The mechanism of chlorpromazine and quinidine inhibition of cardiac sarcotubular ATPase.
Although chlorpromazine and quinidine have dissimilar chemical properties, both are negative inotropic agents and both depress the ATPase activity of cardiac sarcotubular fractions. With the aid of gamma-AT32 P we have identified the step in ATP hydrolysis which is inhibited by each of these agents. By optimizing the conditions for formation of a phosphorylated intermediate (EP) by addition of 5 mM calcium to the incubation medium we found that chlorpromazine (0.25--1 mM) severely depressed EP formation, whereas quinidine (0.25--1 mM) had no effect. After the isolation of EP we showed that chlorpromazine had no effect on the magnesium-facilitated hydrolysis of EP, whereas quinidine was a potent inhibitor of this hydrolytic step. The effects of both quinidine and chlorpromazine on the E + ATP equilibrium EP + ADP reaction were studied. Quinidine had no effect on this reaction, whereas chlorpromazine, at 1 mM, shifted the reaction toward ATP formation.
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D002746:Chlorpromazine / Q000494:pharmacology*; D004285:Dogs; D066298:In Vitro Techniques; D007700:Kinetics; D008433:Mathematics; D009206:Myocardium / Q000201:enzymology*; D011802:Quinidine / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*
D000251:Adenosine Triphosphatases; D011802:Quinidine; D002746:Chlorpromazine