Secretory, biosynthetic and cationic responses to 2-(N-PHENYL-INDOYL)IMIDAZOLE in rat pancreatic islets.
The secretory, biosynthetic and cationic effects of a novel insulinotropic agent with an imidazoline structure, 2-(N-phenyl-indoyl)imidazole hydrochloride (RX 871024) was investigated in rat pancreatic islets. In the 1.0-10-microM range, this agent augmented, in a concentration-related manner, the release of insulin from islets incubated at intermediate concentrations of d-glucose (4.0-7.0 mm), this enhancing action fading out at both lower a nd higher d-glucose levels. When the concentration of RX 871024 was raised to 1.0 mm, severe inhibition of glucose-stimulated insulin output was observed. The imidazole derivative (10 microM) failed to enhance glucose-stimulated biosynthetic activity in islets exposed to l-[4-3H]phenylalanine; a modest inhibition of the islet peptide tritiation was even recorded at 4.0 mm d-glucose. The positive insulinotropic action of RX 871024 (10 microM) coincided with a decrease in 45Ca net uptake, unchanged outflow of 86Rb and stimulation of 45Ca efflux from prelabelled islets, the latter effect being only partially suppressed in the absence of extracellular Ca2+. These findings suggest a multifactorial mode of action of RX 871024 in islet cells, with emphasis on both an apparent stimulation of Ca2+ influx and, independently of this effect, an intracellular redistribution of the divalent cation. The imidazole compound is proposed, therefore, to display suitable attributes to bypass site-specific defects of d-glucose metabolism in the B-cell of non-insulin-dependent diabetic patients.
Laboratory of Experimental Medicine, Brussels Free University, 808 Route de Lennik, Brussels, B-1070, Belgium.
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K
Louchami
A
A
Laghmich
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H
Jijakli
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H
Mest
W J
WJ
Malaisse
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005947:Glucose / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D010649:Phenylalanine / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014316:Tritium
C101943:2-(2-imidazolin-2-yl)-1-phenyl-1H-indole; D002413:Cations, Divalent; D007093:Imidazoles; D007211:Indoles; D007328:Insulin; D014316:Tritium; D010649:Phenylalanine; D005947:Glucose; D002118:Calcium