Inhibition of iNOS Protects the Aging Heart Against β-Adrenergic Receptor Stimulation-Induced Cardiac Dysfunction and Myocardial Ischemic Injury

Li, Dianyuan; Qu, Yan; Tao, Ling; Liu, Huirong; Hu, Aihua; Gao, Feng; Sharifi-Azad, Said; Grunwald, Zvi; Ma, Xin‐Liang; Sun, Jianyong

doi:10.1016/j.jss.2005.06.038

Cited by 61 publications

(43 citation statements)

References 36 publications

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“…It has been, reported that 毬 -AR stimulation upregulated iNOS and significant increases production of NO, which create a nitrosative stress and generate the powerful oxidant molecule peroxynitrite (ONOO-) [26] . Administration of LYP in the present study significantly decreased the elevated tissue nitrite levels which might be due to their antioxidant activity which prevents superoxide generation and thereby peroxinitrite formation.…”

Section: Discussionmentioning

confidence: 99%

Tomato lycopene attenuates myocardial infarction induced by isoproterenol: Electrocardiographic, biochemical and anti–apoptotic study

Upaganlawar

Vaibhav

Balaraman

2012

Asian Pacific Journal of Tropical Biomedicine

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Section: Discussionmentioning

confidence: 99%

Tomato lycopene attenuates myocardial infarction induced by isoproterenol: Electrocardiographic, biochemical and anti–apoptotic study

Upaganlawar

Vaibhav

Balaraman

2012

Asian Pacific Journal of Tropical Biomedicine

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“…Several studies have found that iNOS triggered a significant increased NO production, which could create a nitrative stress and generate the toxic oxidant molecule peroxynitrite (ONOO -) excessively [31] . ONOO -is responsible for nitration of tyrosine residues in proteins, therefore the presence of nitrotyrosine (NT) in plasma proteins is considered an indirect evidence of ONOO -production [30] .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of iNOS protects endothelial-dependent vasodilation in aged rats

Tian

Yan

et al. 2010

Acta Pharmacol Sin

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Aim: To examine whether iNOS contributes to endothelial dysfunction in aged rats. Methods: Male Sprague Dawley rats were divided into three groups: young rats, aged rats treated with vehicle and aged rats treated with N-[3-(Aminomethyl) benzyl] acetamidine (1400W, 1 mg/kg, ip). Vasorelaxation was measured in isolated thoracic aorta. iNOS expression of thoracic aortic arteries was detected using immunohistochemistry and Western blot. Nitrotyrosine (a marker for peroxynitrite formation) content and expression in thoracic aortic tissue were determined using enzyme linked immunosorbent assay and immunohistochemistry. Results: Maximal relaxation induced by acetylcholine (10 -9 to 10 -5 mol/L) in the aged rats treated with vehicle was significantly decreased (70%±15%, P<0.01), as compared with the young rats (95%±8%). However, the maximal relaxation induced by acidified NaNO2 (an endothelium-independent vasodilator) had no significant difference between the two groups. Moreover, iNOS and nitrotyrosine expression increased in the vessels of the aged rats. In the aged rats treated with 1400W (a highly selective iNOS inhibitor) nitrotyrosine expression was reduced and acetylcholine-induced vasorelaxation was markedly improved (maximal relaxation was increased to 87%±8%, P<0.05), but the acidified NaNO 2 -induced vasorelaxation had no significant change. Conclusion: Our study demonstrated that inhibition of iNOS by 1400W increased endothelium-dependent vasodilation in aged rats. The mechanism was related with attenuation of peroxynitrite formation.Keywords: aging; nitric oxide synthase; endothelium; vasodilation; 1400W Acta Pharmacologica Sinica (2010Sinica ( ) 31: 1324Sinica ( -1328 doi: 10.1038/aps.2010 published online 13 Sep 2010 Original Article * To whom correspondence should be addressed. [17,18] , respectively. Thirty minutes after 1400W treatment [18,19] young and aged rats were sacrificed to obtain vessel tissues (n=7 rats per group) for nitrotyrosine content and immunohistochemical studies of iNOS and nitrotyrosine. Determination of endothelial functionEndothelial function was determined by comparing the vasorelaxation response to acetylcholine (ACh), an endothelium-dependent vasodilator, with that of acidified NaNO 2 , an endothelium-independent vasodilator, as described previously [20] . Briefly, thoracic aortic rings were mounted onto hooks, suspended in organ chambers filled with Krebs buffer (mmol/L: NaCl 118.3, KCl 4.7, CaCl 2 2.5, MgSO 4 1.2, KH 2 PO 4 1.2, NaHCO 3 25.0, glucose 11.0, pH=7.4) [21] and aerated with 95% O 2 and 5% CO 2 at 37 °C, and connected to force transducers to record changes in tension via a Chart 5.3 data acquisition system. After equilibration for 60 min at a preload of 1 g, the rings were precontracted with norepinephrine (NE, 1 μmol/L). Once a stable contraction was achieved, the rings were exposed to cumulative concentrations of ACh (10 -9 to 10 -5 mol/L). After the cumulative response was stabilized, the rings were washed and allowed to equilibrate to baseline. The procedur...

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“…Such high levels of NO are recognized as a mediator and regulator of inflammatory responses. Recently, our studies found that acute ␤-AR stimulation in aging ischemic heart triggered a marked increase in NO production, generated toxic peroxynitrite, activated apoptosis, and eventually caused cardiac dysfunction and myocardial injury (Li et al, 2006). However, whether the induction or/and expression of iNOS is beneficial or deleterious over the long term, particularly its effects on myocardial apoptosis and MI/reperfusion (R) injury, remains enigmatic.…”

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confidence: 99%

Chronic β-Adrenergic Receptor Stimulation Induces Cardiac Apoptosis and Aggravates Myocardial Ischemia/Reperfusion Injury by Provoking Inducible Nitric-Oxide Synthase-Mediated Nitrative Stress

Jiao²,

Gao³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

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The present study provides evidence that inducible nitric-oxide synthase (iNOS)-mediated nitrative stress plays a pivotal role in chronic ␤-adrenergic receptor (AR) stimulation-induced cardiac damage. In mice, 14 days of isoproterenol (ISO) stimulation via an osmotic minipump induced an up-regulation of iNOS as evidenced by increases in mRNA, protein expression, and immunochemical staining of myocardial iNOS. Serum level of C-reactive protein, an inflammatory mediator, was also markedly increased. Under chronic ISO stimulation, the up-regulated iNOS produced a significantly increased amount of nitric oxide (NO) and its byproduct, peroxynitrite, in the circulation and heart and subsequently resulted in an accelerated myocardial apoptosis. Forty-minute myocardial ischemia (MI) and 24-h reperfusion (R) further increased NO production and peroxynitrite formation and resulted in an enlarged infarct size in mice receiving chronic ISO stimulation. However, the treatment with a selective iNOS inhibitor [N-(3-(aminomethyl) benzyl)acetamidine] (1400W) or the use of a genetic modified animal (iNOSknockout mice) markedly reduced iNOS-mediated production of NO and formation of peroxynitrite and consequently significantly decreased myocardial apoptosis and infarct size, showing a crucial link between iNOS-mediated nitrative stress and myocardial injury. In conclusion, chronic ␤-AR stimulation upregulates iNOS expression and increases NO production in the heart, which subsequently markedly enhances formation of reactive nitrogen species/peroxynitrite in the heart, thereby eliciting myocardial apoptosis and potentiating MI/R injury.

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Inhibition of iNOS Protects the Aging Heart Against β-Adrenergic Receptor Stimulation-Induced Cardiac Dysfunction and Myocardial Ischemic Injury

Cited by 61 publications

References 36 publications

Tomato lycopene attenuates myocardial infarction induced by isoproterenol: Electrocardiographic, biochemical and anti–apoptotic study

Tomato lycopene attenuates myocardial infarction induced by isoproterenol: Electrocardiographic, biochemical and anti–apoptotic study

Inhibition of iNOS protects endothelial-dependent vasodilation in aged rats

Chronic β-Adrenergic Receptor Stimulation Induces Cardiac Apoptosis and Aggravates Myocardial Ischemia/Reperfusion Injury by Provoking Inducible Nitric-Oxide Synthase-Mediated Nitrative Stress

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