title: Effects of pimobendan and its metabolite on myofibrillar calcium responsiveness and ATPase activity in the presence of inorganic phosphate.
abstract: The effects of the cardiotonic agent pimobendan (CAS 118428-36-7, UD-CG 115 BS) and its main metabolite UD-CG 212 on dog cardiac myofibrillar calcium responsiveness and ATPase activity were studied at nominal free inorganic phosphate (Pi) and at 5 mmol/l Pi. A rightward shift of the pCa-tension relationship with a marked depression of maximal tension was observed in the presence of 5 mmol/l Pi. Pimobendan increased myofibrillar calcium responsiveness at concentrations > or = 10(-5) mol/l. These effects of pimobendan were significantly greater at 5 mmol/l Pi than at nominally free Pi. UD-CG 212 had no influence on myofibrillar calcium responsiveness at nominally free Pi, however, significant effects were observed at 10(-9) mol/l UD-CG 212 in the presence of 5 mmol/l Pi. UD-CG 212 (10(-8) mol/l) did not influence myofibrillar ATPase activity at pCa's 6.23, 5.99, and 4.36 with or without 5 mmol/l Pi, whereas pimobendan (10(-4) mol/l) had an effect only at pCa = 5.99 (without Pi) and pCa = 4.36 (+ 5 mmol/l Pi). The data suggest that the increase in myofibrillar calcium responsiveness at submaximal calcium concentrations by pimobendan and UD-CG 212 in the presence of 5 mmol/l Pi is brought about by a change in cross-bridge kinetics or by enhancement of thin filament activation by adjacent strong cross-bridges. At maximal calcium activation, pimobendan may additionally increase the population of strong cross-bridges.
authors.affiliation: Department of Biological Research, Dr. Karl Thomae GmbH, Biberachl Riss, Germany.
authors.forename: J C
authors.initials: JC
authors.lastname: van Meel
authors.forename: M
authors.initials: M
authors.lastname: Entzeroth
authors.forename: N
authors.initials: N
authors.lastname: Redemann
authors.forename: R M
authors.initials: RM
authors.lastname: Haigh
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology; D066298:In Vitro Techniques; D007700:Kinetics; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009210:Myofibrils / Q000187:drug effects* / Q000201:enzymology; D010710:Phosphates / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D010710:Phosphates; D011724:Pyridazines; C041648:pimobendan; C047936:UD CG 212 Cl; D000251:Adenosine Triphosphatases; D002118:Calcium