A novel thiadiazinone derivative fully reverses acidosis-induced depression of force in cardiac muscle by a calcium-sensitizing effect

1. We examined the effects of the novel thiadiazinone derivative EMD 57033 on developed force and intracellular [Ca²⁺] in cardiac muscle during control conditions (pH 7.35) and in acidosis (pH 6.8).

2. In the control solution, application of EMD 57033 fully activated the muscle. Acidosis reduced developed force to 18% of maximum, but application of EMD 57033 in acid solution was able to fully reverse this effect and restore force to its previous maximum.

3. During the positive inotropic effect in acidosis, the Ca²⁺ transients declined to 62% of their initial amplitude, whereas force increased to 557%.

4. These observations suggest that EMD 57033 increases force by a Ca²⁺-sensitizing action in intact cardiac muscle. Since EMD 57033 is able to fully reverse the effects of acidosis on force without increasing the amplitude of the Ca²⁺ transients, this compound and others with similar mechanisms of action appear to hold particular promise for heart failure therapy.