Danicamtiv affected isometric force and cross-bridge kinetics similarly in skinned myocardial strips from male and female rats

Abstract

Myotropes are pharmaceuticals that have recently been developed or are under investigation for the treatment of heart diseases. Myotropes have had varied success in clinical trials. Initial research into myotropes have widely focused on animal models of cardiac dysfunction in comparison with normal animal cardiac physiology-primarily using males. In this study we examined the effect of danicamtiv, which is one type of myotrope within the class of myosin activators, on contractile function in permeabilized (skinned) myocardial strips from male and female Sprague-Dawley rats. We found that danicamtiv increased steady-state isometric force production at sub-maximal calcium levels, leading to greater Ca²⁺-sensitivity of contraction for both sexes. Danicamtiv did not affect maximal Ca²⁺-activated force for either sex. Sinusoidal length-perturbation analysis was used to assess viscoelastic myocardial stiffness and cross-bridge cycling kinetics. Data from these measurements did not vary with sex, and the data suggest that danicamtiv slows cross-bridge cycling kinetics. These findings imply that danicamtiv increases force production via increasing cross-bridge contributions to activation of contraction, especially at sub-maximal Ca²⁺-activation. The inclusion of both sexes in animal models during the formative stages of drug development could be helpful for understanding the efficacy or limitation of a drug's therapeutic impact on cardiac function.

Keywords: Cardiac muscle; Contraction; Cross-bridge kinetics; Myotrope.

Fig. 1.

Ca²⁺-activated stress is plotted against pCa for myocardial strips from (A) male and (B) female rats. Lines represent fits to a 3-parameter Hill equation (see legend of Table 1). Steady-state isometric tension increased as [Ca²⁺] increased for all myocardial strips. There were not statistical differences in maximal force between groups (individual Max_fit values shown in panel C). Force-pCa relationships were shifted to the left with danicamtiv, showing increased Ca²⁺-sensitivity (pCa₅₀ values shown in panel E) for both sexes. Danicamtiv also produced a lower slope, or Hill coefficient (n_H values shown in panel D). Number of biological and technical replicates for each condition are listed at the bottom of Table 1. * post-hoc effect of danicamtiv at p < 0.001.

Fig. 2.

(A-C) Elastic and (D-F) viscous moduli are plotted against frequency under relaxed conditions (pCa 8.0) for males, females, and combined for both sexes. Number of biological and technical replicates for each condition are listed at the bottom of Table 1.

Fig. 3.

(A-C) Elastic and (D-F) viscous moduli are plotted against frequency under maximally activated conditions (pCa 4.8) for males, females, and combined for both sexes. Number of biological and technical replicates for each condition are listed at the bottom of Table 1. * post-hoc effect of danicamtiv at p < 0.001. † post-hoc effect of danicamtiv at p < 0.05.