Abstract
This study investigated whether drugs with (milrinone (Mil), levosimendan (Levo)) and without (omecamtiv mecarbil (OM)) demonstrated phosphodiesterase (PDE) 3 inhibitory activity improve diastolic function in rats with aortocaval fistula (ACF)‐induced volume overload (VO). ACF or sham surgery was performed in male Sprague‐Dawley rats (200‐240g) 8 weeks prior to acute IV infusion with either Levo (2.8 µg/kg/min), Mil (9.9 µg/kg/min), OM (11.7 µg/kg/min) or vehicle (Veh; 0.4% DMSO) for 30 min. Levo and Mil improved diastolic function compared with Veh (tau; 9.0 and 9.8, respectively vs. 10.7 msec, p<0.05), while OM worsened diastolic function compared with Veh, Levo, and Mil (tau and dP/dtmin; 12.4 msec (p<0.05 vs. ACF‐Veh and p<0.001 vs. ACF‐Levo and ACF‐Mil) and ‐5967 mmHg/sec (p<0.05 vs. ACF‐Veh and p<0.01 vs. ACF‐Levo and ACF‐Mil)). Following infusion, %FS improved in ACF‐Levo, ACF‐Mil and ACF‐OM (39.8, 37.9 and 36.8%, respectively) compared with ACF‐Veh (32.1%; p<0.01), and there was no significant decrease in mean arterial pressure and no increase in arrhythmias. These results suggest that PDE3 inhibition improves diastolic function and that Levo’s improved diastolic function may be due to PDE3 inhibition independent of changes in blood pressure.Grant Funding Source: Supported by: R01 HL‐056046 (to PAL), ACVP/STP Coalition (to KL)
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