Paradoxical inhibitory effect of cromakalim on 86Rb outflow from pancreatic islet cells.
Cromakalim appears to be the most potent pharmacologic agent belonging to the new class of smooth muscle relaxants: the "K+ channel openers." The present study aimed at characterizing the effects of cromakalim on 86Rb outflow, 45Ca outflow and insulin release from prelabeled and perifused rat pancreatic islets. Cromakalim provoked a concentration-dependent reduction in 86Rb outflow. This inhibitory effect was attenuated in islets exposed throughout to glibenclamide or to a Ca+(+)-free medium. In islets exposed to glucose and extracellular Ca++, cromakalim induced a dose-dependent reduction in 45Ca outflow. The drug also inhibited the increase in 45Ca outflow mediated by K+ depolarization. Lastly, cromakalim elicited a concentration-dependent inhibition of insulin release from islets perifused in the presence of glucose and extracellular Ca++. The present data suggest that the paradoxical inhibitory effect of cromakalim on 86Rb outflow probably reflects the capacity of the drug to reduce the activity of the ATP-sensitive K+ channels and to indirectly inhibit the Ca+(+)-activated K+ channels. Furthermore, the cromakalim-induced changes in 45Ca outflow are compatible with an inhibitory effect of the drug on the voltage-dependent Ca++ channels.
Lebrun
P
P
Free University of Brussels, Laboratory of Pharmacology, Faculty of Medicine, Belgium.
Antoine
M H
MH
Devreux
V
V
Hermann
M
M
Herchuelz
A
A
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002132:Calcium Radioisotopes; D019806:Cromakalim; D005110:Extracellular Space / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D010276:Parasympatholytics / Q000494:pharmacology*; D010477:Perfusion; D011189:Potassium Chloride / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D012413:Rubidium / Q000493:pharmacokinetics*; D012414:Rubidium Radioisotopes
D001578:Benzopyrans; D002132:Calcium Radioisotopes; D007328:Insulin; D010276:Parasympatholytics; D011758:Pyrroles; D012414:Rubidium Radioisotopes; D019806:Cromakalim; D011189:Potassium Chloride; D005947:Glucose; D012413:Rubidium; D005905:Glyburide; D002118:Calcium