Abstract
We investigated the mechanisms of the effects of a newly synthesized cyclic AMP phosphodiesterase inhibitor (PDEI: 1,5-dihydro-7-(1-piperidinyl)imidazo[2,1-beta]quinazolin- 2(3H)-one dihydrochloride hydrate, DN-9693) on intracellular Ca2+ transients and tension in ferret papillary muscles. We used the aequorin method to measure Ca2+ transients in intact preparations. DN-9693 (1-100 microM) increased the peaks of both Ca2+ transients and tension. The potentiation of Ca2+ transients by DN-9693 was significant at lower concentrations (1-10 microM) but not at higher concentrations (50 and 100 microM). The peak of tension was significantly increased when the concentration of DN-9693 was increased (1-100 microM). In addition, the time to peak light was shortened at lower concentrations (1 and 5 microM). Other parameters of Ca2+ transients were not significantly altered. The time course of tension was not affected by DN-9693. In Triton X-100-treated skinned preparations, DN-9693 decreased the Ca2+ concentration required for half-maximal activation of the pCa-tension relation. These results suggest that the positive inotropic effect of DN-9693 is attributable to the alteration in Ca2+ handling of sarcoplasmic reticulum (SR) and Ca2+ sensitization of the myofilaments.
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