On the role of Ca++ binding proteins as possible targets for Ca++ sensitizing agents.
We describe the effects of various cardioactive compounds on the Ca++ activation of force production and ATPase activity in isolated contractile structures from mammalian heart and, in some cases, skeletal muscle. We show that: 1) the Ca++ sensitizing activity of APP 201-533 does not discriminate between cardiac and skeletal muscle and is, therefore, not based on interaction with cardiac troponin I phosphorylation at serine 20. 2) compounds like trifluoperazine or bepridil, both known to interact with calmodulin, increase the Ca++ sensitivity of the contractile structures of the heart, in high concentrations, as expected from the high natural abundance of troponin C. 3) DPI 201-106 interacts with calmodulin (and presumably with the structurally closely related troponin C) in the microM concentration range. Its high Ca(++)-sensitizing potency in skinned cardiac muscle and a certain sensitivity of this effect to the detergent Triton X-100 suggest accumulation of the hydrophobic compound in the myofibrillar protein lattice.
Herzig
J W
JW
Department of Research CVS, Ciba-Geigy Ltd., Basel, Switzerland.
Quast
U
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D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D015764:Bepridil / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000187:drug effects* / Q000502:physiology; D002147:Calmodulin / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D020105:Milrinone; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D013552:Swine; D014268:Trifluoperazine / Q000494:pharmacology; D014336:Troponin / Q000502:physiology; D019209:Troponin C
D002135:Calcium-Binding Proteins; D002147:Calmodulin; D002316:Cardiotonic Agents; D010879:Piperazines; D011728:Pyridones; D014336:Troponin; D019209:Troponin C; D014268:Trifluoperazine; D015764:Bepridil; C045982:3-amino-6-methyl-5-phenyl-2(1H)-pyridinone; C046261:DPI 201-106; D020105:Milrinone; D000676:Amrinone; D002118:Calcium