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Characterization of New Selective Somatostatin Receptor Subtype-2 (sst2) Antagonists, BIM-23627 and BIM-23454. Effects of BIM-23627 on GH Release in Anesthetized Male Rats after Short-Term High-Dose Dexamethasone Treatment

Department of Biomedical Sciences and Biotechnology (G.T., D.S., M.B., D.C.), Internal Medicine (A.G.), University of Brescia, 25125 Brescia, Italy; and Biomeasure Inc., (M.D.C., J.E.T.) Milford, Massachusetts

Address all correspondence and requests for reprints to: Dr. Andrea Giustina, Endocrine Section, 2^a Medicina, Spedali Civili di Brescia, 25125 Brescia, Italy. E-mail: . giustina{at}master.cci.unibs.it

We here report a pharmacological characterization of two new somatostatin (SS) receptor subtype-2 (sst2) selective antagonists by evaluating their GH-releasing activity when administered, by different routes, in anesthetized adult rats and in freely moving 10-d-old rats. Moreover, we describe the effect of these SS antagonists on the GH response to GHRH after short-term high-dose dexamethasone (DEX) treatment in young male rats. BIM-23454 and BIM-23627, given iv, were able to counteract the SS-induced inhibition of GH secretion occurring after urethane anesthesia in a dose-dependent manner. In DEX-treated animals, the GH response to GHRH was partially blunted (5-min peak values, 270 ± 50 ng/ml in saline-treated vs. 160 ± 10 ng/ml in DEX-treated, P < 0.05); however, the simultaneous administration of BIM-23627 (0.2 mg/kg, iv) restored higher amplitude GH pulse, leading to a significantly higher overall mean GH response (area under the curve, 4200 ± 120 ng/ml/30 min vs. 2800 ± 100 ng/ml/30 min after GHRH alone; P < 0.05). The SS antagonists showed a reduced GH-releasing effect when administered sc or ip, likely attributable to decreased bioavailability, as compared with the iv route. SS antagonist administration also increased plasma glucagon, insulin, and glucose levels. Based on prior reports that sst2 tonically suppresses glucagon secretion, the antagonist most likely increased glucagon secretion from the pancreatic -cells, with resultant increases in plasma glucose and then insulin.

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