Glimepiride (Hoe490) inhibits the rilmakalim induced decrease in intracellular free calcium and contraction of isolated heart muscle cells from guinea pigs to a lesser extent than glibenclamide.
Glibenclamide is a potent inhibitor of the ATP-dependent potassium channel. Opening of the ATP-dependent potassium channel is regarded as a mechanism of ischemic preconditioning. This in vitro study examines the influence of glibenclamide and glimepiride, a new sulfonylurea, on the negative inotropic action of the potassium channel opener rilmakalim in isolated ventricular myocytes. Cardiac myocytes were isolated from adult guinea pig hearts by collagenase perfusion and incubated with rilmakalim (concentration range 0.1-12.0 microM), glibenclamide (concentration range 0.03-3.0 microM) plus rilmakalim (3.0 or 7.5 microM), and glimepiride (0.03-9.0 microM) plus rilmakalim (3.0 or 7.5 microM) and paced by electrical field stimulation. Contractility of the myocytes was evaluated by digital image analysis, intracellular free calcium was determined by means of fura-2 fluorescence measurements, and cell viability was assessed morphologically as well as by measurement of lactate dehydrogenase activity. Rilmakalim reduced the systolic intracellular free calcium and contractility of ventricular myocytes in a concentration dependent manner. This effect was antagonized by glibenclamide at lower concentrations (0.3 microM) than glimepiride (3.0 microM). The smaller antagonistic action of glimepiride on the negative inotropic effect of rilmakalim as compared with glibenclamide most likely reflects a less potent inhibition of ATP-dependent potassium channels by glimepiride.
Olbrich
H G
HG
Medizinische Klinik IV-Kardiologie, J.W. Goethe-Universität, Frankfurt am Main, Germany. H.Olbrich@em.uni-frankfurt.de
Müller
M
M
Lindner
S
S
Henke
B
B
Zarse
M
M
Riehle
M
M
Oremek
G
G
Mutschler
E
E
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002839:Chromans / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology*; D006168:Guinea Pigs; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects; D011759:Pyrrolidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D002839:Chromans; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D011759:Pyrrolidines; D013453:Sulfonylurea Compounds; C075012:rilmakalim; C057619:glimepiride; D000255:Adenosine Triphosphate; D011188:Potassium; D005905:Glyburide; D002118:Calcium