Inhibition of insulin release by a formamidine pesticide amitraz and its metabolites in a rat beta-cell line: an action mediated by alpha-2 adrenoceptors, a GTP-binding protein and a decrease in cyclic AMP.
We tested the hypothesis that the formamidine pesticide amitraz and its metabolites inhibit insulin release from a rat beta-cell line (RINm5F) by decreasing intracellular cyclic AMP levels and examined whether GTP-binding proteins were involved in the process. Amitraz and its active metabolite BTS27271 (0.1-10 microM) inhibited insulin release that was induced by 100 microM of IBMX in a dose-dependent manner. Other metabolites of amitraz tested failed to inhibit insulin release. A potent and specific alpha-2 adrenoceptor agonist, medetomidine (0.1 microM), abolished the IBMX-induced insulin release. Amitraz, BTS27271 and medetomidine also decreased intracellular cyclic AMP concentrations that were elevated by IBMX administration. Moreover, all three drugs inhibited the insulin release stimulated by forskolin (1 microM), an adenylyl cyclase activator. Yohimbine (0.01, 0.1 and 1 microM), an alpha-2 adrenoceptor antagonist, prevented the inhibitory effect of amitraz and BTS27271 on insulin release, whereas prazosin (1 microM), an alpha-1 adrenoceptor antagonist, did not. Yohimbine, but not prazosin, also prevented the effect of amitraz, BTS27271 and medetomidine on IBMX-stimulated accumulation of cyclic AMP. Pretreatment of cells with PTX (0.1 micrograms/ml) for 16 h, antagonized the effects of amitraz and BTS27271 on IBMX-induced increase in insulin release. Thus, one mechanism by which amitraz and its metabolite BTS27271 decrease insulin release is by inhibiting adenylyl cyclase, an action mediated through a PTX-sensitive G-protein.
Chen
T H
TH
Department of Veterinary Physiology and Pharmacology, Iowa State University, Ames.
Hsu
W H
WH
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D037361:Adenylate Cyclase Toxin; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D007306:Insecticides / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects; D020926:Medetomidine; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000502:physiology; D014052:Toluidines / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D000578:Amidines; D007093:Imidazoles; D007306:Insecticides; D007328:Insulin; D018341:Receptors, Adrenergic, alpha-2; D014052:Toluidines; D010566:Virulence Factors, Bordetella; C025699:U 40481; C014983:amitraz; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D020926:Medetomidine; D015056:1-Methyl-3-isobutylxanthine; D011224:Prazosin