Differential effects of isoproterenol and omecamtiv mecarbil on the contractile properties of unloaded myocytes

Abstract

Patients develop heart failure when their ventricles are unable to maintain adequate cardiac output with normal filling pressures. Omecamtiv mecarbil is a novel small molecule that binds to the myosin head and enhances the rate of Pi release. It is currently in clinical trials as a potential therapy for heart failure. We compared the effects of omecamtiv mecarbil and isoproterenol, a well‐known β‐adrenergic agonist, on the contractile properties of single unloaded cardiac myocytes. Cells were isolated by enzymatic digestion from 3 to 6 month old female Sprague‐Dawley rats and electrically stimulated at 0.5 Hz at 32°C. Sarcomere length shortening profiles were measured using high speed video microscopy. Calcium transients were measured by monitoring Fura‐2AM fluorescence. Experiments measured the effects of 0, 0.1, 1.0, and 10.0 μM omecamtiv mecarbil and 0, 0.01, 0.1, and 1.0 μM isoproterenol. Statistical tests were performed using linear mixed models with Tukey post‐hoc criteria. Isoproterenol increased shortening (p<0.001) and accelerated the rate of shortening and relaxation (both effects, p<0.001). In contrast, 10 μM omecamtiv mecarbil reduced shortening (p<0.001) and slowed shortening and subsequent relaxation (both effects, p<0.001). Our working hypothesis is that at high concentrations, omecamtiv mecarbil increases the duty ratio of myosin heads thereby increasing the number of bound cross‐bridges. These cross‐bridges impose a drag on the myofilaments and slow contraction and relaxation.Support or Funding InformationAHA GRNT2546003, NSF 1538754, NIH TR000117, APS STRIDE, APS UGSRF, HL115473.