Effects of phosphodiesterase‐5 inhibition by sildenafil in the pressure overloaded right heart

Andersen, Asger; Nielsen, Jesper; Peters, Christian Daugaard; Schou, Uffe K.; Sloth, Erik; Nielsen‐Kudsk, Jens Erik

doi:10.1016/j.ejheart.2008.09.016

Cited by 48 publications

(46 citation statements)

References 31 publications

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“…These observations have been confirmed by REX et al [29]. Two recent papers studied the effects of chronic treatment of sildenafil in a model where RV pressure overload was induced by pulmonary artery banding [30,31]. Both studies reported an increase in RV hypertrophy and/or improvement of RV function, which implies that there is a direct effect of sildenafil on the heart.…”

Section: Cardiac Effects Of Current Pah Medicationsupporting

confidence: 65%

Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart

Handoko

Man

Allaart³

et al. 2010

European Respiratory Review

110

111

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Right heart function is the main determinant of prognosis in pulmonary arterial hypertension (PAH). At present, no treatments are currently available that directly target the right ventricle, as we will demonstrate in this article.Meta-analysis of clinical trials in PAH revealed that current PAH medication seems to have limited cardiac-specific effects when analysed by the pump-function graph. Driven by the hypothesis that ''left'' and right heart failure might share important underlying pathophysiological mechanisms, we evaluated the clinical potential of left heart failure (LHF) therapies for PAH, based on currently available literature.As in LHF, the sympathetic nervous system and the renin-angiotension-aldosterone system are highly activated in PAH. From LHF we know that intervening in this process, e.g. by angiotensinconverting enzyme inhibition or b-blockade, is beneficial in the long run. Therefore, these medications could be also beneficial in PAH. Furthermore, the incidence of sudden cardiac death in PAH could be reduced by implantable cardioverter-defibrillators. Finally, pilot studies have demonstrated that interventricular dyssynchrony, present at end-stage PAH, responded favourably to cardiac resynchronisation therapy as well.In conclusion, therapies for LHF might be relevant for PAH. However, before they can be implemented in PAH management, safety and efficacy should be evaluated first in well-designed clinical trials.

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Section: Cardiac Effects Of Current Pah Medicationsupporting

confidence: 65%

Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart

Handoko

Man

Allaart³

et al. 2010

European Respiratory Review

110

111

View full text Add to dashboard Cite

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“…Furthermore, the biological effects for Sildenafil may differ depending on the experimental setup. A recent report by Andersen et al (2) has shown that high-dose Sildenafil treatment (100 mg ⅐kg Ϫ1 ⅐day Ϫ1 ) in a model for pulmonary trunk banding was not able to attenuate PAH development; in fact, it increased RV hypertrophy.…”

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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“…2,7 The rats were placed on a heating pad during the procedure to maintain body temperature at 37˚C. The pulmonary trunk was accessed through a thoracotomy on the left side of the sternum.…”

Section: Pulmonary Trunk Bandingmentioning

confidence: 99%

“…Treatment with phosphodiesterase type 5 (PDE-5) inhibitors has been demonstrated to attenuate LV hypertrophy and improve LV function in mice, 1 but this effect was not found in rats with pressure overload-induced RV hypertrophy. [2][3][4] Sildenafil failed to inhibit RV hypertrophy, but some improvement in RV contractile function was seen in long-term sildenafil treatment. The improved function could possibly be explained by direct inhibition of PDE-5 in RV cardiomyocytes.…”

Section: Introductionmentioning

confidence: 99%

Acute Effects of Sildenafil and Dobutamine in the Hypertrophic and Failing Right Heart in Vivo

et al. 2013

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The purpose of this study was to investigate whether acute intravenous administration of the phosphodiesterase type 5 (PDE-5) inhibitor sildenafil in a single clinically relevant dose improves the in vivo function of the hypertrophic and failing right ventricle (RV). Wistar rats (n ¼ 24) were subjected to pulmonary trunk banding (PTB) causing RV hypertrophy and failure. Four weeks after surgery, they were randomized to receive an intravenous bolus dose of sildenafil (1 mg/kg; n ¼ 7), vehicle (n ¼ 6), or dobutamine (10 μg/kg; n ¼ 6 ). Invasive RV pressures were recorded continuously, and transthoracic echocardiography was performed 1,5,15,25, 35, 50, 70, and 90 minutes after injecting the bolus. Cardiac function was compared to baseline measurements to evaluate the in vivo effects of each specific treatment. The PTB procedure caused significant hypertrophy, cardiac fibrosis, and reduction in RV function evaluated by echocardiography (TAPSE) and invasive pressure measurements. Sildenafil did not improve the function of the hypertrophic failing right heart in vivo, measured by TAPSE, RV systolic pressure (RVsP), and dp/dt max . Dobutamine improved RV function 1 minute after injection measured by TAPSE (0:1242 AE 0:03 vs. 0:1565 AE 0:04 cm; P < 0:001 ), RVsP (83 AE 11 vs. 107 AE 11 mmHg; P < 0:001 ), and dp/dt max (3; 136 AE 521 vs. 4; 489 AE 706 mmHg/s; P < 0:001). Acute administration of the PDE-5 inhibitor sildenafil in a single clinically relevant dose did not modulate the in vivo function of the hypertrophic failing right heart of the rat measured by echocardiography and invasive hemodynamics. In the same model, dobutamine acutely improved RV function.

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Effects of phosphodiesterase‐5 inhibition by sildenafil in the pressure overloaded right heart

Cited by 48 publications

References 31 publications

Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart

Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart

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

Acute Effects of Sildenafil and Dobutamine in the Hypertrophic and Failing Right Heart in Vivo

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