Effects of nitroglycerin or pentaerithrityl tetranitrate treatment on the gene expression in rat hearts: evidence for cardiotoxic and cardioprotective effects

Pautz, Andrea; Rauschkolb, Peter; Schmidt, Nadine; Art, Julia; Oelze, Matthias; Wenzel, Philip; Förstermann, Ulrich; Daiber, Andreas; Kleinert, Hartmut

doi:10.1152/physiolgenomics.00035.2009

Cited by 25 publications

(24 citation statements)

References 116 publications

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“…Treatment of rats with PETN is known to induce many cardioprotective genes in the heart. 25 It is possible that maternal PETN treatment also cause gene expression changes in the heart of the offspring. In optimal case, this gene regulation may lead to changes that resemble physiological cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Maternal Treatment of Spontaneously Hypertensive Rats With Pentaerythritol Tetranitrate Reduces Blood Pressure in Female Offspring

Siuda

Xia

et al. 2015

Hypertension

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Pentaerythritol tetranitrate is devoid of nitrate tolerance and shows no reproductive or developmental toxicity in animal studies. Recently, pentaerythritol tetranitrate has been demonstrated to reduce the risk of intrauterine growth restriction and the risk of preterm birth in women with abnormal placental perfusion. This study was conducted to test the perinatal programming effect of pentaerythritol tetranitrate in spontaneously hypertensive rats, a rat model of genetic hypertension. Parental spontaneously hypertensive rats were treated with pentaerythritol tetranitrate (50 mg/kg per day) during pregnancy and lactation periods; the offspring received standard chow without pentaerythritol tetranitrate after weaning. Maternal treatment with pentaerythritol tetranitrate had no effect on blood pressure in male offspring. In the female offspring, however, a persistent reduction in blood pressure was observed at 6 and 8 months. This long-lasting effect was accompanied by an upregulation of endothelial nitric oxide synthase, mitochondrial superoxide dismutase, glutathione peroxidase 1, and heme oxygenase 1 in the aorta of 8-month-old female offspring, which was likely to result from epigenetic changes (enhanced histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation) and transcriptional activation (enhanced binding of DNA-directed RNA polymerase II to the transcription start site of the genes). In organ chamber experiments, the endothelium-dependent, nitric oxide–mediated vasodilation to acetylcholine was enhanced in aorta from female offspring of the pentaerythritol tetranitrate–treated parental spontaneously hypertensive rats. In conclusion, maternal pentaerythritol tetranitrate treatment leads to epigenetic modifications, gene expression changes, an improvement of endothelial function and a persistent blood pressure reduction in the female offspring.

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Section: Discussionmentioning

confidence: 99%

Maternal Treatment of Spontaneously Hypertensive Rats With Pentaerythritol Tetranitrate Reduces Blood Pressure in Female Offspring

Siuda

Xia

et al. 2015

Hypertension

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“…Evidence consonant with the hypothesis that the mediator is different among different nitrate molecules in this class was also provided by a recent study demonstrating that so-called NO donors such as GTN and pentaerythrityl tetranitrate (PETN) have different effects on myocardial gene expression. 26 Treatment with GTN resulted in a larger expression of cardiotoxic genes and inhibition of the expression of cardioprotective proteins, whereas PETN treatment enhanced the expression of genes in the opposite direction. A possible explanation for this differential gene expression profiles in response to both compounds may be the release of different vasoactive molecules on bioactivation 26 (Figure 3).…”

Section: No Nitric Oxide From Glyceryl Trinitrate?mentioning

confidence: 99%

“…26 Treatment with GTN resulted in a larger expression of cardiotoxic genes and inhibition of the expression of cardioprotective proteins, whereas PETN treatment enhanced the expression of genes in the opposite direction. A possible explanation for this differential gene expression profiles in response to both compounds may be the release of different vasoactive molecules on bioactivation 26 (Figure 3). …”

Section: No Nitric Oxide From Glyceryl Trinitrate?mentioning

confidence: 99%

Nitrate Therapy

2011

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A lthough the short-term vasodilatory properties of organic nitrates are potent and well known, a number of vascular and extravascular changes have been shown to compromise their hemodynamic effects on long-term administration. Among these changes, systemic phenomena such as neurohormonal activation and intravascular volume expansion 1 as well as specific vascular changes such as increased vascular superoxide (O 2 ·Ϫ ) production, 2 increased sensitivity to vasoconstrictors, 3 and decreased responsiveness to nitric oxide (NO) donors 4,5 have long been identified as playing a role. Several hypotheses have been proposed to explain these abnormalities, and over the last 15 years, our groups have focused on the concept that an inappropriate production of reactive oxygen species (ROS), an impairment in the scavenging of these mediators (Figure 1), or both might have a crucial mechanistic importance in all these modifications. 6,7 Independently of the role of ROS in tolerance, the possibility that nitrate-induced oxidative stress might affect patients' prognosis has important implications, and the observation that long-term therapy with most of the drugs in this class causes endothelial dysfunction, the prognostic significance of which is well accepted in patients with coronary artery disease, hypertension, and heart failure, 8 should not be taken as an academic curiosity.Beyond these as-yet insufficiently investigated prognostic implications, recognition of the role of ROS suggests that a number of interventions thought to interfere with the vascular redox balance might also retard or prevent the development of nitrate tolerance and nitrate-induced side effects. Evidence that therapy with angiotensin-converting enzyme (ACE) inhibitors, angiotensin-1 receptor blockers, certain ␤-blockers, statins, and vitamins such as folic acid or vitamin C beneficially influence nitrate tolerance and glyceryl trinitrate (GTN)-induced endothelial dysfunction suggests that nitrate therapy might have profoundly different implications since these therapies have become diffusely available. In addition, the recognition of important differences in the mechanisms triggered by different nitrates should also be attributed clinical relevance, and evidence suggests that, rather than the generic nitrate tolerance, more specific expressions (GTN tolerance, isosorbide mononitrate [ISMN] tolerance, etc) should be used. 9 This review summarizes the current concepts underlying tolerance and endothelial dysfunction in response to longterm therapy with different nitrates and addresses the question of whether the use of these drugs remains indicated despite these side effects. The Hemodynamic Effects of NitratesVenous capacitance vessels, large and medium-sized coronary arteries, and collateral vessels are most sensitive to GTN, whereas coronary and peripheral arterioles with a diameter Ͻ100 m are relatively more resistant. In the setting of stable angina, the preferential venodilatation induced by antiischemic doses of GTN results in venous pooling an...

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“…Beneficial modulation of cardioprotective/cardiotoxic genes by PETN treatment has also been reported in the myocardium of healthy rats. 38 Therefore, we cannot exclude cardioprotective effects of PETN therapy in rats without coronary ligation.…”

Section: Discussionmentioning

confidence: 99%

Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure

et al. 2015

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Reduced nitric oxide bioavailability contributes to progression of cardiac dysfunction and remodeling in ischemic heart failure. Clinical use of organic nitrates as nitric oxide donors is limited by development of nitrate tolerance and reactive oxygen species formation. We investigated the effects of long-term therapy with pentaerythritol tetranitrate (PETN), an organic nitrate devoid of tolerance, in rats with congestive heart failure after extensive myocardial infarction. Seven days after coronary artery ligation, rats were randomly allocated to treatment with PETN (80 mg/kg BID) or placebo for 9 weeks. Long-term PETN therapy prevented the progressive left ventricular dilatation and improved left ventricular contractile function and relaxation in rats with congestive heart failure. Mitochondrial superoxide anion production was markedly increased in the failing left ventricular myocardium and nearly normalized by PETN treatment. Gene set enrichment analysis revealed that PETN beneficially modulated the dysregulation of mitochondrial genes involved in energy metabolism, paralleled by prevention of uncoupling protein-3, thioredoxin-2, and superoxide dismutase-2 downregulation. Moreover, PETN provided a remarkable protective effect against reactive fibrosis in chronically failing hearts. Mechanistically, induction of heme oxygenase-1 by PETN prevented mitochondrial superoxide generation, NOX4 upregulation, and ensuing formation of extracellular matrix proteins in fibroblasts from failing hearts. In summary, PETN targeting reactive oxygen species generation prevented the changes of mitochondrial antioxidant enzymes and progressive fibrotic remodeling, leading to amelioration of cardiac functional performance. Therefore, PETN might be a promising therapeutic option in the treatment of ischemic heart diseases involving oxidative stress and impairment in nitric oxide bioactivity.

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Effects of nitroglycerin or pentaerithrityl tetranitrate treatment on the gene expression in rat hearts: evidence for cardiotoxic and cardioprotective effects

Cited by 25 publications

References 116 publications

Maternal Treatment of Spontaneously Hypertensive Rats With Pentaerythritol Tetranitrate Reduces Blood Pressure in Female Offspring

Maternal Treatment of Spontaneously Hypertensive Rats With Pentaerythritol Tetranitrate Reduces Blood Pressure in Female Offspring

Nitrate Therapy

Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure

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