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

Abstract

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.

Comparison of preventive effect of sildenafil and therapeutic effect of sildenafil treatment in rats with monocrotaline-induced pulmonary arterial hypertension

“…Previous studies have shown that sildenafil has little effect on TAPSE, supporting the notion that sildenafil does not have intrinsic effects on the myocardium [2, 20]. Additionally, systolic function parameters do not indicate any vasodilatory effect of sildenafil, but suggest the lack of an inotropic effect of sildenafil [2, 20]. These findings are consistent with another previous study, which showed that sildenafil has slightly positive intrinsic inotropic effects [19].…”

“…Sm is an index of right ventricular systolic function and is well correlated with the right ventricular ejection fraction as derived from magnetic resonance imaging [29]. Previous studies have shown that sildenafil has little effect on TAPSE, supporting the notion that sildenafil does not have intrinsic effects on the myocardium [2, 20]. Additionally, systolic function parameters do not indicate any vasodilatory effect of sildenafil, but suggest the lack of an inotropic effect of sildenafil [2, 20].…”

Riociguat, sildenafil and inhaled nitric oxide reduces pulmonary vascular resistance and improves right ventricular function in a porcine model of acute pulmonary embolism

“…A direct inotropic effect of NO-sGC-cGMP stimulation has previously been hypothesized, but published results are few and conflicting. 14,[30][31][32][33][34] Sildenafil and riociguat decreased RV/LV ratio both in end systole and end diastole, indicating attenuation of RV dilatation and improved emptying of the RV, presumably due to afterload reduction. This was further indicated by an increase in RV stroke volume in animals treated with sildenafil.…”

Prostacyclins have no direct inotropic effect on isolated atrial strips from the normal and pressure‐overloaded human right heart

“…Right heart failure is the terminal event of several diseases causing sustained pressure-overload of the right ventricle (RV), including pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and various congenital heart diseases. 1 – 3 Despite extensive research in the field, 4 – 8 there is still a lack of safe and effective targeted therapies for the right heart. Characterization of currently used pharmacologic agents with a potential beneficial effect on the right ventricle and development of new treatments for the right heart are required.…”