Potency, selectivity, and consequences of nonselectivity of PDE inhibition

Bischoff, Erwin

doi:10.1038/sj.ijir.3901208

Cited by 194 publications

(177 citation statements)

References 8 publications

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“…10,13 It has been suggested that elevated levels of cGMP, caused by PDE5 inhibitors, could inhibit PDE3, an enzyme responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP) and increase cAMP levels, resulting in elevated HR and contractility. 19 Our results showed that tadalafil did not increase HR nor induce arrhythmias.…”

Section: Discussionmentioning

confidence: 55%

The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size

et al. 2006

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The aim of this study was to determine, in an animal model, the effects of tadalafil on myocardial infarct size (IS), hemodynamics and regional myocardial blood flow after myocardial ischemia and reperfusion. Patients with erectile dysfunction (ED) often have risk factors for coronary artery disease. Tadalafil, a long-acting inhibitor of the enzyme phosphodiesterase-5 (PDE5), is used for the treatment of ED; there are no previous data regarding tadalafil in the setting of coronary artery occlusion (CAO). Sprague-Dawley male rats were treated with tadalafil or vehicle (10 mg/kg, by gastric gavage), 2 h before a 30 min CAO. Heart rate was comparable between tadalafil and control groups. Tadalafil reduced mean arterial pressure (P ¼ 0.009), systolic (P ¼ 0.035) and diastolic (P ¼ 0.009) blood pressures during ischemia/reperfusion. Tadalafil significantly reduced IS (4272%) versus controls (5473%) (P ¼ 0.006). For the first time, we showed that the PDE5 inhibitor, tadalafil, was well tolerated and cardioprotective in the setting of an experimental myocardial infarction, by substantially reducing ischemic cell death.

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Section: Discussionmentioning

confidence: 55%

The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size

et al. 2006

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“…Vardenafil, a highly selective PDE5A inhibitor is an on‐demand treatment for erectile dysfunction and it displays the highest potency compared with its comparators 9. Restoration of the impaired cGMP signalling by the PDE5A inhibitor vardenafil has been proven cardioprotective in different myocardial pathologies 10, 11, 12…”

Section: Introductionmentioning

confidence: 99%

Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

Mátyás

Németh

Oláh

et al. 2016

European J of Heart Fail

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AimsHeart failure with preserved ejection fraction (HFpEF) has a great epidemiological burden. The pathophysiological role of cyclic guanosine monophosphate (cGMP) signalling has been intensively investigated in HFpEF. Elevated levels of cGMP have been shown to exert cardioprotective effects in various cardiovascular diseases, including diabetic cardiomyopathy. We investigated the effect of long‐term preventive application of the phosphodiesterase‐5A (PDE5A) inhibitor vardenafil in diabetic cardiomyopathy‐associated HFpEF.Methods and resultsZucker diabetic fatty (ZDF) rats were used as a model of HFpEF and ZDF lean rats served as controls. Animals received vehicle or 10 mg/kg body weight vardenafil per os from weeks 7 to 32 of age. Cardiac function, morphology was assessed by left ventricular (LV) pressure–volume analysis and echocardiography at week 32. Cardiomyocyte force measurements were performed. The key markers of cGMP signalling, nitro‐oxidative stress, apoptosis, myocardial hypertrophy and fibrosis were examined. The ZDF animals showed diastolic dysfunction (increased LV/cardiomyocyte stiffness, prolonged LV relaxation time), preserved systolic performance, decreased myocardial cGMP level coupled with impaired protein kinase G (PKG) activity, increased nitro‐oxidative stress, enhanced cardiomyocyte apoptosis, and hypertrophic and fibrotic remodelling of the myocardium. Vardenafil effectively prevented the development of HFpEF by maintaining diastolic function (decreased LV/cardiomyocyte stiffness and LV relaxation time), by restoring cGMP levels and PKG activation, by lowering apoptosis and by alleviating nitro‐oxidative stress, myocardial hypertrophy and fibrotic remodelling.ConclusionsWe report that vardenafil successfully prevented the development of diabetes mellitus‐associated HFpEF. Thus, PDE5A inhibition as a preventive approach might be a promising option in the management of HFpEF patients with diabetes mellitus.

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“…Mechanism of the positive chronotropic and inotropic effects of sildenafil PDE3 is expressed in various tissues including myocardium, vascular smooth muscle, penile tissue and adipose tissue, which hydrolyzes cyclic AMP (Bischoff, 2004). Under physiological conditions, PDE3 has been proved to play an important role in regulating the automaticity and contractility primarily through the modulation of the cyclic AMP/protein kinase A signaling (Beca et al, 2011;Knight and Yan, 2012).…”

Section: Rationale Of the Doses Of Sildenafil For The Positive Inotromentioning

confidence: 99%

Cardiac safety profile of sildenafil: chronotropic, inotropic and coronary vasodilator effects in the canine isolated, blood-perfused heart preparations

et al. 2016

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-Sildenafil is a phosphodiesterase type-5 inhibitor. We evaluated the effects of sildenafil on the sinoatrial rate, developed tension of the papillary muscle and coronary blood flow by using the canine isolated, blood-perfused sinoatrial node and papillary muscle preparations. The former preparation had a regular automaticity rate of 106 ± 1 beats/min (n = 4), whereas the latter showed a developed tension of 22 ± 4 mN (n = 4) and a coronary blood flow of 3.9 ± 0.1 mL/min (n = 4). Intracoronary injection of 10, 30 and 100 μg of sildenafil, which would provide about 20 to 200 times higher plasma drug concentrations than its therapeutic level, increased the automaticity rate by 4, 12 and 22%, the developed tension by 19, 55 and 118% and the coronary blood flow by 42, 95 and 142%, respectively. These results indicate that supratherapeutic concentration of sildenafil possesses direct positive chronotropic and inotropic effects together with a coronary vasodilator action, confirming that caution has to be paid on the use of sildenafil for patients with ischemic heart diseases, obstructive hypertrophic cardiomyopathy and/ or ventricular arrhythmias. The information on sildenafil reported in this study may help establish a guidance on cardiac safety assessment of newer phosphodiesterase type-5 inhibitors.

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Potency, selectivity, and consequences of nonselectivity of PDE inhibition

Cited by 194 publications

References 8 publications

The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size

The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size

Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

Cardiac safety profile of sildenafil: chronotropic, inotropic and coronary vasodilator effects in the canine isolated, blood-perfused heart preparations

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