In vivo evidence of positive inotropism of EMD 57033 through calcium sensitization.

The previous separation of the racemic cardiotonic thiadiazinone derivative EMD 53998 yielded two enantiomers with different pharmacologic properties: EMD 57,033, a potent Ca2+ sensitizer with some residual phosphodiesterase III (PDE III) inhibition, and EMD 57,439, a pure PDE III inhibitor. Although numerous in vitro studies demonstrated the ability of EMD 57,033 to increase the responsiveness of cardiac contractile proteins to Ca2+, in vivo evidence for such an action is lacking. Because there is no possibility of directly proving Ca2+ sensitization in vivo, we attempted to exclude PDE III inhibition as a major contributing component of the positive inotropic action of EMD 57,033.

Preischaemic as well as postischaemic application of a Na+/H+ exchange inhibitor reduces infarct size in pigs.

Background: During reperfusion of ischaemic myocardium, Na+/H+ exchange promotes recovery from acidosis resulting in an accumulation of intracellular Na+. This leads to calcium overload via Na+/Ca2+ exchange and might result in cell necrosis contributing to reperfusion injury.

Methods And Results: We assessed whether HOE 694, a specific inhibitor of Na+/H+ exchange, is able to reduce infarct size in swine myocardium.

Involvement of ATP-sensitive potassium channels in preconditioning protection.

Single or multiple brief periods of ischemia (preconditioning, PC) have been shown to protect the myocardium from infarction during a subsequent more prolonged ischemic insult. To test the hypothesis that opening of ATP-sensitive potassium channels (KATP) is involved in this mechanism, either bimakalim, a KATP channel opener, or glibenclamide, a KATP channel blocker, were administered to mimic or to block preconditioning protection in barbital-anesthetized pigs. PC was elicited by a single period of 10 min left anterior descending coronary artery (LADCA) occlusion followed by 15 min of reperfusion before the LADCA was reoccluded for 60 min.

Effect of bimakalim (EMD 52692), an opener of ATP sensitive potassium channels, on infarct size, coronary blood flow, regional wall function, and oxygen consumption in swine.

Objective: The aim was to assess whether bimakalim, an opener of ATP sensitive potassium channels, can reduce infarct size in swine myocardium.

Methods: Experiments were performed in open chest pigs subjected to a 60 min occlusion of a branch of the left anterior descending coronary artery and to 2 h reperfusion. Five groups of animals were studied.