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Myofibrillar Ca++ activation and heart failure--Ca++ sensitization by the cardiotonic agent APP 201-533
J W Herzig1, L H Botelho, R J Solaro
1Department Research CVS, Ciba-Geigy Ltd., Basel, Switzerland.
Abstract:
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.
Insights
This study introduces APP 201-533, a novel cardiotonic agent that enhances cardiac contractile function by increasing calcium sensitivity. It offers a new therapeutic approach for heart failure by targeting myofibrillar activation.
Area of Science:
- Cardiology
- Biochemistry
- Pharmacology
Background:
- Cardiac failure can involve reduced Ca++ sensitivity in contractile structures, potentially linked to troponin I phosphorylation.
- Current cardiotonic drugs primarily focus on Ca++ influx, not myofibrillar Ca++ activation, suggesting a gap in causal therapeutic strategies for heart failure.
Purpose of the Study:
- To investigate the cardiotonic effects of APP 201-533, a novel compound.
- To explore the mechanism of action of APP 201-533, specifically its impact on myofibrillar Ca++ sensitivity and activation.
Main Methods:
- Assessing the effects of APP 201-533 on functionally isolated cardiac contractile structures.
- Evaluating the compound's influence on Ca++ sensitivity and Ca++ affinity.
- Investigating the inhibitory effect of APP 201-533 on cAMP-dependent protein kinase from rat liver.
Main Results:
- APP 201-533, at 100 microM, significantly increased Ca++ sensitivity and Ca++ affinity in cardiac contractile structures.
- The compound demonstrated an inhibitory effect on cAMP-dependent protein kinase from rat liver.
- APP 201-533 does not act via beta adrenoceptor stimulation or Na+/K+ ATPase inhibition.
Conclusions:
- APP 201-533 represents a novel cardiotonic agent with a unique mechanism of action.
- Its ability to enhance myofibrillar Ca++ sensitivity suggests a potential causal therapeutic strategy for cardiac insufficiency.
- The observed inhibition of cAMP-dependent protein kinase may be related to the regulation of troponin I phosphorylation in cardiac muscle.