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-mu M 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 and higher D-glucose levels. When the concentration of FX 871024 was raised to 1.0 mM, severe inhibition of glucose-stimulated insulin output was observed. The imidazole derivative (10 mu M) failed to enhance glucose-stimulated biosynthetic activity in islets exposed to L-[4-H-3]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 mu M) coincided with a decrease in Ca-45 net uptake, unchanged outflow of Rb-86 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. (C) 1998 The Italian Pharmacological Society.