Role of VIP in the regulation of LH secretion in the female rat.

Vasoactive intestinal peptide (VIP) is found within neurons throughout the body. It influences the secretion of several hormones of the anterior pituitary by neural and pituitary actions. We review work from our laboratory that indicates that VIP inhibits the secretion of luteinizing hormone (LH) by a hypothalamic action. Experiments involving neural lesions indicate that VIP acts on the receptor field in the paraventricular nuclei of neurons whose cell bodies are located in the suprachiasmatic nuclei. The effect on LH secretion is subsequently mediated by a nonVIPergic pathway, which does not appear to involve either dopamine or endogenous opioids. Experiments with the specific VIP antagonist, [4Cl-D-Phe6,Leu17]VIP, indicate that the actions on LH secretion of VIP and of the related peptides, growth hormone-releasing hormone and secretin, are mediated by VIP-preferring receptors. VIP also blocks the steroid-induced LH surge in the ovariectomized rat. The VIP antagonist induces a significant, but small increase in LH secretion in the intact rat, indicating that VIP has a modulatory, rather than deterministic, role in the regulation of LH secretion.

Effect of [4Cl-D-Phe6,Leu17]VIP on the inhibition of pulsatile LH release by VIP and related peptides in the ovariectomized rat.

Pulsatile LH secretion in the ovariectomized (OVX) rat is inhibited by intracerebroventricular (icv) infusion of vasoactive intestinal peptide (VIP). VIP, rat growth hormone-releasing hormone (rGRH) and secretin with and without an antagonist to VIP, [4Cl-D-Phe6,Leu17]VIP (VIPA), were infused icv into OVX rats. Both VIP and rGRH at an infusion rate of 3.5 nmol/h lowered mean LH concentrations and pulse frequency without affecting pulse amplitude, and these effects were blocked by concurrent infusion of VIPA (10.5 nmol/h). Secretin also inhibited pulsatile LH secretion, but was only fully effective at the higher infusion rate of 7 nmol/h. This effect of secretin was also blocked by concurrent infusion of 10.5 nmol/h of VIPA. These results suggest that all three of these peptide hormones inhibit pulsatile LH secretion by an interaction with VIP receptors.

Vasoactive intestinal peptide inhibits the steroid-induced LH surge in the ovariectomized rat.

The LH surge was induced in ovariectomized rats by sequential treatment with oestradiol benzoate and progesterone. Vasoactive intestinal peptide (VIP) or saline was infused into the third cerebral ventricle from 13.30 to 16.30 h on the afternoon of the anticipated LH surge. Two blood samples were taken by jugular puncture from each animal, one at 12.00 h as a control sample and the other at 16.00, 18.00, 20.00 or 22.00 h. Saline-infused animals showed a normal LH surge, with mean plasma LH concentrations reaching a peak at 18.00 h, declining by 20.00 h and reaching control (12.00 h) levels by 22.00 h. Plasma LH in animals infused with VIP was not significantly higher than control levels at 16.00 or 18.00 h. By 20.00 h, mean LH levels in VIP-infused rats had risen to the levels seen at that time in saline-infused rats, and by 22.00 h LH had returned to control levels in VIP-infused animals. We interpret these findings to mean that VIP inhibits LH secretion during the LH surge. It does not block the surge completely, as pentobarbital during the critical period would have done; nor does VIP appear to affect the timing of the LH surge. Rather, VIP inhibits the increased LH secretion rates of the LH surge only during the period of VIP treatment and for a short time afterward.

Differential glucocorticoid regulation of glucagon gene expression in cell lines derived from rat and hamster islet cell tumors.

Glucocorticoid regulation of peptide hormone gene expression was studied in two cell lines derived from rodent islet cell tumors. In rat RIN1056A cells, dexamethasone reduced the levels of glucagon mRNA transcripts while markedly inducing the expression of the angiotensinogen gene. In contrast, dexamethasone had no effect on the regulation of glucagon gene expression in hamster InR1-G9 cells. Wild type InR1-G9 cells did not support the induction of the murine mammary tumor virus promoter by glucocorticoids, suggesting that these cells lacked the necessary cellular factor(s) for glucocorticoid responsiveness. Introduction of the glucocorticoid receptor into wild type InR1-G9 cells restored glucocorticoid induction of the murine mammary tumor virus promoter, but not glucocorticoid regulation of glucagon gene expression. Dexamethasone treatment of Sprague-Dawley rats had no effect on the levels of pancreatic glucagon mRNA transcripts. The results of these studies demonstrate that glucocorticoid regulation of glucagon gene expression is restricted to the immortalized RIN1056A cell line, providing additional evidence for cell-specific diversity in the regulation of peptide hormone gene expression in neuroendocrine tumors.

Proglucagon-derived peptides in the neuroendocrine system.

Using several novel in vitro culture systems, we have examined the tissue-specific regulation of the proglucagon-derived peptides, at the levels of proglucagon gene expression and pGdp synthesis and secretion. Our studies indicate that proglucagon gene expression in intenstine, hypothalamus and pancreas is under the regulatory control of protein kinase A- but not a protein kinase C-dependent pathway. PKA and PKC stimulate secretion of the intestinal pGdp's, whereas only PKA stimulates secretion of the hypothalamic peptides. Pancreatic glucagon secretion in response to PKA is subject to further modulation by prevailing glucose concentrations. This diversity in intracellular regulation of the pGdp's may account for some of the tissue-specific differences in synthesis and secretion of the pGdp's that we have observed in diabetes and during development.

Effects of lesions of the suprachiasmatic and paraventricular nuclei on the inhibition of pulsatile luteinizing hormone release by exogenous vasoactive intestinal peptide in the ovariectomized rat.

Vasoactive intestinal peptide (VIP) inhibits pulsatile luteinizing hormone (LH) secretion in the ovariectomized rat. Hypothalamic nuclei known to contain VIPergic neurons were destroyed electrolytically to determine whether either an increased response or a loss of response to exogenous VIP would result. Bilateral electrolytic lesions were made of either the suprachiasmatic (SCN) or paraventricular (PVN) nuclei in separate experiments; all animals received an intracerebroventricular cannula at the same time. Sham-lesioned animals were used as a control. One week later, a catheter was placed in the jugular vein of each rat and, after a recovery period of at least 2 h, blood samples were taken every 5 min for 3 h. After a control period of 1.5 h, either VIP or saline was infused into the third ventricle for an additional 1.5 h. Two doses of VIP were used: 3.5 nmol/h, previously shown to be inhibitory, and 0.4 nmol/h, which is ineffective in ovariectomized rats. LH was measured in the plasma by radioimmunoassay. The high dose of VIP lowered mean LH levels and pulse frequency but had no effect on pulse amplitude in both sham-lesioned and SCN-lesioned rats. The low dose of VIP did not affect pulsatile LH patterns in sham-lesioned rats, but did lower mean LH and pulse frequency in SCN-lesioned rats, indicating a denervation hypersensitivity subsequent to SCN lesions. Destruction of the PVN abolished the inhibitory effect of the high dose of VIP on pulsatile LH release. The low dose of VIP was ineffective in both PVN- and sham-lesioned animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasoactive intestinal peptide inhibits luteinizing hormone secretion: the inhibition is not mediated by dopamine.

Vasoactive intestinal peptide (VIP) is a neuropeptide that is present in the hypothalamus and is probably a neuroendocrine regulator. The effect of VIP on pulsatile LH secretion in the long-term ovariectomized rat was re-examined in the light of earlier conflicting reports. VIP or saline was infused into the third ventricle at the rat of 15 microliters/h and blood was sampled frequently before and during the infusion. VIP at 3.5 nmol/h significantly depressed mean LH levels (p less than 0.05) and lowered pulse frequency (p less than 0.05), but had no effect on LH pulse amplitude (p greater than 0.05). VIP at lower levels was not consistently effective, and intraventricular saline was without influence. We examined indirectly whether the site of action of VIP (3.5 nmol/h) was the brain or pituitary by injecting various doses of gonadotropin-releasing hormone (GnRH; 0.5-4.0 ng/100 g BW i.v.) during VIP-induced inhibition of LH secretion and in saline-infused controls. VIP did not alter the response of the pituitary to GnRH or the slope of the GnRH-LH dose-response curve (p greater than 0.05). We conclude that the inhibitory action of VIP on pulsatile LH secretion is probably exerted in the hypothalamus. To test the hypothesis that dopamine mediates the inhibitory effects of VIP (3.5 nmol/h), animals were pretreated with the dopamine receptor blocking agent pimozide (1.26 mg/kg) in an attempt to block the actions of VIP. Pimozide did not affect the response of LH to VIP infusion (p greater than 0.05). We conclude that dopamine is not a likely mediator of the action of VIP.

Serotonin stimulates prolactin secretion in the hypophysectomized adenohypophyseal grafted rat.

Normal male, oestrogen (F2) primed male and hypophysectomized adenohypophyseal grafted male rats (HAG rats) were used in the experiments. Serotonin creatinine sulphate was injected as a bolus via an indwelling atrial cannula in the conscious free moving rat. Serotonin caused a dose-dependent increase in plasma prolactin (Prl) in normal (1, 3 and 10 mg/kg serotonin) and E2 primed (1 and 3 mg/kg serotonin) male rats that began immediately after injection and reached a peak within 12-15 min of injection. Oestrogen priming significantly increased the magnitude of the response to serotonin. To analyze the site of action of serotonin in the rat, serotonin (1 mg/kg) was injected into HAG rats. Serotonin increased plasma Prl in this rat preparation, indicating that serotonin acts directly on the ectopic pituitary.