Expression of Constitutive and Inducible Nitric Oxide Synthases in the Vascular Wall of Young and Aging Rats

Cernadas, M R; Miguel, Lourdes Sánchez de; Garcı́a-Durán, Margarita; González-Fernández, Fernando; Millás, Inmaculada; Montón, Mercedes; Rodrigo, José; Rico, Luís; Fernández, Ana Patricia; Frutos, Trinidad de; Rodríguez-Feo, Juan A.; Guerra, José; Caramelo, Carlos; Casado, Santos; López‐Farré, Antonio

doi:10.1161/01.res.83.3.279

Cited by 287 publications

(236 citation statements)

References 25 publications

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“…The role of the L-arginine/NO pathway in the pathophysiology of vascular aging is controversial. Both reduced levels of eNOS mRNA (Challah et al, 1997) and increased eNOS enzyme expression combined with reduced activity (Cernadas et al, 1998) have been reported. Therefore, our first aim was to clarify whether age-associated endothelial dysfunction is causally related to alterations of the L -arginine/NO system.…”

Section: Introductionmentioning

confidence: 94%

Superoxide as a Messenger of Endothelial Function

Ullrich

Bachschmid²

2000

Biochemical and Biophysical Research Communications

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Section: Introductionmentioning

confidence: 94%

Superoxide as a Messenger of Endothelial Function

Ullrich

Bachschmid²

2000

Biochemical and Biophysical Research Communications

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“…Animals were age-matched to minimize differences in both the angiogenic response (36) and vascular NOS III expression (37).…”

Section: Tumor Implantsmentioning

confidence: 99%

Antitumor Actions of Ruthenium(III)-Based Nitric Oxide Scavengers and Nitric Oxide Synthase Inhibitors

Flitney

Pritchard²,

Kennovin³

et al. 2011

Molecular Cancer Therapeutics

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The role of endogenous nitric oxide (NO) in the growth and vascularization of a rat carcinosarcoma (P22) has been investigated. Tumor-bearing animals were treated with (i) nitric oxide synthase (NOS) inhibitors, administered via the drinking water, including N G -nitro-L-arginine methyl ester (L-NAME), a nonisoform-selective inhibitor, and 2 others that target the inducible (NOS II) enzyme preferentially, namely 1-amino-2-hydroxyguanidine or N-[3-(aminomethyl)benzyl]acetamidine hydrochloride; or (ii) daily injections (intraperitoneally) of 2 Ru(III) polyaminocarboxylates, AMD6221 and AMD6245, both of which are effective NO scavengers. L-NAME, AMD6221, and AMD6245 reduced tumor growth by approximately 60% to 75% of control rates. Tumor sections stained with abs to CD-31/platelet endothelial cell adhesion molecule-1 or NOS III showed that this was associated with a marked reduction (60%-77%) of tumor microvascular densitiy (MVD). Tumors resumed growing promptly when treatment was discontinued, accompanied by partial or complete restoration of MVDs. In contrast, NOS-II selective inhibitors had no effect on tumor growth or vascularization, indicating that both responses require complete blockade of NO production. The results corroborate the view that endogenous NO facilitates tumor development. We suggest that NO deprivation causes tumor feeder vessels to constrict, reducing tumor blood flow. The delivery of oxygen and essential nutrients to the developing tumor is impaired as a consequence, hampering further growth. Normalizing NO levels by withholding treatment causes tumor feeder vessels to dilate, increasing tumor perfusion and reestablishing conditions that allow tumors to begin growing again.

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“…Most previous studies suggested that decreased endothelialdependent vasodilatation was mainly associated with down regulation of eNOS and endogenous NO [13,14] . Recent research found that, iNOS expression increased in vascular tissue of aged rats [15,16] . However, it is unclear that whether elevated iNOS plays a role in the decline of endothelium-dependent vasodilatation.…”

Section: Introductionmentioning

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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Expression of Constitutive and Inducible Nitric Oxide Synthases in the Vascular Wall of Young and Aging Rats

Cited by 287 publications

References 25 publications

Superoxide as a Messenger of Endothelial Function

Superoxide as a Messenger of Endothelial Function

Antitumor Actions of Ruthenium(III)-Based Nitric Oxide Scavengers and Nitric Oxide Synthase Inhibitors

Inhibition of iNOS protects endothelial-dependent vasodilation in aged rats

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