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Regulation of CRH-induced secretion of ACTH and corticosterone by SOM230 in rats

Novartis Institutes for BioMedical Research, Basel, Switzerland

(Correspondence should be addressed to H Schmid; Email: herbert.schmid{at}novartis.com)

Abstract

Objective: Adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome is biochemically characterized by increased plasma concentrations of ACTH inducing hypersecretion of cortisol. Somatostatin is known to inhibit ACTH secretion, and in vitro data have shown the inhibition of ACTH secretion by agonists activating sst2 and sst5 receptors. The present study aimed to determine the inhibitory effect of the multireceptor ligand SOM230, compared with the sst2-preferring agonist octreotide, on corticotropin-releasing hormone (CRH)-stimulated secretion of ACTH and corticosterone in rats.

Methods: Secretion of ACTH and corticosterone was induced by i.v. application of CRH (0.5 µg/kg) in rats pretreated 1 h before by i.v. application of SOM230 (1, 3, or 10 µg/kg), octreotide (10 µg/kg) or NaCl 0.9%.

Results: SOM230 (3 and 10 µg/kg) inhibited CRH-induced ACTH release by 45±3% and 51±2%, respectively, and corticosterone release by 43±5% and 27±16%, respectively. 10 µg/kg of octreotide tended to be less potent at inhibiting ACTH release (34±6% inhibition) and did not alter the secretion of corticosterone.

Conclusion: SOM230 has a stronger inhibitory effect on ACTH and corticosterone secretion than octreotide in rats. This difference can be explained by its higher affinity to sst1, sst3 and especially sst5 receptors compared with octreotide.

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