Effects of pimobendan and its active metabolite, UD-CG 212 Cl, on Ca2+-activated K+ channels in vascular smooth-muscle cells.
The aim of this study was to clarify the mechanisms of activation of Ca2+-dependent K+ (K(Ca)) channels by pimobendan, a new cardiotonic and vasodilator agent with phosphodiesterase inhibition properties, and its main metabolite, UD-CG 212 Cl, in vascular smooth-muscle cells from porcine coronary arteries. Both pimobendan and UD-CG 212 Cl induced relaxation of porcine coronary artery strips. However, in the presence of 100 microM Rp-cAMPS (Rp diastereomer of adenosine cyclic 3',5'-phosphorothioate), a membrane-permeable antagonist of cAMP, the effects of pimobendan decreased significantly. Application of 1 microM pimobendan activated K(Ca) channels in cell-attached patches, and this increase in activity was suppressed by 100 nM H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide), a cAMP-dependent protein-kinase inhibitor. Pimobendan was ineffective in altering the activity of K(Ca) channels in inside-out patches. In contrast, UD-CG 212 Cl, at a concentration of 1 microM, activated K(Ca) channels not only in cell-attached patches but also in inside-out patches. Application of 100 nM H-89 also inhibited UD-CG 212 Cl-induced K(Ca) channels activity but to a lesser degree than that induced by pimobendan in cell-attached patches. In conclusion, there are two mechanisms of activation of K(Ca) channels by pimobendan and UD-CG 212 Cl. Activation by pimobendan occurs primary through the cAMP pathway, whereas UD-CG 212 Cl activates K(Ca) channels directly as well as through the cyclic AMP pathway.
Chen
C H
CH
Department of Nutrition, School of Medicine, University of Tokushima, Japan.
Nakaya
Y
Y
Minami
K
K
Kubo
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D007546:Isoquinolines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D013449:Sulfonamides; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D015221:Potassium Channels; D011724:Pyridazines; D013449:Sulfonamides; C041648:pimobendan; C047936:UD CG 212 Cl; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium