1. Intracellular recordings were made from submucosal neurones in guinea‐pig ileum. In some animals, the extrinsic (sympathetic) nerves to the submucosal plexus were severed 5‐7 days previously. The actions of somatostatin and somatostatin analogues on membrane potential, membrane current and inhibitory postsynaptic potentials (IPSPs) were examined. 2. Somatostatin, somatostatin(1‐28), [D‐Trp8]somatostatin and the somatostatin analogue CGP 23996 all produced equivalent maximum hyperpolarizations or outward currents; half‐maximal concentrations (EC50 values) were 9‐11 nM. The somatostatin analogue MK 678 had an EC50 of 0.9 nM. Extrinsic sympathectomy did not alter concentration‐response relations for somatostatin or its analogues. 3. Somatostatin (> 100 nM) produced hyperpolarization or outward current that declined almost completely during superfusion for 2‐4 min; decline of the somatostatin current was exponential with a time constant of 30 s in the presence of 2 microM somatostatin. Desensitization was not altered by extrinsic denervation. 4. Recovery from desensitization was rapid and followed the time course of agonist wash‐out. Forskolin, phorbol esters, dithiothreitol, hydrogen peroxide, concanavalin A, or reducing temperature from 35 to 29 degrees C did not alter the time course, degree of, or recovery from desensitization. 5. The somatostatin‐induced desensitization was of the homologous type; no cross‐desensitization to opiate or alpha 2‐adrenoceptor agonists (which activate the same potassium conductance) occurred. 6. Somatostatin desensitization did not alter the adrenergic IPSP seen in sympathetically innervated preparations but abolished the non‐adrenergic IPSP recorded from normal preparations and from preparations in which the extrinsic sympathetic nerve supply had been surgically removed. 7. The selective blockade of the non‐adrenergic IPSP by the homologous‐type somatostatin desensitization characterized in the present study provides strong support for the hypothesis that somatostatin is the neurotransmitter underlying the non‐adrenergic IPSP in both normal and extrinsically denervated submucosal neurones.
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