Effector systems involved in the insulin secretory responses to efaroxan and RX871024 in rat islets of Langerhans.
One component of the mechanism by which imidazoline compounds promote insulin secretion involves closure of ATP-sensitive K+ channels in the beta-cell plasma membrane. Recently, however, it has also been proposed that these compounds may exert important effects on more distal effector systems. In the present work, we have investigated the contribution played by protein kinases A and C to the insulin secretory responses of isolated rat islets of Langerhans treated with efaroxan and RX871024 (1-phenyl-2-(imidazolin-2-yl) benzimidazole). Removal of extracellular Ca2+ or blockade of voltage-sensitive Ca2+ channels prevented stimulation of insulin secretion by efaroxan, confirming a critical role for increased Ca2+ influx in the secretory response. By contrast, inhibition of protein kinases A or C failed to alter efaroxan-induced insulin secretion. RX871024 dose-dependently increased insulin secretion from cultured islets incubated with 20 mM glucose. This effect was unaffected by modulation of protein kinase C, but was significantly attenuated by a selective inhibitor of protein kinase A (Rp-cAMPs). Measurements of cAMP revealed that RX871024 increased the islet cAMP content by more than 3-fold; reaching values similar in magnitude to those elicited by 50 microM 3-isobutyl-1-methyl xanthine. The results reveal that neither protein kinase A nor protein kinase C is obligatory for stimulation of insulin secretion by imidazolines. However, they suggest that a rise in cAMP may contribute to the amplified secretory response observed when cultured islets are incubated with RX871024 in the presence of a stimulatory glucose concentration.
Department of Biological Sciences, Keele University, Staffs, UK.
M
M
Mourtada
S A
SA
Smith
N G
NG
Morgan
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D051381:Rats; D017208:Rats, Wistar
C101943:2-(2-imidazolin-2-yl)-1-phenyl-1H-indole; D000317:Adrenergic alpha-Antagonists; D001572:Benzofurans; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; D007328:Insulin; D047428:Protein Kinase Inhibitors; D000242:Cyclic AMP; D011493:Protein Kinase C; C062597:efaroxan; D002118:Calcium