Antagonists of stretch-activated ion channels restore contractile function in hamster dilated cardiomyopathy

Stretch-activated ion channels (SACs) mediate abnormal ion currents in dilated cardiomyopathy (DCM), but their role in the contractile defect of DCM is undefined. We hypothesized that SAC antagonists would enhance contractile function in a hamster model of DCM.

Left ventricular papillary muscles from Syrian hamsters with a genetic DCM (n = 26), and from non-myopathic controls (n = 26), were superfused and stimulated to contract. Maximum active force (F(max); milli-Newtons per square millimeter) was determined before (baseline) and after subjecting the muscle to a 60-minute period of overstretch (resting length associated with a 20% decay in baseline maximum force [F(max)]). Gadolinium (10 micromol/liter) and streptomycin (40 micromol/liter) were used separately to antagonize SACs.

In the absence of SAC antagonist, baseline F(max) was greater in controls (1.79 +/- 0.26) vs DCM (0.69 +/- 0.12; p < 0.05). Overstretch caused further decrease in F(max) in DCM (to 0.50 +/- 0.08; p = 0.03 vs baseline), but not in controls. The SAC antagonists increased baseline F(max) in DCM to equal that of untreated controls (gadolinium 1.64 +/- 0.34, streptomycin 2.13 +/- 0.33), but neither agent increased baseline F(max) in controls (gadolinium 1.91 +/- 0.20, streptomycin 2.25 +/- 0.49). Both agents abolished the stretch-induced decrease in contractile function in DCM.

Antagonists of SACs enhance contractile function in DCM to equal that of normal controls, and abolish sensitivity to further stretch. They do not alter contractile function in normal muscle. These data suggest an important role of SACs in the contractile dysfunction of DCM and further suggest that SAC antagonists may represent novel therapy in heart failure.