Somatostatin-mediated inhibitory postsynaptic potential in sympathetically denervated guinea-pig submucosal neurones.

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.