Effect of In Vivo Nitroglycerin Therapy on Endothelium-Dependent and Independent Vascular Relaxation and Cyclic GMP Accumulation in Rat Aorta

Molina, César; Andresen, J. W.; Rapoport, Robert M.; Waldman, Scott A.; Murad, Ferid

doi:10.1097/00005344-198710000-00001

Cited by 121 publications

(69 citation statements)

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“…Indeed, chronic vitamin C treatment increases nitric-oxide synthase enzymatic activity in aortas of C57BL/6J mice (d'Uscio et al, 2003). Consistent with previous reports, increased local concentration of vascular NO caused reduced smooth muscle reactivity to both endogenous NO released by acetylcholine or exogenous NO generated by DEA-NONOate (Molina et al, 1987;Ohashi et al, 1998;d'Uscio et al, 2003). However, the most important finding of the present study is that chronic treatment with vitamin C has beneficial effect on endothelial function in hypercholesterolemic apoE Ϫ/Ϫ mice carotid artery.…”

Section: Protective Effect Of Chronic Vitamin C Treatment 105supporting

confidence: 92%

Protective Effect of Chronic Vitamin C Treatment on Endothelial Function of Apolipoprotein E-Deficient Mouse Carotid Artery

Matsumoto

d’Uscio

Eguchi

et al. 2003

J Pharmacol Exp Ther

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Endothelium-dependent relaxations are impaired in carotid artery of apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. This impairment seems to be due to increased formation of superoxide anions and inactivation of endothelial nitric oxide (NO). In the present study, we tested hypothesis that chronic treatment with vitamin C may prevent endothelial dysfunction by increasing release of NO from endothelial cells. C57BL/6 and apoE Ϫ/Ϫ mice were treated for 26 weeks with Western-type fat diet with and without 1% vitamin C. Vasomotor function of isolated carotid arteries was studied by video dimension analyzer. Expression of endothelial NO synthase (eNOS) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) protein were evaluated by Western blotting. Levels of cGMP and cAMP were measured by radioimmunoassay. In apoE Ϫ/Ϫ mice, vitamin C significantly augmented relaxations to acetylcholine (10 Ϫ9 -10 Ϫ5 mol/l), but did not affect relaxations to NO donor diethylammonium-(Z)-1-(N,N-diethylamino) diazen-1-1,2-diolate (DEA-NONOate; 10 Ϫ9 -10 Ϫ5 mol/l). In contrast, vitamin C reduced relaxations to acetylcholine and DEA-NONOate in C57BL/6 mice. Interestingly, vitamin C significantly increased basal cGMP levels in C57BL/6 mice but did not affect cGMP formation in apoE Ϫ/Ϫ . Vitamin C treatment did not affect expression of eNOS protein, whereas elevated expression of PECAM-1 protein in apoE Ϫ/Ϫ mice was returned to normal level. Our findings demonstrate that chronic treatment with vitamin C prevents endothelial dysfunction of carotid artery induced by hypercholesterolemia. This effect seems to be mediated by preservation of NO bioavailability in endothelial cells.

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Section: Protective Effect Of Chronic Vitamin C Treatment 105supporting

confidence: 92%

Protective Effect of Chronic Vitamin C Treatment on Endothelial Function of Apolipoprotein E-Deficient Mouse Carotid Artery

Matsumoto

d’Uscio

Eguchi

et al. 2003

J Pharmacol Exp Ther

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“…It appears unlikely that activation of a phospho-VASP phosphatase or an increased activity of a cGK-I inhibitor or of phosphodiesterases could account for decreased VASP phosphorylation. This is supported by the observations that the vascular relaxation in response to direct cGK-I activators such as 8-bromo-cGMP 5 and the extent of maximal SNP-induced P-VASP ( Figure 5) are not altered during nitrate tolerance.…”

supporting

confidence: 67%

“…Previously, we and others have shown that treatment of rats and rabbits with NTG leads to a marked attenuation of vasodilator responses to NTG as well as to NO/EDRFeliciting agonists. 4,5 Because in vivo NTG tolerance is associated with decreased basal and NO-induced cGMP level in vascular tissue, Molina et al 5 hypothesized that sGC in vascular smooth muscle was desensitized by chronic exposure to NTG. Recent studies have shown that chronic NTG treatment increases superoxide in endothelial as well as in smooth muscle cells 4,15 and that removal of endothelium as well as treatment with liposomal superoxide dismutase (SOD) partially but not completely improved NTG-elicited relaxations in tolerant tissue.…”

Section: Discussionmentioning

confidence: 99%

“…3 Although short-term application of NTG exhibits high vasodilator and anti-ischemic efficacy, this activity is rapidly lost on long-term treatment because of the development of tolerance. 4 The mechanisms underlying this phenomenon are likely to be multifactorial and may involve neurohormonal adjustments as well as changes intrinsic to the vasculature itself, such as desensitization of the sGC 5 and/or decreased expression of the cGMP-dependent kinase I (cGK-I). 6 Using lucigenin-derived chemiluminescence, we recently showed that NTG increases vascular superoxide in endothelial but also in smooth muscle cells.…”

mentioning

confidence: 99%

“…The active enzyme is an obligate heterodimer, which in most mammalian tissues consists of ␣ 1 (76-to 82-kDa) and ␤ 1 (70-kDa) protein subunits. 7 Chronic in vivo NTG treatment attenuates the increase in vascular cGMP levels in response to acute challenge with endotheliumderived NO and other nitrovasodilators 5 because of so-called cross-tolerance. Furthermore, in vitro exposure of cells and tissues with high NO concentrations desensitizes sGC to nitrovasodilators, a phenomenon called in vitro tolerance.…”

mentioning

confidence: 99%

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Effects of In Vivo Nitroglycerin Treatment on Activity and Expression of the Guanylyl Cyclase and cGMP-Dependent Protein Kinase and Their Downstream Target Vasodilator-Stimulated Phosphoprotein in Aorta

et al. 2001

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Background-Chronic in vivo treatment with nitroglycerin (NTG) induces tolerance to nitrates and cross-tolerance to nitrovasodilators and endothelium-derived nitric oxide (NO). We previously identified increased vascular superoxide formation and reduced NO bioavailability as one causal mechanism. It is still controversial whether intracellular downstream signaling to nitrovasodilator-derived NO is affected as well. Methods and Results-We therefore studied the effects of 3-day NTG treatment of rats and rabbits on activity and expression of the immediate NO target soluble guanylyl cyclase (sGC) and on the cGMP-activated protein kinase I (cGK-I). Tolerance was induced either by chronic NTG infusion via osmotic minipumps (rats) or by NTG patches (rabbits). Western blot analysis, semiquantitative reverse transcription-polymerase chain reaction, and Northern blot analysis revealed significant and comparable increases in the expression of sGC ␣ 1 and ␤ 1 subunit protein and mRNA. Studies with the oxidative fluorescent dye hydroethidine revealed an increase in superoxide in the endothelium and smooth muscle. Stimulation with NADH increased superoxide signals in both layers. Although cGK-I expression in response to low-dose NTG was not changed, a strong reduction in vasodilator-stimulated phosphoprotein (VASP) serine239 phosphorylation (specific substrate of cGK-I) was observed in tolerant tissue from rats and rabbits. Concomitant in vivo and in vitro treatment with vitamin C improved tolerance, reduced oxidative stress, and improved P-VASP. Conclusions-We therefore conclude that increased expression of sGC in the setting of tolerance reflects a chronic inhibition rather than an induction of the sGC-cGK-I pathway and may be mediated at least in part by increased vascular superoxide. (Circulation. 2001;103:2188-2194.)

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Continuous long‐term dosing with oral slow‐release isosorbide dinitrate does not reduce incidence of cardiac events in patients with healed myocardial infarction

Kanamasa

Hayashi

Takenaka

et al. 2001

Clinical Cardiology

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Background:In the short term, isosorbide dinitrate (ISDN) is considered to be therapeutically effective. The long-term effects of treatment with slow-release ISDN are less clear.Hypothesis: The study was undertaken to investigate the effects of continuous, long-term dosing with oral slow-release ISDN on the incidence of cardiac events in patients with healed myocardial infarction (MI). The study was carried out in accordance with the intention-to-treat principle.Methods: In all, I, 102 in-and outpatients, of either gender, with healed MI were randomly divided into groups treated with ISDN (n = 470) and not treated with ISDN (n = 632). Patients in the ISDN group received a continuous regimen of 20 mg of oral, long-acting ISDN three times a day, after meals. The mean observation period was 15.0 k 18.5 months. The primary endpoints were nonfatal and fatal recurrent MI, death from congestive heart failure, and sudden death.Results: There were no significant differences in the baseline characteristics of the patients in the ISDN and no-treatment groups; nevertheless, significantly more patients in the ISDN group experienced cardiac events. In the ISDN group, 35 patients (7.4%) experienced cardiac events during the observation period, versus only 28 patients (4.4%) in the notreatment group (p c 0.05; odds ratio 1.74; 95% confidence interval 1.04-2.90).Conclusion: Continuous long-term dosing with oral, slowrelease ISDN does not reduce and probably increases the incidence of cardiac events among patients with healed MI.

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Effect of In Vivo Nitroglycerin Therapy on Endothelium-Dependent and Independent Vascular Relaxation and Cyclic GMP Accumulation in Rat Aorta

Cited by 121 publications

References 0 publications

Protective Effect of Chronic Vitamin C Treatment on Endothelial Function of Apolipoprotein E-Deficient Mouse Carotid Artery

Protective Effect of Chronic Vitamin C Treatment on Endothelial Function of Apolipoprotein E-Deficient Mouse Carotid Artery

Effects of In Vivo Nitroglycerin Treatment on Activity and Expression of the Guanylyl Cyclase and cGMP-Dependent Protein Kinase and Their Downstream Target Vasodilator-Stimulated Phosphoprotein in Aorta

Continuous long‐term dosing with oral slow‐release isosorbide dinitrate does not reduce incidence of cardiac events in patients with healed myocardial infarction

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