor (GR) and to emphasize the role of mineralocorticoid receptor, we used GR small interfering RNA and knocked down GR expression in several experiments. NO output was estimated by intracellular cGMP concentration. Reactive oxygen species production increased significantly in Aldo-treated HUVECs but was abolished by pretreatment with eplerenone. Transcripts of p47 phox were increased by Aldo treatment. Vascular endothelial growth factor-induced eNOS Ser 1177 but not Akt Ser 473 phosphorylation levels were reduced significantly by pretreatment with Aldo. Pretreatment with either eplerenone or okadaic acid restored phosphorylation levels of eNOS Ser 1177 in Aldo-treated cells, suggesting that protein phosphatase 2A was upregulated by Aldo via mineralocorticoid receptor. The decrease in NO output caused by Aldo pretreatment was reversed significantly by 5,6,7,8-tetrahydrobiopterin, GTP cyclohydrolase-1 overexpression, or p47 phox knockdown. These results suggest that Aldo inhibits eNOS function through bimodal mechanisms of 5,6,7,8-tetrahydrobiopterin deficiency and protein phosphatase 2A activation. Key Words: aldosterone Ⅲ nitric oxide synthase A ldosterone (Aldo) is the major hormone controlling sodium reabsorption. Aldo elevates blood pressure as a result of volume expansion after sodium absorption in the renal distal tubules. Whereas this increase in blood pressure has unfavorable effects on the vasculature, patients with primary aldosteronism (PA) have been believed to have a relatively good prognosis, because renin activity is usually suppressed in these patients. However, numerous studies have shown unexpectedly that PA is associated with an increased prevalence of cardiovascular complications, such as aortic dissection, myocardial infarction, or stroke. [1][2][3] In addition, recent clinical trials, the Randomized ALdactone Evaluation Study (RALES) and Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS), showed that mineralocorticoid receptor (MR) antagonists improved the prognosis of chronic heart failure patients even at doses below the threshold that caused significant renal effects. 4,5 This finding suggested that MR antagonism may have a...

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Section: Western Blot Analysismentioning

confidence: 99%

Molecular Mechanism of the Inhibitory Effect of Aldosterone on Endothelial NO Synthase Activity

et al. 2006

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“…Angiotensin-I-converting enzyme (ACE) inhibitors (ACEIs) reduce not only chronic cardiovascular remodeling after ischemia but also acute tissue injury caused by I/R in the heart (3), lung (4), liver (5), and kidneys (6,7). Several observations indicate that the beneficial effects of ACEIs in the acute phase are mainly due to activation of the bradykinin nitric oxide (NO) cascade as a result of inhibition of the inactivation of bradykinin, rather than due to suppression of angiotensin II formation.…”

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confidence: 99%

Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury

Kakoki

McGarrah

Kim

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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To explore the role of the kallikrein-kinin system in relation to ischemia/reperfusion injury in the kidney, we generated mice lacking both the bradykinin B1 and B2 receptor genes (B1RB2R-null, Bdkrb1 ؊/ ؊/Bdkrb2 ؊/؊ ) by deleting the genomic region encoding the two receptors. In 4-month-old mice, blood pressures were not significantly different among B1RB2R-null, B2R-null (Bdkrb2 ؊/؊ ), and WT mice. After 30 min of bilateral renal artery occlusion and 24 h of reperfusion, mortality rates, renal histological and functional changes, 8-hydroxy-2 -deoxyguanosine levels in total DNA, mtDNA deletions, and the number of TUNEL-positive cells in the kidneys increased progressively in the following order (from lowest to highest): WT, B2R-null, and B1RB2R-null mice. Increases in mRNA levels of TGF-␤1, connective tissue growth factor, and endothelin-1 after ischemia/reperfusion injury were also exaggerated in the same order (from lowest to highest): WT, B2R-null, and B1RB2R-null. Thus, both the B1 and B2 bradykinin receptors play an important role in reducing DNA damage, apoptosis, morphological and functional kidney changes, and mortality during renal ischemia/reperfusion injury.hypoxia ͉ mitochondria ͉ oxidative stress I schemic tissue injuries, including stroke, myocardial infarction, and ischemic acute renal failure, are devastating complications in patients with hypertension, diabetes, atherosclerosis, and senescence. In organ transplantation, damage to allografts during any ischemic period before the transplant markedly influences short-term and long-term graft function and outcome (1). Furthermore, although reoxygenation after ischemia is essential for cell survival, damage also develops during the reperfusion period. Previous studies have shown that acute ATP depletion, intracellular Ca 2ϩ accumulation, and increased generation of reactive oxygen species by mitochondria all play important roles in the pathogenesis of ischemia/reperfusion (I/R) injury (2).Angiotensin-I-converting enzyme (ACE) inhibitors (ACEIs) reduce not only chronic cardiovascular remodeling after ischemia but also acute tissue injury caused by I/R in the heart (3), lung (4), liver (5), and kidneys (6, 7). Several observations indicate that the beneficial effects of ACEIs in the acute phase are mainly due to activation of the bradykinin nitric oxide (NO) cascade as a result of inhibition of the inactivation of bradykinin, rather than due to suppression of angiotensin II formation. Thus, ACEIs are much more effective than angiotensin type I receptor antagonists in protecting against I/R (8-10), and bradykinin B2 receptor (B2R) antagonists and NO synthase blockers markedly attenuate the protective effects of ACEIs (8, 9, 11).Bradykinin and lysyl-bradykinin (kallidin) are generated from kininogens by the kallikreins and some other serine proteases. ACE, which is a carboxydipeptidase, inactivates both peptides by removing two amino acids from their carboxyl termini. In mammals, at least two receptors have been identified: the bradykinin B1 receptor (B...

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“…Thus ACE inhibitors could exert a beneficial effect on endothelial function by diminishing superoxide production and reducing NO breakdown. This idea is supported by the finding of Kakoki et al that an ACE inhibitor had a beneficial effect on endothelial function in rats (30).…”

Section: Fig 3 the Vasodilatory Response To Acetylcholine Was Signimentioning

confidence: 63%

Effects of Angiotensin Converting Enzyme Inhibitor and Calcium Antagonist on Endothelial Function in patients with Essential Hypertension.

Kim

et al. 2002

Hypertens Res

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Effects of Vasodilatory Antihypertensive Agents on Endothelial Dysfunction in Rats with Ischemic Acute Renal Failure.

Cited by 55 publications

References 31 publications

Molecular Mechanism of the Inhibitory Effect of Aldosterone on Endothelial NO Synthase Activity

Molecular Mechanism of the Inhibitory Effect of Aldosterone on Endothelial NO Synthase Activity

Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury

Effects of Angiotensin Converting Enzyme Inhibitor and Calcium Antagonist on Endothelial Function in patients with Essential Hypertension.

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