Acute effects of sildenafil and dobutamine in the hypertrophic and failing right heart in vivo

Abstract

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 ([Formula: see text]) 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; [Formula: see text]), vehicle ([Formula: see text]), or dobutamine (10 μg/kg; [Formula: see text]). 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/dtmax. Dobutamine improved RV function 1 minute after injection measured by TAPSE ([Formula: see text] vs. [Formula: see text] cm; [Formula: see text]), RVsP ([Formula: see text] vs. [Formula: see text] mmHg; [Formula: see text]), and dp/dtmax ([Formula: see text] vs. [Formula: see text] mmHg/s; [Formula: see text]). 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.

Figure 1

Baseline characteristics. Results are plotted as mean ± standard error of the mean. One asterisk, ; three asterisks, . Numbers plotted in the columns denote the number of animals used for analysis. RVW/LV+SW, right ventricle/left ventricle plus septum weight; TAPSE, tricuspid annular plane systolic excursion measured by transthoracic echocardiography; RVsP, right ventricular systolic pressure; dp/dt_max, maximum pressure development over time. PTB, pulmonary trunk banding; veh, vehicle; sil, sildenafil; dob, dobutamine.

Figure 2

Acute effects of sildenafil and dobutamine. Results are plotted as mean ± standard error of the mean. Three asterisks, . Numbers plotted in the column denote the number of animals used for analysis. RVsP, right ventricular systolic pressure; TAPSE, tricuspid annular plane systolic excursion measured by transthoracic echocardiography; dp/dt_max, maximum pressure development over time; PTB, pulmonary trunk banding; ns, not significant.

Figure 3

Pulmonary trunk banding animals treated by dobutamine. Hemodynamic measurements at baseline and after injection of a single bolus of dobutamine 10 μg/kg. Results are plotted as mean ± standard error of the mean. Two asterisks, ; three asterisks, compared to baseline measurement. TAPSE, tricuspid annular plane systolic excursion measured by transthoracic echocardiography; RVsP, right ventricular systolic pressure; RVPP, right ventricular pulse pressure product; dp/dt_max, maximum pressure development over time; dp/dt_min, minimum pressure development over time.

Figure 4

Pulmonary trunk branding animals treated by sildenafil. Hemodynamic measurements at baseline and after injection of a single bolus of sildenafil 1 mg/kg. Results are plotted as mean ± standard error of the mean. One asterisk, ; two asterisks, ; three asterisks, compared to baseline measurement. TAPSE, tricuspid annular plane systolic excursion measured by transthoracic echocardiography; RVsP, right ventricular systolic pressure; RVPP, right ventricular pulse pressure product; dp/dt_max, maximum pressure development over time; dp/dt_min, minimum pressure development over time.

Figure 5

Pulmonary trunk branding animals treated by vehicle. Hemodynamic measurements at baseline and after injection of a single bolus of vehicle. Results are plotted as mean ± standard error of the mean. One asterisk, compared to baseline measurement. TAPSE, tricuspid annular plane systolic excursion measured by transthoracic echocardiography; RVsP, right ventricular systolic pressure; RVPP, right ventricular pulse pressure product; dp/dt_max, maximum pressure development over time; dp/dt_min, minimum pressure development over time.

Figure 6

Sham-oriented animals treated by sildenafil. Hemodynamic measurements at baseline and after injection of a single bolus of sildenafil 1 mg/kg. Results are plotted as mean ± standard error of the mean. One asterisk, ; two asterisks, compared to baseline measurement. TAPSE, tricuspid annular plane systolic excursion measured by transthoracic echocardiography; RVsP, right ventricular systolic pressure; RVPP, right ventricular pulse pressure product; dp/dt_max, maximum pressure development over time; dp/dt_min, minimum pressure development over time.