Somatostatin Inhibits Basal and Vasoactive Intestinal Peptide-Stimulated Hormone Release by Different Mechanisms in GH Pituitary Cells*

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Abstract
Somatostatin (SRIF) inhibits both basal and vasoactive intestinal peptide (VIP)-stimulates hormone secretion by the GH4C1 clonal strain of rat pituitary tumor cells. SRIF inhibits cAMP accumulation stimulated by VIP but does not alter basal cAMP levels in this cell line. To determine the importance of changes in cAMP accumulation in the mechanism of SRIF action, the effect of SRIF on hormone release stimulated by VIP and two other secretagogues, which increase effective intracellular cAMP concentration were compared: forskolin and 8-bromo-cAMP (8-Br-cAMP). VIP stimulated GH [growth hormone] and PRL [prolactin] secretion to the same maximal extent (220% of control) with similar ED50 values (0.37 .+-. 0.03 and 0.43 .+-. 0.08 mM, mean .+-. SE, respectively), SRIF (100 nM) reduced maximal VIP-stimulation of both GH and PRL release from 220 to 140% of control; however, it did not significantly change the ED50 values for VIP. The effect of SRIF on VIP-stimulated hormone release parallels its action on VIP-stimulated cAMP accumulation. The concentrations of SRIF required to produce half-maximal inhibition of VIP-stimulated GH and PRL release (0.8 .+-. 0.2 nM and 0.7 .+-. 0.1 nM, respectively) were similar to its potency to inhibit VIP-stimulated cAMP accumulation (1.2 .+-. 0.1 nM). Changes in cAMP levels mediate inhibition of VIP-stimulated hormone secretion by SRIF. Forskolin increased cAMP accumulation with an ED50 value of 2.4 .+-. 0.5 .mu.M. A maximal concentration of forskolin (100 .mu.M) stimulated a cAMP accumulation to a greater extent than 100 nM VIP (34 .+-. 4-fold vs. 9 .+-. 1-fold). Together, forskolin (100 .mu.M) and VIP (100 nM) stimulated cAMP accumulation by more than 50-fold. However, PRL secretion in response to maximal conentrations of VIP forskolin individually or together were the same (.apprx. 200% of control). These results support the conclusion that both compounds stimulate PRL secretion by a cAMP-mediated mechanism which can be fully activated by either one alone. SRIF decreased maximal forskolin-stimulated cAMP accumulation from 34-fold to 24-fold in the absence of VIP and from 62-fold to 56-fold in the presence of 100 nM VIP. In the presence of a maximal concentration of forskolin, SRIF never reduced cAMP levels to value below that observed with 100 nM VIP alone. Consistent with these results, SRIF did not inhibit stimulation of PRL release by maximal concentrations of forskolin. In addition, forskolin prevented inhibition of VIP-stimulated PRL release by SRIF. Therefore, inhibition of VIP-stimulated cAMP accumulation to submaximal levels appears to be required for SRIF inhibition of VIP-stimulated hormone release. Concentrations of 8-Br-cAMP from 1.0-2.0 mM produced a dose-dependent stimulation of PRL release up to 230% of control values. SRIF (100 nM) decreased basal PRL secretion by 25%, and the effects of SRIF and 8-Br-cAMP on PRL release were strictly additive. Therefore, inhibition of basal hormone secretion by SRIF must occur by a mechanism which is independent of changes in intracellular cAMP levels. This conclusion is consistent with the previous observation that SRIF inhibits basal hormone release but does not alter basal cAMP levels. SRIF-induced inhibition of VIP-stimulated hormone release is tightly coupled to inhibition of VIP-stimulated cAMP accumulation, while regulation of basal hormone secretion by SRIF occurs by a mechanism which is independent of intracellular cAMP levels.

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