Sildenafil citrate concentrations not affecting oxidative phosphorylation depress H2O2 generation by rat heart mitochondria

Férnandes, Meg da Silva; Marques, Ricardo; Vicente, Joaquim A.F.; Santos, Maria S.; Monteiro, Pedro; Moreno, António J.; Custódio, José B.A.

doi:10.1007/s11010-007-9645-9

Cited by 43 publications

(32 citation statements)

References 37 publications

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“…Recent studies have shown that Sildenafil is able to reduce the production of ROS by mitochondria (17) and that it exerts cardioprotective effects through opening of Ca 2ϩ -sensitive, ATP-sensitive K ϩ channels (13,52). Whether this is related to an increase in oxidative capacity remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension

Mouchaers

Schalij

Versteilen³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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We determined the effects of single and combination treatment with Bosentan [an ET type A (ET A)/type B (ETB) receptor blocker] and Sildenafil (a PDE5 inhibitor) on RV function and oxidative metabolism in monocrotaline (MCT)-induced PAH. Fourteen days after MCT injection, male Wistar rats were orally treated for 10 days with Bosentan, Sildenafil, or both. RV catheterization and echocardiography showed that MCT clearly induced PAH. This was evidenced by increased RV systolic pressure, reduced cardiac output, increased pulmonary vascular resistance (PVR), and reduced RV fractional shortening. Quantitative histochemistry showed marked RV hypertrophy and fibrosis. Monotreatment with Bosentan or Sildenafil had no effect on RV systolic pressure or cardiac function, but RV fibrosis was reduced and RV capillarization increased. Combination treatment did not reduce RV systolic pressure, but significantly lowered PVR, and normalized cardiac output, RV fractional shortening, and fibrosis. Only combination treatment increased the mitochondrial capacity of the RV, as reflected by increased succinate dehydrogenase and cytochrome c oxidase activities, associated with an activation of PKG, as indicated by increased VASP phosphorylation. Moreover, significant interactions were found between Bosentan and Sildenafil on PVR, cardiac output, RV contractility, PKG activity, and mitochondrial capacity. These data indicate that the combination of Bosentan and Sildenafil may beneficially contribute to RV adaptation in PAH, not only by reducing PVR but also by acting on the mitochondria in the heart. Bosentan; Sildenafil; mitochondria; oxidative capacity; chronic heart failure PULMONARY ARTERIAL HYPERTENSION (PAH) is a severe progressive disease of the small lung vasculature leading to increased pulmonary vascular resistance (PVR). The right ventricle (RV) hypertrophies to withstand the rise in PVR and maintain cardiac output (CO) (16,48). Subsequently, RV contractile dysfunction occurs, and failure may develop (8, 51). Many factors influence the capacity of the RV to adapt to PAH, such as the degree of RV wall stress, myocardial ischemia, or microvascular endothelial dysfunction. However, the exact sequence of events leading the RV toward failure, and the effects of treatments to counteract this process remain uncertain (51).Various treatments for PAH have been developed over time, which primarily act as vasodilators of the pulmonary vasculature. These treatments include anticoagulant therapy, prostacyclin infusion, endothelin (ET) receptor blockade, and phosphodiesterase-5 (PDE5) inhibition (9, 25). ET receptor blockade by Bosentan and PDE5 inhibition by Sildenafil are both common strategies in PAH treatment (9,25,43). The ET system is highly active in PAH and causes sustained vasoconstriction of pulmonary arteries. It increases the mitogenic activity of smooth muscle cells and fibroblasts in the pulmonary vessel wall, thereby decreasing the lumen of pulmonary vessels, also contributing to increased pulmonary vascular resistance (PVR) ...

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Section: Discussionmentioning

confidence: 99%

Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension

Mouchaers

Schalij

Versteilen³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…Fernandes et al (2008) reported that the physiological concentrations of sildenafil (Ͻ50 M) decreased H 2 O 2 generation by mitochondria respiring glutamate/malate. Moreover, it was shown that sildenafil decreased superoxide radical generated by a hypoxanthine/xanthine oxidase system without affecting either mitochondrial bioenergetics or Ca 2ϩ -induced mitochondrial permeability transition (Ferandes et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Long-Acting Phosphodiesterase-5 Inhibitor Tadalafil Attenuates Doxorubicin-Induced Cardiomyopathy without Interfering with Chemotherapeutic Effect

Koka

Das²,

Zhu³

et al. 2010

J Pharmacol Exp Ther

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Doxorubicin (DOX) is one of the most effective anticancer drugs. However, its cardiotoxicity remains a clinical concern that severely restricts its therapeutic usage. We designed this study to investigate whether tadalafil, a long-acting phosphodiesterase-5 (PDE-5) inhibitor, protects against DOX-induced cardiotoxicity. We also sought to delineate the cellular and molecular mechanisms underlying tadalafil-induced cardioprotection. Male CF-1 outbred mice were randomized into three groups (n ϭ 15-24/group) to receive either saline (0.2 ml i.p.), DOX (15 mg/kg, given by a single intraperitoneal injection), or tadalafil (4 mg/kg p.o. daily for 9 days) plus DOX. Left ventricular function was subsequently assessed by transthoracic echocardiography and Millar conductance catheter. Cardiac contractile function was impaired by DOX, and it was significantly improved by cotreatment with tadalafil. Tadalafil attenuated DOX-induced apoptosis and depletion of prosurvival proteins, including Bcl-2 and GATA-4, in myocardium. Cardiac oxidative stress was attenuated and antioxidant capacity was enhanced by tadalafil possibly via up-regulation of mitochondrial superoxide dismutase (MnSOD). Moreover, the tadalafiltreated group demonstrated increased cardiac cGMP level and protein kinase G (PKG) activity. Tadalafil did not interfere with the efficacy of DOX in killing human osteosarcoma cells in vitro or its antitumor effect in vivo in tumor xenograft model. We conclude that tadalafil improved left ventricular function and prevented cardiomyocyte apoptosis in DOX-induced cardiomyopathy through mechanisms involving up-regulation of cGMP, PKG activity, and MnSOD level without interfering with the chemotherapeutic benefits of DOX.

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“…3). Sildenafil may reduce local oxidative stress by extending the inhibitory action of the NO-cGMP axis on NAD[P]H oxidase expression and activity, thereby suppressing generation of superoxide in tissues [36]; in addition, sildenafil may act as a superoxide dismutase mimetic agent [37]. Suppressed renal oxidative stress would favor a reduction in tubulointerstitial inflammation which can in turn contribute to ameliorate hypertension in SHR [19,22].…”

Section: Discussionmentioning

confidence: 99%

Chronic Sildenafil Treatment Corrects Endothelial Dysfunction and Improves Hypertension

et al. 2010

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Background: Nitric oxide (NO) availability plays a critical role in the regulation of blood pressure, endothelial function and arterial structure. Many of the biological actions of NO are mediated by 3′5′-guanosine monophosphate (cGMP), which is rapidly degraded by cGMP phosphodiesterase (PDE). Short-term cardiovascular effects of PDE inhibitors have been studied but the changes resulting from their chronic administration in hypertension have not been evaluated. We investigated if retarding the degradation of cGMP by long-term inhibition of PDE-5 would have beneficial consequences in spontaneously hypertensive rats (SHR), a commonly used experimental model of human essential hypertension. Methods: Subgroups of hypertensive 13-week-old male SHR and normotensive Wistar-Kyoto rats were treated with sildenafil, 2.5 mg/kg/day, or vehicle, by gastric gavage for 6 months. Results: As expected, the untreated SHR had endothelial dysfunction and a steady increment of the blood pressure. In contrast, chronic sildenafil administration reversed endothelial dysfunction, reduced renal oxidative stress and renal macrophage accumulation, and ameliorated the severity of hypertension in SHR. Conclusions: These results demonstrate beneficial effects of long-term PDE-5 inhibition in SHR and suggest that its use as an adjunct therapy in essential hypertension should be investigated.

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Sildenafil citrate concentrations not affecting oxidative phosphorylation depress H2O2 generation by rat heart mitochondria

Cited by 43 publications

References 37 publications

Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension

Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension

Long-Acting Phosphodiesterase-5 Inhibitor Tadalafil Attenuates Doxorubicin-Induced Cardiomyopathy without Interfering with Chemotherapeutic Effect

Chronic Sildenafil Treatment Corrects Endothelial Dysfunction and Improves Hypertension

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