Stimulation of insulin secretion from isolated rat islets by SaRI 59-801. Relation to cAMP concentration and Ca2+ uptake.
The mechanism of stimulation of insulin release from isolated rat islets by 0.3 mM SaRI 59-801 (DL-alpha-dimethylaminomethyl-2-[ 3-ethyl-5-methyl-4-isoxazoyl]-1H-indole-3-methanol) was investigated, considering cAMP concentration and Ca2+ uptake. Ten millimolar theophylline or 1 mM 1-methyl-3-isobutylxanthine, which inhibit cAMP phosphodiesterase, each greatly increased the stimulation of insulin release by 59-801. Forskolin (0.1 mM), an activator of adenylate cyclase, or 1 mM dibutyryl cAMP also potentiated 59-801, suggesting that 59-801 does not elevate islet cAMP but is potentiated by other compounds that do. Measurement of cAMP in islets by radioimmunoassay confirmed that it was not significantly elevated by 59-801 but was increased sevenfold by forskolin or 1-methyl-3-isobutylxanthine. SaRI 59-801 was not effective in the absence of Ca2+ and presence of 1 mM EGTA. Agents that block entry of Ca2+ into beta-cells, verapamil, nifedipine, or CoCl2, inhibited the release of insulin in response to 59-801. Studies of 45Ca2+ uptake by isolated islets revealed an increased uptake in the presence of 59-801 and blockage of this effect by 50 microM verapamil. Thus, the stimulation of insulin secretion by 59-801 appears to involve a stimulation of Ca2+ uptake rather than an increase of cAMP concentration. The mechanism of stimulation of Ca2+ uptake by 59-801 requires further investigation.
R L
RL
Hanson
C M
CM
Isaacson
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D005576:Colforsin; D000242:Cyclic AMP / Q000032:analysis / Q000502:physiology*; D004224:Diterpenes / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013806:Theophylline / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D004224:Diterpenes; D007004:Hypoglycemic Agents; D007328:Insulin; D007555:Isoxazoles; D010080:Oxazoles; D005576:Colforsin; D003994:Bucladesine; C045735:SaRI 59-801; D014044:Tolbutamide; D013806:Theophylline; D014700:Verapamil; D000242:Cyclic AMP; D009543:Nifedipine; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine