On the reversal of myocardial stunning: A role for Ca2+-sensitizers

The mechanism underlying myocardial stunning is still unknown, but current views hold that generation offree radicals and disturbances in the calcium homeostasis, mechanisms which are not mutually exclusive, are the two most likely causes of prolonged postischemic dysfunction. 1.2 Several groups of investigators have indeed shown that the capacity of cardiac sarcoplasrnic reticulum (SR) to sequester Ca2+ decreases during i~chernia.~.~ In a recent study we have shown that the phosphorylation rate of phospholamban was unchanged, and that Ca2+ uptake by the sarcoplasmic reticulum was even slightly increased in myocardium of intact open-chest pigs, while function was still reversibly depressed.5 These data and earlier work by Marban and coworkers6 in isolated stunned ferret hearts strongly suggest that a decreased response of the myofilaments to Ca2+ rather than a change in the active Ca2+ transport of the SR is involved in the contractile dysfunction of stunned myocardium. In vivo evidence of this hypothesis has been very difficult to obtain because available agents that increase the responsiveness of the myofilaments to Ca2+ usually also increase contractility via inhibition of phosphodiesterase. We now report on the effects of the thiadiazinone derivative EMD 60263, which in in vitro experiments has been shown to be a potent Ca2+ sensitizer devoid of any phosphodiesterase inhibiting properties (Ravens et al., unpublished data). The compound also affects the delayed rectifier current I K ~ in a way characteristic for a class I11 antiarrhythmic action. The latter property may lead to a reduction in heart rate.