title: Cyclic AMP-dependent and cyclic AMP-independent actions of a novel cardiotonic agent, OPC-8212.
abstract: Possible cAMP-dependent and cAMP-independent mechanisms of action for the cardiac effects of OPC-8212, a novel piperazinyl-quinolinone derivative, were evaluated. OPC-8212 was tested for in vitro potency as an inhibitor of soluble bovine cardiac phosphodiesterases using a rapid isolation and assay method involving monoclonal antibodies that distinguish among isozymes. The drug was selective for a low-Km, cGMP-inhibited phosphodiesterase (CGI-PDE) with an IC50 (half-maximal inhibition concentration) of 7.4 mumol/l when measured at a substrate level of 0.35 mumol/l cAMP. Under the conditions used, sulfolane, the solvent for OPC-8212, did not affect CGI-PDE activity. In electrophysiological measurements, OPC-8212 prolonged the action potential duration in canine Purkinje strand preparations up to 148% (APD90) at 10 mumol/l. Concomitantly, OPC-8212 produced a 100% increase in developed force. Both prolongation of the action potential duration and the positive inotropic effect were readily reversed after exposure to tetrodotoxin, 3 mumol/l. Using Na-selective microelectrodes, intracellular Na+ ion activity increased 225% upon exposure to 10 mumol/l OPC-8212. OPC-8212 represents a novel type of positive inotropic agent, possessing both cAMP-dependent (selective PDE isozyme inhibition) and cAMP-independent (activation of intracellular Na+) mechanism of action.
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Ohio 45267-0575.
authors.forename: S T
authors.initials: ST
authors.lastname: Rapundalo
authors.forename: D A
authors.initials: DA
authors.lastname: Lathrop
authors.forename: S A
authors.initials: SA
authors.lastname: Harrison
authors.forename: J A
authors.initials: JA
authors.lastname: Beavo
authors.forename: A
authors.initials: A
authors.lastname: Schwartz
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002417:Cattle; D000242:Cyclic AMP / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism; D004594:Electrophysiology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D011719:Pyrazines; D011804:Quinolines / Q000494:pharmacology*; D012964:Sodium / Q000502:physiology; D012997:Solvents; D013997:Time Factors
chemical_list: D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D011804:Quinolines; D012997:Solvents; C041667:vesnarinone; D012964:Sodium; D000242:Cyclic AMP; D006152:Cyclic GMP