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The Novel Insulinotropic Mechanism of Pimobendan: Direct Enhancement of the Exocytotic Process of Insulin Secretory Granules by Increased Ca²⁺ Sensitivity in ß-Cells¹

Department of Metabolism and Clinical Nutrition, Kyoto University Faculty of Medicine, Kyoto 606–01; and the Department of Internal Medicine, Kitano Hospital (K.T.), Osaka 530, Japan

Address all correspondence and requests for reprints to: Shimpei Fujimoto, M.D., Department of Metabolism and Clinical Nutrition, Kyoto University Faculty of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606, Japan. E-mail: fujimoto{at}metab.kuhp.kyotou.ac.jp

Pimobendan is a new class of inotropic drug that augments Ca²⁺ sensitivity and inhibits phosphodiesterase (PDE) activity in cardiomyocytes. To examine the insulinotropic effect of pimobendan in pancreatic ß-cells, which have an intracellular signaling mechanism similar to that of cardiomyocytes, we measured insulin release from rat isolated islets of Langerhans. Pimobendan augmented glucose-induced insulin release in a dose-dependent manner, but did not increase cAMP content in pancreatic islets, indicating that the PDE inhibitory effects may not be important in ß-cells. This agent increased the intracellular Ca²⁺ concentration ([Ca²⁺]_i) in the presence of 30 mM K⁺, 16.7 mM glucose, and 200 µM diazoxide, but failed to enhance the 30 mM K⁺-evoked [Ca²⁺]_i rise in the presence of 3.3 mM glucose. Insulin release evoked by 30 mM K⁺ in 3.3 mM glucose was augmented. Then, the direct effects of pimobendan on the Ca²⁺-sensitive exocytotic apparatus were examined using electrically permeabilized islets in which [Ca²⁺]_i can be manipulated. Pimobendan (50 µM) significantly augmented insulin release at 0.32 µM Ca²⁺, and a lower threshold for Ca²⁺-induced insulin release was apparent in pimobendan-treated islets. Moreover, 1 µM KN93 (Ca²⁺/calmodulin-dependent protein kinase II inhibitor) significantly suppressed this augmentation. Pimobendan, therefore, enhances insulin release by directly sensitizing the intracellular Ca²⁺-sensitive exocytotic mechanism distal to the [Ca²⁺]_i rise. In addition, Ca²⁺/calmodulin-dependent protein kinase II activation may at least in part be involved in this Ca²⁺ sensitization for exocytosis of insulin secretory granules.

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