A multi-tyrosinated sst1/2 receptor preferring somatostatin agonist inhibits reflex and immune-mediated secretion in the guinea pig colon

Abstract

Somatostatin and its analogs such as WOC 3B were compared for their ability to alter the release of 5-hydroxytryptamine (5-HT) and prostaglandins and to affect chloride secretory capacity, determined by activity of neural reflexes or by the influence of immune mediators and other secretagogues. In guinea pig colon set up in flux chambers, the multi-tyrosinated sst1/sst2 receptor preferring somatostatin agonist, WOC 3B, inhibited stroking-evoked 5-HT release without affecting basal release. WOC 3B had no effect on stroking-induced or basal prostaglandin E2 release (PGE2). Neither 5-HT nor PGE2 release was dependent on neural input. Tetrodotoxin induced a decrease in basal short circuit current (Isc) indicative of a decrease in chloride secretion. The decrease in basal Isc during neural blockade was highly correlated with the decrease in basal Isc when WOC 3B was used. In piroxicam- and atropine-treated tissues, to eliminate prostaglandins and cholinergic muscarinic input to crypts, WOC 3B further reduced the piroxicam-resistant and not the atropine resistant Isc during brush stroking the mucosa. Somatostatin and WOC 3B reduced the stroking-evoked Isc with similar half maximum concentrations of 1-2 nM. WOC 3B reduced by more than 50% dimaprit-evoked cyclical Isc. The rank order of potencies in inhibiting dimaprit-evoked Isc was: Somatostatin-14=WOC 3B>CH275=DC-32-92>DC-23-48>> >>DC-32-87=DC-32-97. Low nanomolar concentrations of WOC 3B primarily inhibited the neural effects of carbachol and forskolin on Isc without altering their epithelial effects. Equi-molar concentrations (4 nM) of CH275, a somatostatin sst1 receptor agonist, and the somatostatin sst2 receptor agonist, [Tyr(3)]-octreotide, inhibited dimaprit-evoked Isc by 25% and 26%, and their effects were additive. The results suggest that WOC 3B, a somatostatin analogue containing three tyrosine residues, has anti-secretory effects due to activation of somatostatin sst1 and sst2 receptors on enteric neurons.