Up-Regulation of Endothelial Nitric Oxide Synthase through β2-Adrenergic Receptor—The Role of a β-Blocker with NO-Releasing Action

Jayachandran, Muthuvel; Hayashi, Toshio; Sumi, Daigo; Thakur, Navin Kumar; Kano, Hatsuyo; Ignarro, Louis J.; Iguchi, Akihisa

doi:10.1006/bbrc.2000.4177

Cited by 28 publications

(16 citation statements)

References 20 publications

(15 reference statements)

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“…Furthermore, nipradilol has been reported to increase NO production by binding to β 2 -adrenergic receptors in aortic smooth muscle cells [abstract; Nishida M: Circulation 1998;98(suppl 1):404] and endothelial cells [22]and by upregulating eNOS protein and mRNA [22]. In the study with L-NAME, which inhibits endogenous NO production, nipradilol increased the urinary excretion of NO – 2 + NO – 3 and decreased glomerulosclerosis and proteinuria, whereas propranolol did not.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, we selected a novel vasodilating β-blocker with a nitroxy (ONO 2 ) group [20, 21], which has been reported to increase NO in aortic endothelial cells by in vitro, about 50% as an NO donor, and the rest as a result of eNOS upregulation [22], as well as to inhibit rat mesangial mitogenesis [23, 24]. For the purpose of estimating the role of an ONO 2 group, the comparison with propranolol, a typical nonselective β-blocker without an ONO 2 group, was made.…”

Section: Introductionmentioning

confidence: 99%

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A Nitric Oxide-Generating Beta-Blocking Agent Prevents Renal Injury in the Rat Remnant Kidney Model

Takamitsu¹,

Nakanishi²,

Nishihara³

et al. 2003

Nephron Physiol

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Background: The L-arginine-nitric oxide (NO) pathway plays an important role in the modulation of glomerular disease. We investigated whether β-blocking agents, with and without an NO-generating function, had renoprotective effects in the 5/6 nephrectomized rats (Nx), an animal model of glomerulosclerosis. Methods: Nipradilol, a β-blocker with an ONO₂ group (5, 10 or 15 mg/kg/day) and propranolol, a β-blocker without this group (50 mg/kg/day) were administered for 12 weeks to Nx together with and without nitro-L-arginine methyl ester (L-NAME). We evaluated the effects of both drugs on proteinuria, hypertension, renal function, glomerulosclerosis and urinary excretion of NO metabolites (U_NOx) and cyclic GMP (U_cGMP). Results: Both drugs similarly attenuated the elevated blood pressure in Nx. However, nipradilol, at doses of 10 and 15 mg/kg/day, significantly decreased proteinuria and glomerulosclerosis, while propranolol did not. Nx showed reduced U_NOx in comparison with the sham-operated rats. Nipradilol increased U_NOx and U_cGMP significantly and in a dose- dependent manner, whereas propranolol reduced them to levels lower than those in Nx. Nx receiving L-NAME reduced U_NOx. The addition of nipradilol increased U_NOx and decreased urinary protein excretion and glomerulosclerosis, suggesting that the NO released from the drug contributed to its renoprotective effect. Conclusion: These findings indicate that nipradilol exerts its renoprotective effect through NO generation, and not by lowering blood pressure. The β-adrenergic blocking action per se does not seem to be related to the renoprotective effect of these agents.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Nitric Oxide-Generating Beta-Blocking Agent Prevents Renal Injury in the Rat Remnant Kidney Model

Takamitsu¹,

Nakanishi²,

Nishihara³

et al. 2003

Nephron Physiol

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“…An effect of sympathetic activation is less likely since b-receptor blockade appears to stimulate eNOS expression in vitro (25). However, it may be suggested that the increased frequency of cyclic stretching of the aorta, mechanically induced by the increased HR could be responsible for the increased eNOS expression seen in the aorta.…”

Section: Enos Expression and Localisationmentioning

confidence: 99%

GH and IGF-I regulate the expression of endothelial nitric oxide synthase (eNOS) in cardiovascular tissues of hypophysectomized female rats

Wickman

Jonsdottir

Bergström

et al. 2002

European Journal of Endocrinology

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Objective: This study explored whether short-term replacement therapy with growth hormone (GH) affects blood pressure (BP), heart rate (HR) and endothelial nitric oxide synthase (eNOS) expression in cardiovascular tissues in hypophysectomized (Hx) female rats. Design and Methods: BP, HR and the expression of eNOS in the aorta, caval vein and heart were studied in Hx female rats and in Hx female rats that underwent 7 days treatment with GH and thyroxine þ glucocorticoids ð½T 4 þ GCÞ: Insulin-like growth factor-I (IGF-I) was included in a second experimental protocol to explore the indirect effect of GH. The expression and localisation of eNOS was analysed by immunoblotting and immunohistochemistry. Results: Decreased BP (Hx 98^1; Intact 129^3 mmHg; P , 0:05), HR (Hx 297^14; Intact 399^31 beats=min; P , 0:05) and unchanged eNOS expression was demonstrated in Hx compared with intact rats. None of the hormones affected BP, but both GH and IGF-I increased HR compared with Hx rats (GH 358^10; IGF-I 337^7; Hx 306^11 beats=min; P , 0:05). Replacement of GH, GH þ ½T 4 þ GC and IGF-I resulted in an increased aortic eNOS expression (GH 161^24; GH þ ½T 4 þ GC 177^25; IGF-I 153^21; Hx 109^7%; P , 0:05), whereas in caval vein only GH þ ½T 4 þ GC affected eNOS expression. None of the hormones changed the level of eNOS in the heart. eNOS was localised in the intima layer of the aorta, whereas in the caval vein eNOS was localised in all cell layers. Conclusions: These findings support the suggested positive role of GH in the regulation of the cardiovascular homeostasis. The observed up-regulation of eNOS, and presumably an increased NO bioavailability, may result in improved endothelial and cardiovascular function.

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“…26,27 In the present study, we investigated whether a highly specific β 2 -AR agonist protects against MI/R injury in an in vivo murine model of AMI. For this study, we used the specific, β 2 -adrenergic agonist arformoterol (ARF), administered at the time of reperfusion.…”

mentioning

confidence: 99%

Selective β ₂ -Adrenoreceptor Stimulation Attenuates Myocardial Cell Death and Preserves Cardiac Function After Ischemia–Reperfusion Injury

Bhushan

Kondo²,

Predmore³

et al. 2012

ATVB

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Objective β2-adrenoreceptor activation has been shown to protect cardiac myocytes from cell death. We hypothesized that acute β2-adrenoreceptor stimulation, using arformoterol (ARF), would attenuate myocardial ischemia/reperfusion (R) injury via NO synthase activation and cause a subsequent increase in NO bioavailability. Methods and Results Male C57BL/6J and endothelial NO synthase (eNOS) knockout mice were subjected to 45 minutes of myocardial ischemia and 24 hours of R. ARF or vehicle was administered 5 minutes before R. Serum troponin-I was measured, and infarct size per area-at-risk was evaluated at 24 hours of R. Echocardiography was performed at baseline and 2 weeks after R. Myocardial cAMP, protein kinase A, eNOS/Akt phosphorylation status, and NO metabolite levels were assayed. ARF (1 μg/kg) reduced infarct size per area-at-risk by 53.1% (P<0.001 versus vehicle) and significantly reduced troponin-I levels (P<0.001 versus vehicle). Ejection fraction was significantly preserved in ARF-treated hearts compared with vehicle hearts at 2 weeks of R. Serum cAMP and nuclear protein kinase A C-α increased 5 and 15 minutes after ARF injection, respectively (P<0.01). ARF increased Akt phosphorylation at Thr308 (P<0.001) and Ser473 (P<0.01), and eNOS phosphorylation at Ser1177 (P<0.01). ARF treatment increased heart nitrosothiol levels (P<0.001) at 15 min after injection. ARF failed to reduce infarct size in eNOS−/− mice. Conclusions Our results indicate that β2-adrenoreceptor stimulation activates cAMP, protein kinase A, Akt, and eNOS and augments NO bioavailability. Activation of this prosurvival signaling pathway attenuates myocardial cell death and preserves cardiac function after ischemia/reperfusion.

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Up-Regulation of Endothelial Nitric Oxide Synthase through β2-Adrenergic Receptor—The Role of a β-Blocker with NO-Releasing Action

Cited by 28 publications

References 20 publications

A Nitric Oxide-Generating Beta-Blocking Agent Prevents Renal Injury in the Rat Remnant Kidney Model

A Nitric Oxide-Generating Beta-Blocking Agent Prevents Renal Injury in the Rat Remnant Kidney Model

GH and IGF-I regulate the expression of endothelial nitric oxide synthase (eNOS) in cardiovascular tissues of hypophysectomized female rats

Selective β ₂ -Adrenoreceptor Stimulation Attenuates Myocardial Cell Death and Preserves Cardiac Function After Ischemia–Reperfusion Injury

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Up-Regulation of Endothelial Nitric Oxide Synthase through β2-Adrenergic Receptor—The Role of a β-Blocker with NO-Releasing Action

Cited by 28 publications

References 20 publications

A Nitric Oxide-Generating Beta-Blocking Agent Prevents Renal Injury in the Rat Remnant Kidney Model

A Nitric Oxide-Generating Beta-Blocking Agent Prevents Renal Injury in the Rat Remnant Kidney Model

GH and IGF-I regulate the expression of endothelial nitric oxide synthase (eNOS) in cardiovascular tissues of hypophysectomized female rats

Selective β 2 -Adrenoreceptor Stimulation Attenuates Myocardial Cell Death and Preserves Cardiac Function After Ischemia–Reperfusion Injury

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Selective β ₂ -Adrenoreceptor Stimulation Attenuates Myocardial Cell Death and Preserves Cardiac Function After Ischemia–Reperfusion Injury