The novel insulinotropic mechanism of pimobendan: direct enhancement of the exocytotic process of insulin secretory granules by increased Ca2+ sensitivity in beta-cells

Endocrinology. 1998 Mar;139(3):1133-40. doi: 10.1210/endo.139.3.5771.


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 beta-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 beta-cells. This agent increased the intracellular Ca2+ concentration ([Ca2+]i) in the presence of 30 mM K+, 16.7 mM glucose, and 200 microM 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 microM) significantly augmented insulin release at 0.32 microM Ca2+, and a lower threshold for Ca2+-induced insulin release was apparent in pimobendan-treated islets. Moreover, 1 microM 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Benzylamines / pharmacology
  • Calcium / metabolism*
  • Cardiotonic Agents / pharmacology*
  • Cyclic AMP / analysis
  • Cytoplasmic Granules / drug effects*
  • Cytoplasmic Granules / metabolism
  • Exocytosis / drug effects*
  • Glucose / pharmacology
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Male
  • Nitrendipine / pharmacology
  • Potassium / pharmacology
  • Protein Kinase C / physiology
  • Pyridazines / pharmacology*
  • Rats
  • Rats, Wistar
  • Sulfonamides / pharmacology
  • Wortmannin


  • Androstadienes
  • Benzylamines
  • Cardiotonic Agents
  • Insulin
  • Pyridazines
  • Sulfonamides
  • KN 93
  • pimobendan
  • Nitrendipine
  • Cyclic AMP
  • Protein Kinase C
  • Glucose
  • Potassium
  • Calcium
  • Wortmannin