Myofibrillar Ca++ activation and heart failure--Ca++ sensitization by the cardiotonic agent APP 201-533.
Certain forms of cardiac failure appear to be associated with a decrease in the Ca++ sensitivity of the contractile structures, possibly due to troponin I phosphorylation. Interference of cardiotonic drugs with myofibrillar Ca++ activation instead of enhancement of Ca++ influx may therefore provide a more causal therapeutic concept in the treatment of cardiac insufficiency. APP 201-533 (3-Amino-6-methyl-5-phenyl-2(1H)-pyridinone) (the structure of which is shown below) is a novel cardiotonic agent acting neither via beta adrenoceptor stimulation nor inhibition of Na+/K+ ATPase. In the 100 microM concentration range, it increases the Ca++ sensitivity and the Ca++ affinity of functionally isolated cardiac contractile structures. This coincides with an inhibitory effect on the cAMP-dependent protein kinase from rat liver. A possible relation with the regulation of troponin I phosphorylation is discussed.
Herzig
J W
JW
Department Research CVS, Ciba-Geigy Ltd., Basel, Switzerland.
Botelho
L H
LH
Solaro
R J
RJ
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D006333:Heart Failure / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology; D009200:Myocardial Contraction / Q000187:drug effects; D009210:Myofibrils / Q000378:metabolism*; D011494:Protein Kinases / Q000032:analysis; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats
D002316:Cardiotonic Agents; D011728:Pyridones; C045982:3-amino-6-methyl-5-phenyl-2(1H)-pyridinone; D011494:Protein Kinases; D002118:Calcium