EFFECTS OF PIMOBENDAN AND ITS METABOLITE ON MYOFIBRILLAR CALCIUM RESPONSIVENESS AND ATPASE ACTIVITY IN THE PRESENCE OF INORGANIC-PHOSPHATE

The effects of the cardiotonic agent pimobendan (CAS 118428-36-7, UD-C G 115 BS) and its main metabolite UD-CG 212 on dog cardiac myofibrilla r calcium responsiveness and ATPase activity were studied at nominal f ree inorganic phosphate (P-i) and at 5 mmol/l P-i. A rightward shift o f the pCa-tension relationship with a marked depression of maximal ten sion was observed in the presence of 5 mmol/l P-i. Pimobendan increase d myofibrillar calcium responsiveness at concentrations greater than o r equal to 10(-5) mol/l. These effects of pimobendan, were significant ly greater at 5 mmol/l P-i than at nominally free P-i. UD-CG 212 had n o influence on myofibrillar calcium responsiveness at nominally free P -i however significant effects were observed at 10(-9) mol/l UD-CG 212 in the presence of 5 mmol/l P-i. UD-CG 212 (10(-8) mol/l) did not inf luence myofibrillar ATPase activity at pCa's 6.23, 5.99, and 4.36 with or without 5 mmol/l P-i whereas pimobendan (10(-4) mmol/l) had an eff ect only at pCa = 5.99 (without P-i) and pCa = 4.36 (+ 5 mmol/l P-i). The data suggest that the increase in myofibrillar calcium responsiven ess at submaximal calcium concentrations by pimobendan and UD-CG 212 i n the presence of 5 mmol/l P-i is brought about by a change in crossbr idge kinetics or by enhancement of thin filament activation by adjacen t strong cross-bridges. At maximal calcium activation, pimobendan may additionally, increase the population of strong cross-bridges.