Ventricular hypertrophy and arterial hemodynamics following deprivation of nitric oxide in rats

Hu, Cheng-Tao; Chang, Huai-Ren; Hsu, Yung‐Hsiang; Liu, Chia-Jui; Chen, Hsing I.

doi:10.1016/j.lfs.2005.04.061

Cited by 18 publications

(15 citation statements)

References 33 publications

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“…Others and we previously suggested (12,19) a role of MMP activation and E-M uncoupling in cardiac remodeling and dysfunction in chronic heart failure. The results of this study showed that impaired arterial function in the HHcy model of arterial hy- Recently we demonstrated (20) that Hcy instigates a "negative vascular remodeling" or inward directed increase in arterial wall thickness and hypertension.…”

Section: Discussionmentioning

confidence: 75%

3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice

Ovechkin¹,

Tyagi²,

Sen³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chronic hyperhomocysteinemia (HHcy) is an important factor in development of arterial hypertension. HHcy is associated with activation of matrix metalloproteinases (MMPs); however, it is unclear whether HHcy-dependent extracellular matrix (ECM) accumulation plays a role in arterial hypertrophy and hypertension. We tested the hypothesis that in HHcy the mechanism of arterial hypertension involves arterial dysfunction in response to ECM accumulation between endothelial and arterial smooth muscle cells and subsequent endothelium-myocyte (E-M) uncoupling. To decrease plasma Hcy, dietary supplementation with 3-deazaadenosine (DZA), the S-adenosylhomocysteine hydrolase inhibitor, was administered to cystathionine ␤-synthase (CBS) knockout (KO) mice. Mice were grouped as follows: wild type (WT; control), WTϩDZA, CBSKO, and CBSKOϩDZA (n ϭ 4/group). Mean aortic blood pressure and heart rate were monitored in real time with a telemetric system before, during, and after DZA treatment (6 wk total). In vivo aorta function and morphology were analyzed by M-mode and Doppler echocardiography in anesthetized mice. Aorta MMP activity in unfixed cryostat sections was measured with DQ gelatin. Aorta MMP-2, MMP-9, and connexin 43 expression were measured by RT-PCR and Western blot analyses, respectively. HHcy caused increased aortic blood pressure and resistance, tachycardia, and increased wall thickness and ECM accumulation in aortic wall vs. control groups. There was a linear correlation between aortic wall thickness and plasma Hcy levels. MMP-2, MMP-9, and connexin 43 expression were increased in HHcy. In the CBSKOϩDZA group, aortic blood pressure and levels of MMP and connexin 43 were close to those found in control groups. However, removal of DZA reversed the aortic lumen-to-wall thickness ratio in CBSKO mice, suggesting, in part, a role of vascular remodeling in the increase in blood pressure in HHcy. The results show that arterial hypertension in HHcy mice is, in part, associated with arterial remodeling and E-M uncoupling in response to MMP activation. cardiovascular dysfunction; aorta; echocardiography; extracellular matrix remodeling; in situ matrix metalloproteinase activity; cystathionine ␤-synthase; connexin; DQ gelatin; telemetry EXPERIMENTAL AND CLINICAL studies have shown that chronic elevation of homocysteine (Hcy) levels, known as hyperhomocysteinemia (HHcy), is a significant independent risk factor for cardiovascular disease (31), particularly in the development of arterial hypertension and atherosclerosis (3,24,26). The mechanisms by which HHcy affects arterial wall and induces arterial hypertension have remained unclear. It has been shown that HHcy leads to arterial damage (4) and increased arterial wall stiffness (2,22).Hcy is a product of methionine metabolism that under normal conditions is converted to cystathionine by cystathionine ␤-synthase (CBS). It has been established that mice carrying a disrupted CBS gene are adequate models for HHcy. Systemic vascular cells lacking CBS (7,8) are the prime target for...

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Section: Discussionmentioning

confidence: 75%

3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice

Ovechkin¹,

Tyagi²,

Sen³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…19 The improved cardiac hemodynamic profile of nebivolol may be because of the induction of NO. Actually, NO improves coronary blood flow, reduces peripheral resistance, improves cardiac output, 20 attenuates cardiac hypertrophy, 21 and mediates the protective effects of ischemic preconditioning. 22 Thus, induction of cardiac NO by nebivolol but not by other ␤-adrenergic receptor antagonists, such as atenolol, may account for the improved cardiac profile of the drug.…”

Section: Discussionmentioning

confidence: 99%

Nebivolol Induces Nitric Oxide Release in the Heart Through Inducible Nitric Oxide Synthase Activation

et al. 2007

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Abstract-Nebivolol is a ␤1-adrenergic receptor antagonist that also reduces blood pressure by evoking endothelial NO production and vasodilation. We aimed at assessing whether nebivolol induces NO production also in the heart and delineating the molecular mechanisms involved. Using the fluorescent probe diaminofluorescein, we found that nebivolol induces a dose-dependent NO production in the heart, statistically significant already at 10 Ϫ7 mol/L. It is not an effect because of the blockade of ␤1-adrenergic receptor, because this effect is not shared by another drug of the same class, atenolol. Because nebivolol has been reported to act as an agonist on other ␤-adrenergic receptors, we tested NO production in the presence of receptor antagonists. Nebivolol was not able to induce NO production in presence of the ␤3-antagonist SR59230A, indicating a fundamental role for ␤3-adrenergic receptors in cardiac NO production by nebivolol. Moreover, inducible NO synthase inhibition abolishes NO release in the heart, indicating that nebivolol induces NO production by acting on the inducible isoform of the enzyme. The action of nebivolol on inducible NO synthase was confirmed by real-time PCR experiments, showing cardiac overexpression of inducible NO synthase but not neuronal NO synthase or endothelial NO synthase, after 5 hours of treatment with nebivolol. In conclusion, our study demonstrates that nebivolol also stimulates NO production in the heart. This action of nebivolol is exerted via a signaling pathway starting from the activation of ␤3-adrenergic receptors and leading to overexpression of inducible NO synthase. Cardiac NO production by nebivolol could participate in the cardiovascular effects of nebivolol treatment in patients affected by hypertension and heart failure. Key Words: adrenergic agents Ⅲ adrenergic beta receptors Ⅲ heart Ⅲ NO Ⅲ NO synthase ␤ -Blockers are among the antihypertensive drugs most indicated against heart failure. 1 ␤-Blockers act principally to inhibit the adverse effects of the sympathetic nervous system in patients with heart failure. 2,3 In fact, whereas cardiac adrenergic drive initially supports the performance of the failing heart, long-term activation of the sympathetic nervous system exerts deleterious effects that can be antagonized by the use of ␤-blockers.In addition to the inhibitory effects on ␤1-adrenergic receptors, the novel ␤-blocker nebivolol has additional hemodynamic properties. 4 In particular, nebivolol is able to stimulate endogenous production of NO by inducing phosphorylation of the endothelial enzyme endothelial NO synthase (NOS; eNOS). 5 The particular properties of nebivolol also determine favorable effects on cardiac function in patients with heart failure when compared with classical ␤-blockers, 6 but the mechanisms underlying these beneficial differences have not been well characterized. In this regard, whereas nebivolol action on NO can result in favorable outcomes at vascular levels, the effects of NO on the heart are not so straightforwardly beneficial.In...

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“…Various authors that have demonstrated cardiac hypertrophy induced by chronic NO synthesis blockade, used treatment timeframes of more than four weeks even though the daily L-NAME doses were lower than those used in our study 3,33 . On the other hand, the purpose of the present study was to investigate blood pressure trends and cardiac morphometric alterations in animals submitted to an established aerobic exercise protocol with the main objective of evaluating the ability of the established training program to preventively attenuate these alterations.…”

Section: Discussionmentioning

confidence: 94%

“…NO, in addition to its potent vasodilator action, induces other important vascular, renal and cardiac effects including inhibiting platelet aggregation, modulation of the glomerular filtration rate and effect on vascular and cardiac remodeling 2,3 . In turn the diminished endogenous NO production is related to the reduction of endothelial-dependent vasodilatation in patients with hypertension, hypercholesterolemia, diabetes or arteriosclerosis 4 .…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, other studies have shown that NO is also more directly involved in cardiac remodeling, since its reduction causes significant morphological alterations such as necrosis foci, increased fibrosis, apoptosis, reduction of cardiac angiogenesis and consequent pathological hypertrophy [7][8][9][10][11] . Nevertheless, literature on cardiac hypertrophy development and the effects of acute or chronic NO synthesis inhibition with L-arginine analogous agents, such as N G -monomethyl-L-arginine (L-NMMA) or N G -nitro-L-arginine methyl ester (L-NAME) that result in the consequent elevation of BP is controversial 2,3,[12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

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O bloqueio da síntese do óxido nítrico promove aumento da hipertrofia e da fibrose cardíaca em ratos submetidos a treinamento aeróbio

Souza¹,

Penteado²,

Martin-Pinge³

et al. 2007

Arq. Bras. Cardiol.

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SummaryObjective: The objective of the present study was to evaluate cardiac tissue adaptations in rats submitted to aerobic training after nitric oxide (NO) synthesis blockade.Methods: The animals (n=48) were divided into four groups: sedentary (CONTROL group); hypertensive after administration of NG-nitro-L-arginine methyl ester for 7 days (L-NAME Group); trained for 8 weeks through swimming exercises (TRAINED Group);trained and treated with L-NAME during the last week (L-NAME TRAINED Group). All the animals were submitted to the experiment procedures for blood pressure (BP) readings and cardiac morphometric evaluation.Results: In comparison to the other groups, the L-NAME and L-NAME TRAINED groups were hypertensive (p<0.05); however, BP elevation in the L-NAME TRAINED group was significantly lower than the L-NAME group (p<0.05). The heart weight indexes for the TRAINED and L-NAME TRAINED groups were higher than the CONTROL and L-NAME groups (p<0.05). Also they had presented higher rates of macroscopic cardiac area and cardiac fibrosis in relation to the rest (p<0.05); comparisons revealed that the values for the L-NAME TRAINED group were significantly higher (p<0.05) than the others. Conclusion

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Ventricular hypertrophy and arterial hemodynamics following deprivation of nitric oxide in rats

Cited by 18 publications

References 33 publications

3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice

3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice

Nebivolol Induces Nitric Oxide Release in the Heart Through Inducible Nitric Oxide Synthase Activation

O bloqueio da síntese do óxido nítrico promove aumento da hipertrofia e da fibrose cardíaca em ratos submetidos a treinamento aeróbio

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