Special Neuroendocrine Systems Neuroendocrinology 1991 ;53(suppl I ):45—51
© 19 9 1 S. Karger A G , Basel 0028-3835/91/0537-0045 S 2.75/0
Vasoactive Intestinal Peptide in the Hypothalamus and Pituitary Karen S.L. Lam Department o f Medicine, University o f Hong Kong, Hong Kong
Key Words. Vasoactive intestinal peptide • Anterior pituitary • Gene expression ■ Estrogen ■ Posttranslational processing • Peptide histidine isoleucine Abstract. Data are presented to show that vasoactive intestinal peptide (VIP) is synthesized and secreted by the hypothalamus and anterior pituitary and that it participates in the regulation o f pituitary functions. Immunoreactive V IP in the hypothalamus and pituitary is increased following estrogen treatment and adrenalectomy and is reduced in hyperprolactinemic states. The level o f VIP m R N A in the hypothalamus is increased during lactation and sexual maturation, while that in the anterior pituitary shows a sexual dimorphism and is increased with estrogen treatment and hypothyroidism. All these findings suggest a physiological regulation of hypothalamic and pituitary V IP gene expression in relation to its potential role as a neuroendocrine hormone. Furthermore, VIP stimulates prolactin (PRL) release at concentrations attainable in the hypophyseal-portal blood. Passive immunoneutralization studies with anti-VIP antisera suggest that endogenous V IP acts at multiple loci in the hypothalamic-pituitary axis to regulate PRL secretion, interacting possibly with other regulators o f P RL secretion such as estrogen, serotonin, cholecystokinin. prostaglandins, galanin and oxytocin. Regarding other pituitary functions, although V IP has been shown to release growth hormone, A C T H , and vasopressin in vivo and in vitro, the physiological significance o f these findings remains to be determined.
Localization and Concentration of VIP in the Hypothalamus Within the hypothalamus, the highest concentration o f VIP is found in the suprachiasmatic nucleus [9, 32]. A significant population o f VIP-containing cell bodies has also been demonstrated in the parvocellular region o f the paraventricular nucleus [10, 34] with VIP-positive fibres projecting to the ex ternal zone o f the median eminence. While only a few VIP positive fibres can be identified in the rat median eminence under basal conditions, the human median eminence contains high concentrations o f V IP which can be released into the por tal circulation [59]. Adrenalectomy and lactation combined with colchicine treatment result in a marked increase in VIPimmunopositivity in the paraventriculo-tuberoinfundibular system [34]. An increase in VIP in the rat median eminence has also been reported after estrogen treatment [45]. In addi tion, the levels o f hypothalamic V IP m R N A increase during lactation and at the time o f sexual maturation [16]. A recent study using in situ hybridization has shown that this increase occurs predominantly in the suprachiasmatic nucleus [15]. Taken together, the above findings suggest a physiological regulation o f hypothalamic VIP gene expression and synthesis in relation to its potential role as a neuroendocrine hormone. Furthermore, the reduction of hypothalamic and pituitary VIP content and hypophyseal portal blood V IP levels in experi-
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Vasoactive intestinal peptide (VIP) is a highly basic 28amino acid peptide which was originally isolated from the por cine duodenum [51, 52], It is structurally related to other mem bers o f the secretin-glucagon family such as secretin, peptide histidine isoleucine (PHI), growth-hormone-releasing hormone and gastric inhibitory factor. The primary structure o f V IP was reported to be identical in almost all mammalian species [39], The human V IP gene has been cloned and sequenced [66]. It codes for a polyprotein pre-pro-VIP which consists o f 170 amino acid residues, including the sequences o f V IP and the co-synthesized peptide histidine methionine (PHM-27). A high degree o f nucleotide sequence homology exists between the human and rat pre-pro-VIP cD N A s [41]. In the rat precursor hormone P H M is replaced by PHI which differs from P H M by 4 amino acids [41 [. V IP has been shown to be widely distributed in the central and peripheral nervous system, the gastrointestinal, respiratory and urogenital tracts, various exocrine glands, and endocrine glands including the thyroid [2] and ovary [28]. It exhibits a broad spectrum o f effects ranging from smooth muscle relaxa tion, vasodilatation, and neurotransmission to neuroendocrine regulation [47, 53]. The demonstration ofVIPimmunoreactivity in the hypothalamus, median eminence, anterior pituitary and the hypophyseal-portal blood [ 13, 54, 58, 59, 62], suggests that it also regulates anterior pituitary function.
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Tabic 1. Basal and stimulated PR L and G H release from hypo thyroid pituitary cell cultures in the presence o f anti-VIP antisera (A -V IP )
PR L release ng/106 cells basal
A -V IP NRS
(n = 12) (n = 12)
Pituitary VIP content
Pituitary VIP mRNA
G H release ng/10b cells TRH 10-« M
836 ± 2 1 * 1,225 ± 2 9 * 1,011 ± 3 7 1,439 ± 24
basal
GRH 10-«W
282 ± 13 272 ± 1 4
626 ± 27 638 ± 2 4
n = Number o f pooled samples from 3 separate cultures. *p < 0.005 compared to N R S (normal rabbit serum) [25].
Euthyroid
Hypothyroid
Fig. 1. Northern blot o f R N A from pituitaries o f euthyroid and hypothyroid rats, hybridized with 32P-labelled c D N A probe for rat VIP. Hypothyroid rats show a marked increase in pituitary V IP m R N A (61|.
mental hyperprolactinemic states [46, 60] suggests a negative feedback regulation by prolactin (PRL), in keeping with the role o f V IP as a PRL-releasing factor [1],
Localization and Regulation of VIP in the Anterior Pituitary Various workers have reported that small concentrations of immunoreactive V IP can be detected in the anterior pituitary [13, 37, 69] and that this immunoreactivity is increased with es trogen treatment [33, 45]. It has always been assumed that V IP in the anterior pituitary originates from the hypothalamus and is taken up into the lacto tropes. This was the conclusion o f Morel et al. [37] who report ed V IP to be contained in lactotropes o f the rat pituitary al though its presence in granules could not be established with certainty in their immunocytochemical study. Recent studies
from various laboratories including our own suggest that V IP is also synthesized in the anterior pituitary. It has been shown that pituitary fragments can incorporate labelled amino acids into immunoreactive V IP [5]. Exposure o f cultured pituitaiy cells to anti-VIP antisera [17, 25, 40] or a VIP receptor antagonist [40] inhibits basal release o f PRL while growth hormone (G H ) se cretion remains unchanged (table 1) [25, 40], suggesting a rela tively selective stimulation o f PRL secretion by endogenous pi tuitary VIP. The demonstration o f VIPgene expression in the rat anterior pituitary [61] provides further evidence for de novo synthesis of V IP in vivo. Using Northern blot analysis (fig. 1) and in situ hybridization, we can detect VIP m R N A in the rat anterior pitu itary [25] with higher levels being detected in the male rats [27], Increased V IP m R N A levels were detected in the hypothyroid pituitary [25] in parallel with increases in the peptide content (fig. 2). This increase in V IP synthesis in the hypothyroid pitu itary makes it possible to identify a population o f V IP immuno reactive cells which are not detectable in the normal rat pituitary and are apparently not lactotropes or thyrotropes [24], Release of V IP from hypothyroid pituitary cells can be demonstrated in vitro [25] and is enhanced by the addition o f thyrotropin-releasing hormone (TRH) (fig. 3) and growth hormone-releasing hormone (G H R H ) (fig. 4). On the other hand, luteinizing hor mone-releasing hormone (LH RH ) and corticotropin-releasing hormone (C R H ) have no effect on V IP release.
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Fig. 2. Parallel increases in pituitary VIP m R N A and VIPcontent in hypothyroid rats - reversal by T4 replacement, o = Control; o = thionamide-treated; = thionamide + T4 3 p g / 100 g BW; = thionamide + T4 10 pg/100 g BW[61].
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V IP in the Hypothalamus and Pituitary
I------- //------ [
log dose TRH, M
Fig. 3. Effect o f incremental doses o f T R H on VIP and P R L release from hypothyroid pituitary cell cultures. Each point represents 9 wells from 3 separate cultures. Significant differences from control are indi cated by asterisks. F values were 7.0 (p < 0.0001) and 28.2 (p < 0.0001) for V IP and P R L changes, respectively (25).
Fig. 4. Effect o f incremental doses o f G H R H on VIP and G H re lease from hypothyroid pituitary cell cultures. Each point represents 9 wells from 3 separate cultures. Significant differences from control are indicated by asterisks. F values were 10.6 (p < 0.0001) and 28 (p < 0.0001) for V IP and G H changes, respectively [25).
More recently, we have shown that estrogen treatment of oophorectomized rats also results in an increase in V IP gene expression in the pituitary [26]. However, whereas parallel in creases in VIP and PHI levels are found in the hypothyroid pi tuitary, estrogen treatment results in an increase predominantly o f immunoreactive VIP. These findings suggest that posttranslational processing o f pre-pro-VIP may vaiy under different phys iological conditions. Indeed, tissue-specific posttranslational processing o f pre-pro-VIPhas been previously reported, the an terior pituitary having the lowest PHI to V IP ratio in all tissues studied [35]. The increase in pre-pro-VIP m R N A in the pitu itary o f estrogen-treated or hypothyroid rats also allows the clear demonstration o f a second V IP transcript o f 1.0 kb in the rat pituitary, in addition to the classical 1.7-kb transcript. With prolonged exposure o f the autoradiograph, the 1.0-kb tran-
script can also be detected in the cerebral cortex, and possibly in the hypothalamus and control pituitaries (fig. 5). The pres ence o f these two V IP transcripts probably results from polyadenylation at 2 different sites, as described in the published c D N A sequence [41 ].
V IP appears to play an important role in the regulation of PRL secretion. In vivo [14, 20| and in vitro [11] experiments in various mammalian species including man [29] and rat have shown that V IP stimulates prolactin secretion at concentrations attainable in the hypophyseal-portal blood [54, 62], Labelled V IP has been shown to bind to lactotropes [50] and stimulate
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VIP and PRL Secretion
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abolishes VIP-induced cAMPaccumulation and PRL release in vitro. These findings, together with the loss o f nocturnal rise in serum PRL in patients with Cushing’s disease [23], suggest that the interaction between VIP and glucocorticoids may be impor tant in the circadian fluctuation o f serum PRL. VIP has also been shown to stimulate the growth o f lacto tropes [44], This, together with the increase in VIP content in the median eminence [45] and pituitary [37] during estrogen treatment suggest that VIP mediates, at least in part, the lacto trope hyperplasia induced by estrogen.
Cortex
Hypothalamus
Pituitary
Fig. 5. Northern blot analysis o f R N A from cerebral cortex, hypo thalamus and anterior pituitary o f sham-operated, control (c) and estro gen-treated (E2) oophorectomised rats after 4 days' exposure o f the autoradiograph [26].
P R L secretion via the activation o f adenyl cyclase [48], an effect independent o f other known factors influencing PRL secretion such as dopamine and TRH [11]. Moreover, passive immunoneutralization with anti-VIP antisera blocks [1] or reduces [19] the P R L responses to stress, delays the onset o f PRL release in response to suckling [I] and blocks the proestrus PRL surge [19], suggesting that V IP is a physiological regulator o f P R L re lease. In this regard, it may also interact with other regulators of P R L secretion such as estrogen [45], serotonin, prostaglandins, cholecystokinin, galanin and oxytocin. Prolactin release in re sponse to central administration o f serotonin [38], prostaglan dins [63], cholecystokinin [64] and galanin [22] can be blocked by intravenous administration o f anti-VIP antisera, suggesting that such effects are mediated via a release o f hypothalamic VIP [22,38,64]. Since the brain serotoninergic mechanism is closelyrelated to stress and suckling-induced PRL release as well as surges during proestrus, such findings give further support to the physiological role o f VIP in PRL release. Furthermore, it has been shown that the effect o f centrally administered V IP on PRL secretion may be mediated via the release o f oxytocin [55]. Thus, it appears that V IP may act at more than one locus in the hypothalamic-pituitary axis to regulate PRL secretion. Recently, results from in vitro immunoneutralization studies using incubated pituitary cells [17, 25] or the reverse hemolytic plaque technique suggest that in addition to VI P o f hypothalamic origin, endogenous pituitary VIP also plays a paracrine or auto crine role in the regulation o f PRL secretion. The effect o f adrenal steroids on P R L secretion may also be mediated via changes in pituitary V IP secretion. Adrenalectomy increases pituitary VIP content [49] and serum PRL [31], both effects being abolished by glucocorticoid treatment. On the other hand, dexamethasone
There is some evidence that V IP also stimulates the secretion o f G H . In rats, V IP induces a rapid but transient increase in plasma G H when given intravenously and causes a dose-depen dent stimulation o f G H release from incubated rat pituitaries [8]. VIP also stimulates G H release from human pituitary adenomas in vitro and in some patients with acromegaly in vivo [21], Part o f the effect o f VIP on G H release in vivo may be mediated via a reduction in somatostatin release [12]. In addi tion, V IP also interacts with somatostatin at the pituitary level to reduce the response o f somatotropes to somatostatin [65]. It appears that V IP has no direct action on gonadotropin secretion [56]. Though it seems likely that VIP can influence go nadotropin secretion by an action at the hypothalamic level [42, 57], conflicting results have been reported regarding the effect o f V IP on L H R H release [3, 67], V IP induces a dose-dependent and biphasic stimulation o f A C T H and endorphin secretion from mouse pituitary tumor cells, an effect which is inhibited by dexamethasone [68]. However, only very large doses o f V IP stimulate A C T H release from primary cultures o f rat anterior pituitary cells [68]. In vivo studies suggest that VIP may increase A C T H secretion in rats via an increase in C R H release [ 18]. There are also some in vitro data to suggest that V IP can potentiate the effect o f C R H on A C T H se cretion [30]. While V IP does not stimulate A C T H release in nor mal human subjects, it may enhance A C T H levels in some pa tients with Cushing’s disease, an effect which disappears after successful removal o f the pituitary microadenomas [4], There is no convincing evidence that V IP stimulates TSH se cretion in vivo or in vitro [56] although in a single report, it was shown that increases in circulating T RH , TSH and thyroid hor mones were observed following the intravenous injection of large doses o f V IP [36], It appears that V IP may also regulate posterior pituitary functions. V IP and PHI have been localized with vasopressin in the canine hypothalamic-neurohypophysial neuronal system [43]. Intraventricular administration o f VIP increases plasma levels o f oxytocin and vasopressin, an effect which is not blocked by intravenous anti-VIP antiserum [7], Thus, VIP may regulate the secretion o f oxytocin and vasopressin via actions at the hypothalamic level.
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VIP and Other Pituitary Hormones
Conclusion In summary, hypothalamic and pituitary V IP participates in the regulation o f anterior and posterior pituitary functions and appears to play a physiological role as a PRL-releasing factor, at least in the rat. In this respect, it interacts closely with other regulators o f P R L secretion. Further studies should be done to determine whether V IP plays any significant role in the various hyperprolactinemic states in man.
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VIP in the Hypothalamus and Pituitary
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leasing factor (G R F ) with corticotropin releasing factor (CRF) on corticotropin secretion in vitro. Neuropeptides 1 2 : 131-133 (1988). Leung, F .C .; Chen, H .T.; Verkaik, S .J.; Steger, R.W .; Peluso, J .J .; Cam pbell, G .A .; Meites, J.: Mechanisms by which adrenalectomy and corticosterone influence prolactin release in the rat. J . endocr. 87: 131-140(1980). Loren, L ; Emson, P .C .; Fahrenkrug, J .; Bjorklund, A .; Ahumets, J .; Hakanson, R .; Sundler, F.: Distribution o f vasoactive intestinal polypeptide in the rat and mouse brain. Neuroscience 4: 1953— 1976(1979). Maletti, M .; Rotsztejn, W .H .; Carr, L .; Scherrer, H .; Retten, D .; Kordon, C ; Rosselin, G .: Interaction between estradiol and prolac tin on vasoactive intestinal peptide concentrations in the hypothala mus and in the anterior pituitary o f the female rat. Neurosci. Lett. 3 2 : 307-313 (1982). Mezey, E .; Kiss, J.Z .: Vasoactive intestinal peptide-containing neu rons in the paraventricular nucleus may participate in regulating prolactin secretion. Proc. natn. Acad. Sci. U S A 8 2 : 245-247 (1985). Minamitani, N .; Reichlin, S.: Tissue specific processing o f the pep tide histidine isoleucine (PHI) vasoactive intestinal peptide (VIP) prohormone in rat tissues (abstract). Proc. 69th Ann. Meet. Endocr. Soc. p. 198. Mitsuma, T ; Nogimori, T ; Chayd, M .: Effects o f vasoactive intesti nal polypeptide on hypothalamic-pituitary-thyroid axis in rats. En docr. exp. 18: 93-100 (1983). Morel, G .; Chayvealle, J .A .; Kerdelhne, B.; Dubois, P.M .: Ultrastructural evidence for endogenous vasoactive intestinal peptide like immunoreactivity in the pituitaiy gland. Neuroendocrinology 3 4 : 85-89 (1982). Murai, L; Reichlin, S .; Ben-Jonathan, N .: The peak phase o f the proestrus prolactin surge is blocked by either posterior pituitary lo bectomy or antisera to VIP. Endocrinolgoy 124: 1050-1055(1989). Mutt, V.: Isolation and structure o f vasoactive intestinal peptide from various species; in Said, Vasoactive intestinal peptide, pp. 1-10 (Raven Press, New York 1982). Nagy, G .; Mulchahey, J .J .; Neille, J .D .: Autocrine control o f pro lactin secretion by vasoactive intestinal peptide. Endocrinology 122: 364-366(1988). Nishizawa, M .; Hayakawa, Y .; Yanaihara, N .; Okamoto, H .: Nu cleotide sequence divergence and functional constraint in V IP pre cursor m R N A evolution between human and rat. F E B S Lett. 183: 55-59(1985). Ohtsuka, S .; Miyaka, A .; Nishizaki, T.; Tasaka, K .; Tanizama, O .: Vasoactive intestinal peptide stimulates gonadotropin-releasing hormone release from rat hypothalamus in vitro. Acta endocr. 117: 399-402(1988). Okamura, H .; Murakami, S.; Fukui, K .; Uda, K .; Kawamoto, K .; Kawashima, S .; Yanaihara, N .; Ibata, Y .: Vasoactive intestinal pep tide- and peptide histidine isoleucine amide-like immunoreactivity colocalize with vasopressin-like immunoreactivity in the canine hypothalamo-neuro-hypophyseal neuronal system. Neurosci. Lett. (59:227-232(1986). Prysor-Jones, R .A .; Silverlight, J .J .; Jenkins, J.S .: Oestradiol, va soactive intestinal peptide and fibroblast growth factor in the growth o f human pituitary tumour cells in vitro. J . Endocr. 120: 171-177(1989). Prysor-Jones, R .A .; Silverlight, J .J .; Kennedy, S .J.; Jenkins, J.S .: Vasoactive intestinal peptide and the stimulation o f lactotroph growth by oestradiol in the rats. J. Endocr. 116: 259-265 (1988).
46 Prysor-Jones, R .A .; Silverlight, J .J .; Jenkins, J.S .: Hyperprolactinaemia reduces V IP in the anterior pituitary gland o f rats. Neurosci. Lett. 8 0 : 333-338 (1987). 47 Rostene, W .H .: Neurobiological and neuroendocrine functions o f vasoactive intestinal peptide (VIP). Prog. Neurobiol. 22: 103-129 (1984). 48 Rotsztejn, W .H .; Dussaillant, M .; Nobon, F.; Rosselin, G .: Rapid glucocorticoid inhibition o f vasoactive intestinal peptide-induced cyclic A M P accumulation and prolactin release in rat pituitary cells in culture. Proc. natn. Acad. Sri. U S A 7 8: 7584-7588 (1981). 49 Rotsztejn, W .H .; Besson, J .; Briaud, B.; Gagnant, L .; Rosselin, G .; Kordon, C .: Effect o f steroids on vasoactive intestinal peptide indis crete brain regions and peripheral tissues. Neuroendocrinology 31: 287-291 (1980). 50 Rotsztejn, W .H .; Benoist, L .; Besson, J .; Béraud, G .; Bluet-Pajot, M . T.; Kordon, C .; Rosselin, G .; Duval, J .: Effect o f vasoactive in testinal peptide (VIP) on the release o f adenohypophysea! hor mones from purified cells obtained by unit gravity sedimentation: Inhibition by dexamethasone o f VIP-induced prolactin release. Neuroendocrinology 3 1 : 282-286 (1980). 51 Said, S .I.; Mutt, V.: Isolation from porcine intestinal wall o f a va soactive octacosapeptide related to secretin and to glucagon. Eur. J. Biochem. 28: 199-204 (1972). 52 Said, S .I., Mutt, V.: Polypeptide with broad biological activity: Iso lation from small intestine. Science 169: 1217-1218 (1970). 53 Said, S .I.: Vasoactive intestinal peptide (Raven Press, New York 1982). 54 Said, S .I.; Porter, J.C .: Vasoactive intestinal polypeptide: release into hypophyseal portal blood. Life Sci. 2 4 : 227-230 (1979). 55 Samson, W .K .; Bianchi, R.; Mogg, R .J.; Rivier, J .; Vale, W .; Melin, P.: Oxytocin mediates the hypothalamic action o f V IP to stimulate P R L secretion. Endocrinology 124: 812-819 (1989). 56 Samson, W .K .; Said, S .I.; Snyder, G .; M cCann, S .M .: In vitro stim ulation o f prolactin release by vasoactive intestinal peptide. Pep tides 1 : 325-332 (1980). 57 Samson, W .K .; Burton, K .P .; Reeves, J.P .; M cCann, S .M .: Vasoac tive intestinal peptide stimulates luteinizing hormone releasing hor mone release from median eminence synaptosomes. Regul. Pep tides 2 : 253-264 ( 1981). 58 Samson, W .K .; Said, S .F .; M cCann, S .M .: Radioimmunologie lo calization o f vasoactive intestinal peptide in hypothalamic and extrahypothalamic sites in the rat brain. Neurosci. Lett. 12: 265-269 (1979). 59 Samson, W .K .; Said, S .I.; Graham, J.W .; M cCann, S .M .: Vasoac tive intestinal polypeptide concentrations in median eminence o f hypothalamus. Lancet ii: 901-902 (1978). 60 Sarkar, D .K .: Evidence for prolactin feedback actions on hypotha lamic oxytocin, vasoactive intestinal peptide and dopamine secre tion. Neuroendocrinolgoy 4 9 : 520-524 (1989). 61 Segerson, T .P.; Lam , K .S .L .; Cacicedo, L .; Minamitani, N .; Fink, J.S .; Lechan, R .M .; Reichlin, S.: Thyroid hormone regulates vasoac tive intestinal peptide (VIP) m R N A levels in the rat anterior pitu itary gland. Endocrinology 125:2221-2223 (1989). 62 Shimatsu, A .; Kato, Y .; Matsushita, N .; Katakami, H .; Yanaihara, N . ; Imura, H .: Immunoreactive vasoactive intestinal polypeptide in rat hypophyseal portal blood. Endocrinology 108: 395-398 (1981). 63 Shimatsu, A .; Kato, Y .; Matsushita, N .; Katakami, H .; Ohta, H .; Yanaihara, N .; Imura, H.: Effects o f prostaglandin E l on vasoactive intestinal polypeptide release from the hypothalamus and on pro
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67 Vijayan, E .; Samson, W .K .; Said, S .I.; M cCann, S .M .: Vasoactive intestinal peptide: Evidence fora hypothalamic site o f action to re lease growth hormone, luteinizing hormone, and prolactin in con scious ovariectomised rats. Endocrinology 104: 53-57 (1979). 68 Westendorf, J .M .; Phillips, M .A .; Schonbrunn, A .: Vasoactive in testinal peptide stimulates hormone release from corticotrope cells in culture. Endocrinology 112:550-557 (1983).
Karen S .L . Lam Department o f Medicine University o f Hong Kong Hong Kong
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lactin secretion from the pituitary in rats. Endocrinology 113: 2059-2064(1983). 64 Tanimoto, K .; Tamminga, C .A .; Chase, T .N .; Nilavev, G .: Intracerebroventricular injection o f cholecystokinin octapeptide elevates plasma prolactin levels through stimulation o f vasoactive intestinal peptide. Endocrinology 121: 127-132(1987). 65 Tapia-Arancibia, L .; Arancibia S .; Bluet-Pajot, M .-T.; Enjalbert, A .; Epelbaum, J . ; Priam, M .; Kordon, C .: Effect o f vasoactive intestinal peptide (VIP) on somatostatin inhibition on pituitary growth hor mone secretion in vitro. Eur. J. Pharmacol. 6 3 : 235-236 (1980). 66 Tsukada, T.; Horovitch, S .J.; Montminy, M .R .; Mandel, G .; G o o d man, G .H .: Structure o f the human vasoactive intestinal polypep tide gene. D N A 4 : 293-300 (1985).
© 19 9 1 S. Karger A G , Basel 0028-3835/91/0537-0045 S 2.75/0
Vasoactive Intestinal Peptide in the Hypothalamus and Pituitary Karen S.L. Lam Department o f Medicine, University o f Hong Kong, Hong Kong
Key Words. Vasoactive intestinal peptide • Anterior pituitary • Gene expression ■ Estrogen ■ Posttranslational processing • Peptide histidine isoleucine Abstract. Data are presented to show that vasoactive intestinal peptide (VIP) is synthesized and secreted by the hypothalamus and anterior pituitary and that it participates in the regulation o f pituitary functions. Immunoreactive V IP in the hypothalamus and pituitary is increased following estrogen treatment and adrenalectomy and is reduced in hyperprolactinemic states. The level o f VIP m R N A in the hypothalamus is increased during lactation and sexual maturation, while that in the anterior pituitary shows a sexual dimorphism and is increased with estrogen treatment and hypothyroidism. All these findings suggest a physiological regulation of hypothalamic and pituitary V IP gene expression in relation to its potential role as a neuroendocrine hormone. Furthermore, VIP stimulates prolactin (PRL) release at concentrations attainable in the hypophyseal-portal blood. Passive immunoneutralization studies with anti-VIP antisera suggest that endogenous V IP acts at multiple loci in the hypothalamic-pituitary axis to regulate PRL secretion, interacting possibly with other regulators o f P RL secretion such as estrogen, serotonin, cholecystokinin. prostaglandins, galanin and oxytocin. Regarding other pituitary functions, although V IP has been shown to release growth hormone, A C T H , and vasopressin in vivo and in vitro, the physiological significance o f these findings remains to be determined.
Localization and Concentration of VIP in the Hypothalamus Within the hypothalamus, the highest concentration o f VIP is found in the suprachiasmatic nucleus [9, 32]. A significant population o f VIP-containing cell bodies has also been demonstrated in the parvocellular region o f the paraventricular nucleus [10, 34] with VIP-positive fibres projecting to the ex ternal zone o f the median eminence. While only a few VIP positive fibres can be identified in the rat median eminence under basal conditions, the human median eminence contains high concentrations o f V IP which can be released into the por tal circulation [59]. Adrenalectomy and lactation combined with colchicine treatment result in a marked increase in VIPimmunopositivity in the paraventriculo-tuberoinfundibular system [34]. An increase in VIP in the rat median eminence has also been reported after estrogen treatment [45]. In addi tion, the levels o f hypothalamic V IP m R N A increase during lactation and at the time o f sexual maturation [16]. A recent study using in situ hybridization has shown that this increase occurs predominantly in the suprachiasmatic nucleus [15]. Taken together, the above findings suggest a physiological regulation o f hypothalamic VIP gene expression and synthesis in relation to its potential role as a neuroendocrine hormone. Furthermore, the reduction of hypothalamic and pituitary VIP content and hypophyseal portal blood V IP levels in experi-
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Vasoactive intestinal peptide (VIP) is a highly basic 28amino acid peptide which was originally isolated from the por cine duodenum [51, 52], It is structurally related to other mem bers o f the secretin-glucagon family such as secretin, peptide histidine isoleucine (PHI), growth-hormone-releasing hormone and gastric inhibitory factor. The primary structure o f V IP was reported to be identical in almost all mammalian species [39], The human V IP gene has been cloned and sequenced [66]. It codes for a polyprotein pre-pro-VIP which consists o f 170 amino acid residues, including the sequences o f V IP and the co-synthesized peptide histidine methionine (PHM-27). A high degree o f nucleotide sequence homology exists between the human and rat pre-pro-VIP cD N A s [41]. In the rat precursor hormone P H M is replaced by PHI which differs from P H M by 4 amino acids [41 [. V IP has been shown to be widely distributed in the central and peripheral nervous system, the gastrointestinal, respiratory and urogenital tracts, various exocrine glands, and endocrine glands including the thyroid [2] and ovary [28]. It exhibits a broad spectrum o f effects ranging from smooth muscle relaxa tion, vasodilatation, and neurotransmission to neuroendocrine regulation [47, 53]. The demonstration ofVIPimmunoreactivity in the hypothalamus, median eminence, anterior pituitary and the hypophyseal-portal blood [ 13, 54, 58, 59, 62], suggests that it also regulates anterior pituitary function.
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Tabic 1. Basal and stimulated PR L and G H release from hypo thyroid pituitary cell cultures in the presence o f anti-VIP antisera (A -V IP )
PR L release ng/106 cells basal
A -V IP NRS
(n = 12) (n = 12)
Pituitary VIP content
Pituitary VIP mRNA
G H release ng/10b cells TRH 10-« M
836 ± 2 1 * 1,225 ± 2 9 * 1,011 ± 3 7 1,439 ± 24
basal
GRH 10-«W
282 ± 13 272 ± 1 4
626 ± 27 638 ± 2 4
n = Number o f pooled samples from 3 separate cultures. *p < 0.005 compared to N R S (normal rabbit serum) [25].
Euthyroid
Hypothyroid
Fig. 1. Northern blot o f R N A from pituitaries o f euthyroid and hypothyroid rats, hybridized with 32P-labelled c D N A probe for rat VIP. Hypothyroid rats show a marked increase in pituitary V IP m R N A (61|.
mental hyperprolactinemic states [46, 60] suggests a negative feedback regulation by prolactin (PRL), in keeping with the role o f V IP as a PRL-releasing factor [1],
Localization and Regulation of VIP in the Anterior Pituitary Various workers have reported that small concentrations of immunoreactive V IP can be detected in the anterior pituitary [13, 37, 69] and that this immunoreactivity is increased with es trogen treatment [33, 45]. It has always been assumed that V IP in the anterior pituitary originates from the hypothalamus and is taken up into the lacto tropes. This was the conclusion o f Morel et al. [37] who report ed V IP to be contained in lactotropes o f the rat pituitary al though its presence in granules could not be established with certainty in their immunocytochemical study. Recent studies
from various laboratories including our own suggest that V IP is also synthesized in the anterior pituitary. It has been shown that pituitary fragments can incorporate labelled amino acids into immunoreactive V IP [5]. Exposure o f cultured pituitaiy cells to anti-VIP antisera [17, 25, 40] or a VIP receptor antagonist [40] inhibits basal release o f PRL while growth hormone (G H ) se cretion remains unchanged (table 1) [25, 40], suggesting a rela tively selective stimulation o f PRL secretion by endogenous pi tuitary VIP. The demonstration o f VIPgene expression in the rat anterior pituitary [61] provides further evidence for de novo synthesis of V IP in vivo. Using Northern blot analysis (fig. 1) and in situ hybridization, we can detect VIP m R N A in the rat anterior pitu itary [25] with higher levels being detected in the male rats [27], Increased V IP m R N A levels were detected in the hypothyroid pituitary [25] in parallel with increases in the peptide content (fig. 2). This increase in V IP synthesis in the hypothyroid pitu itary makes it possible to identify a population o f V IP immuno reactive cells which are not detectable in the normal rat pituitary and are apparently not lactotropes or thyrotropes [24], Release of V IP from hypothyroid pituitary cells can be demonstrated in vitro [25] and is enhanced by the addition o f thyrotropin-releasing hormone (TRH) (fig. 3) and growth hormone-releasing hormone (G H R H ) (fig. 4). On the other hand, luteinizing hor mone-releasing hormone (LH RH ) and corticotropin-releasing hormone (C R H ) have no effect on V IP release.
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Fig. 2. Parallel increases in pituitary VIP m R N A and VIPcontent in hypothyroid rats - reversal by T4 replacement, o = Control; o = thionamide-treated; = thionamide + T4 3 p g / 100 g BW; = thionamide + T4 10 pg/100 g BW[61].
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V IP in the Hypothalamus and Pituitary
I------- //------ [
log dose TRH, M
Fig. 3. Effect o f incremental doses o f T R H on VIP and P R L release from hypothyroid pituitary cell cultures. Each point represents 9 wells from 3 separate cultures. Significant differences from control are indi cated by asterisks. F values were 7.0 (p < 0.0001) and 28.2 (p < 0.0001) for V IP and P R L changes, respectively (25).
Fig. 4. Effect o f incremental doses o f G H R H on VIP and G H re lease from hypothyroid pituitary cell cultures. Each point represents 9 wells from 3 separate cultures. Significant differences from control are indicated by asterisks. F values were 10.6 (p < 0.0001) and 28 (p < 0.0001) for V IP and G H changes, respectively [25).
More recently, we have shown that estrogen treatment of oophorectomized rats also results in an increase in V IP gene expression in the pituitary [26]. However, whereas parallel in creases in VIP and PHI levels are found in the hypothyroid pi tuitary, estrogen treatment results in an increase predominantly o f immunoreactive VIP. These findings suggest that posttranslational processing o f pre-pro-VIP may vaiy under different phys iological conditions. Indeed, tissue-specific posttranslational processing o f pre-pro-VIPhas been previously reported, the an terior pituitary having the lowest PHI to V IP ratio in all tissues studied [35]. The increase in pre-pro-VIP m R N A in the pitu itary o f estrogen-treated or hypothyroid rats also allows the clear demonstration o f a second V IP transcript o f 1.0 kb in the rat pituitary, in addition to the classical 1.7-kb transcript. With prolonged exposure o f the autoradiograph, the 1.0-kb tran-
script can also be detected in the cerebral cortex, and possibly in the hypothalamus and control pituitaries (fig. 5). The pres ence o f these two V IP transcripts probably results from polyadenylation at 2 different sites, as described in the published c D N A sequence [41 ].
V IP appears to play an important role in the regulation of PRL secretion. In vivo [14, 20| and in vitro [11] experiments in various mammalian species including man [29] and rat have shown that V IP stimulates prolactin secretion at concentrations attainable in the hypophyseal-portal blood [54, 62], Labelled V IP has been shown to bind to lactotropes [50] and stimulate
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VIP and PRL Secretion
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abolishes VIP-induced cAMPaccumulation and PRL release in vitro. These findings, together with the loss o f nocturnal rise in serum PRL in patients with Cushing’s disease [23], suggest that the interaction between VIP and glucocorticoids may be impor tant in the circadian fluctuation o f serum PRL. VIP has also been shown to stimulate the growth o f lacto tropes [44], This, together with the increase in VIP content in the median eminence [45] and pituitary [37] during estrogen treatment suggest that VIP mediates, at least in part, the lacto trope hyperplasia induced by estrogen.
Cortex
Hypothalamus
Pituitary
Fig. 5. Northern blot analysis o f R N A from cerebral cortex, hypo thalamus and anterior pituitary o f sham-operated, control (c) and estro gen-treated (E2) oophorectomised rats after 4 days' exposure o f the autoradiograph [26].
P R L secretion via the activation o f adenyl cyclase [48], an effect independent o f other known factors influencing PRL secretion such as dopamine and TRH [11]. Moreover, passive immunoneutralization with anti-VIP antisera blocks [1] or reduces [19] the P R L responses to stress, delays the onset o f PRL release in response to suckling [I] and blocks the proestrus PRL surge [19], suggesting that V IP is a physiological regulator o f P R L re lease. In this regard, it may also interact with other regulators of P R L secretion such as estrogen [45], serotonin, prostaglandins, cholecystokinin, galanin and oxytocin. Prolactin release in re sponse to central administration o f serotonin [38], prostaglan dins [63], cholecystokinin [64] and galanin [22] can be blocked by intravenous administration o f anti-VIP antisera, suggesting that such effects are mediated via a release o f hypothalamic VIP [22,38,64]. Since the brain serotoninergic mechanism is closelyrelated to stress and suckling-induced PRL release as well as surges during proestrus, such findings give further support to the physiological role o f VIP in PRL release. Furthermore, it has been shown that the effect o f centrally administered V IP on PRL secretion may be mediated via the release o f oxytocin [55]. Thus, it appears that V IP may act at more than one locus in the hypothalamic-pituitary axis to regulate PRL secretion. Recently, results from in vitro immunoneutralization studies using incubated pituitary cells [17, 25] or the reverse hemolytic plaque technique suggest that in addition to VI P o f hypothalamic origin, endogenous pituitary VIP also plays a paracrine or auto crine role in the regulation o f PRL secretion. The effect o f adrenal steroids on P R L secretion may also be mediated via changes in pituitary V IP secretion. Adrenalectomy increases pituitary VIP content [49] and serum PRL [31], both effects being abolished by glucocorticoid treatment. On the other hand, dexamethasone
There is some evidence that V IP also stimulates the secretion o f G H . In rats, V IP induces a rapid but transient increase in plasma G H when given intravenously and causes a dose-depen dent stimulation o f G H release from incubated rat pituitaries [8]. VIP also stimulates G H release from human pituitary adenomas in vitro and in some patients with acromegaly in vivo [21], Part o f the effect o f VIP on G H release in vivo may be mediated via a reduction in somatostatin release [12]. In addi tion, V IP also interacts with somatostatin at the pituitary level to reduce the response o f somatotropes to somatostatin [65]. It appears that V IP has no direct action on gonadotropin secretion [56]. Though it seems likely that VIP can influence go nadotropin secretion by an action at the hypothalamic level [42, 57], conflicting results have been reported regarding the effect o f V IP on L H R H release [3, 67], V IP induces a dose-dependent and biphasic stimulation o f A C T H and endorphin secretion from mouse pituitary tumor cells, an effect which is inhibited by dexamethasone [68]. However, only very large doses o f V IP stimulate A C T H release from primary cultures o f rat anterior pituitary cells [68]. In vivo studies suggest that VIP may increase A C T H secretion in rats via an increase in C R H release [ 18]. There are also some in vitro data to suggest that V IP can potentiate the effect o f C R H on A C T H se cretion [30]. While V IP does not stimulate A C T H release in nor mal human subjects, it may enhance A C T H levels in some pa tients with Cushing’s disease, an effect which disappears after successful removal o f the pituitary microadenomas [4], There is no convincing evidence that V IP stimulates TSH se cretion in vivo or in vitro [56] although in a single report, it was shown that increases in circulating T RH , TSH and thyroid hor mones were observed following the intravenous injection of large doses o f V IP [36], It appears that V IP may also regulate posterior pituitary functions. V IP and PHI have been localized with vasopressin in the canine hypothalamic-neurohypophysial neuronal system [43]. Intraventricular administration o f VIP increases plasma levels o f oxytocin and vasopressin, an effect which is not blocked by intravenous anti-VIP antiserum [7], Thus, VIP may regulate the secretion o f oxytocin and vasopressin via actions at the hypothalamic level.
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VIP and Other Pituitary Hormones
Conclusion In summary, hypothalamic and pituitary V IP participates in the regulation o f anterior and posterior pituitary functions and appears to play a physiological role as a PRL-releasing factor, at least in the rat. In this respect, it interacts closely with other regulators o f P R L secretion. Further studies should be done to determine whether V IP plays any significant role in the various hyperprolactinemic states in man.
References 1 Abe. H .; Engler, D .; Molitch, M .E .; Bollinger-Gruber, J .: Reichlin, S.: Vasoactive intestinal peptide is a physiological media tor o f prolactin release in the rat. Endocrinology 116: 1383-1390 (1985). 2 Ahren, B .; Hakanson, R .; Rem p, C : VIP-stimulated thyroid hor mone secretion: effects o f other neuropeptides and/or fi-adrenoceptor blockade. Acta physiol, scand. 114:471-473 (1982). 3 Alexander, M .J.; Clifton, D .K .; Steiner, R .A .: Vasoactive intestinal polypeptide effects on central inhibition o f pulsatile luteinizing hor mone secretion in ovariectomised rats. Endocrinology 117: 2134-2139(1985). 4 Ambiosi, B.; Bochicchio, D .; Sartario, A .; Morabito, F.; Faglia, G .: Vasoactive intestinal polypeptide enhances A C T H levels in some patients with adrenocorticotropin-secreting pituitary adenomas. Acta endocr. / 16: 2 16-220 ( 1987). 5 Am aout, M .A .: Garthwaite, T .L .; Martinson, D .R .; Hagen, T .C .: Vasoactive intestinal polypeptide is synthesized in anterior pituitary tissues. Endocrinology 119:2052-2057 (1986). 6 Baes, M .; Denef, C .: Evidence that stimulation o f G H release by epinephrine and V IP is based on cell to cell communication in the pituitary. Endocrinology 120: 280-290 (1987). 7 Bardrum, B .; Ottesen, B.; Fahrenkrug, J .; Fuchs, A .R .: Release o f oxytocin and vasopressin by intracerebroventricular VIP. Endocri nology 123:2249-2254 (1988). 8 Bluet-Pajot, M .-T.; Mounier, F.: Leonard, J.- F .; Kordon. C .; D u rand, D .: Vasoactive intestinal peptide induces a transient release o f growth hormone in the rat. Peptides S: 35-38 (1987). 9 Card, J.P .; Brecha, N .; Kartell, H .J.; Moore, R .Y .: Immunocytochemical localization o f vasoactive intestinal polypeptide-con taining cells and processes in the suprachiasmatic nucleus o f the rat: Light and electron microscopic analysis. J. Neurosci. 11: 1289— 1303(1981). 10 Ceccatelli, S.; Eriksson, M .; Hokfelt, T.: Distribution and coexis tence o f corticotropin-releasing factor-, neurotensin-, enkephalin-, cholecystokinin-, galanin- and vasoactive intestinal polypeptide/ peptide histidine isoleucine-like peptides in the parvocellular part o f the paraventricular nucleus. Neuroendocrinology 49: 309-323 (1989). 11 Enjalbert, A .; Arancibia, S .; Ruberg, M .; Priam, M .; Bluet-Pajot, M .T .; Rotztein, W .H .; Kordon, C .: Stimulation o f in vitro prolactin release. Neuroendocrinolgoy 3 1 : 200-204 (1980). 12 Epelbaum, J .; Tapia-Arancibia, L .; Besson, J .; RoLsztejn, W .H .; Kordon, C .: Vasoactive intestinal peptide inhibits release o f soma tostatin from hypothalamus in vitro. Eur. J. Pharmacol. 58: 493-495 (1979).
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13 Fahrenkrug. J .; Schaffalitzsky de Muckadel, O .B .: Distribution o f vasoactive intestinal polypeptide (VIP) in the porcine central ner vous system. J. Neurochem. 31: 1445-1459 (1978). 14 Frawley, L .S .; Neill, J .D .: Stimulation o f prolactin secretion in rhe sus monkeys by vasoactive intestinal peptide. Neuroendocrinology 33: 79-83 (1981). 15 Gozes, L ; Avidor, R .; Biejon, A .; Baldino, F.: Lactation elevated V IP messenger ribonucleic and in rat suprachiasmatic nucleus. En docrinology 124: 181-186 (1989). 16 Gozes, I.; Shani. Y .: Hypothalamic vasoactive intestinal peptide messenger ribonucleic acid is increased in lactating rats. Endocri nology y/d.- 2497-2501 (1986). 17 Hagen, T .C .; Am aout, M .A .; Scherzer, W .J.; Martinson, D .R .; Garthwaite, T .L .: Antisera to vasoactive intestinal peptide inhibits basal prolactin release from dispersed anterior pituitary cells. Neurocndocrinology 43 : 6 4 1-645 ( 1986). 18 Itoh, S .; Hirota, R.; Kitsunra, G .: Effect o f cholecystokinin and va soactive intestinal polypeptide on adrenocortical secretion in the rat. Jap. J. Physiol. 32: 553-560 (1982). 19 Kaji. H .: Chihara, K .; Kita, T ; Kashio, Y .; Okimura, Y .; Fujita, T.: Administration o f antisera to vasoactive intestinal polypeptide and peptide histidine isoleucine attenuates ether induced prolactin se cretion in rats. Neuroendocrinology 41: 529-531 (1985). 20 Kato. Y .; Iwasaki, Y .; Iwasaki. J .; Abe, H .; Yanaihara, N .; Imura, H .: Prolactin release by vasoactive intestinal polypeptide in rats. En docrinology 103: 554-558 (1978). 21 Kato, Y .; Shimatsu, A .; Matsushita, N .; Ohta, H .; Imura. H .: Role o f vasoactive intestinal peptide (VIP) in regulating the pituitary function in man. Peptides 5: 389-394 (1984). 22 Koshiyama, H .; Kato, Y .; Inoue, T ; Murakami, Y .; Ishikawa, Y .; Yanaihara, N .; Imura, H.: Central galanin stimulates pituitary pro lactin secretion in rats: Possible involvement o f hypothalamic va soactive intestinal polypeptide. Neurosci. Lett. 75: 49-54 (1987). 23 Krieger, D .J .; Howanitz, P .J.; Frantz, A G .: Absence o f nocturnal elevation o f plasma prolactin concentrations in Cushing’s disease. J. clin. Endocr. Metab. 4 2 : 260-272 (1976). 24 Lam, K .S .L .; Lechan, R .M .; Minamitani, N .; Segerson, T.P.; Reichlin, S.: Vasoactive intestinal peptide in the anterior pituitary is increased in hypothyroidism. Endocrinology 124: 1077-1084 (1989). 25 Lam , K .S .L .; Reichlin, S.: Pituitary vasoactive intestinal peptide regulates prolactin secretion in the hypothyroid rat. Neuroendocri nology 50: 524-528 ( 1989). 26 Lam, K .S .L .; Srivastava, G .; Lechan, R .M .; Lee, T : Reichlin S.: Estrogen regulates the gene expression o f vasoactive intestinal pep tide in the anterior pituitary. Neuroendocrinology (in press, 1990). 27 Lam, K .S .L .; Srivastava, G .: Sex-related differences and thyroid hormone regulation o f vasoactive intestinal peptide gene expression in the rat brain and pituitary. Brain Res. (in press, 1990). 28 Larsson, L.T .; Fahrenkurg, J.; Schalfalitzky de Muckadell, O .B .: Vasoactive intestinal peptide occurs in nerves o f the female genitou rinary tract. Science 197: 1374-1375 (1977). 29 Lightman, S .L .; Unwin, R .J.; Graham , K .; Dimaline, R .; McGarrick, G .: Vasoactive intestinal polypeptide, stimulation o f prolactin release and renin activity in normal man and patients with hyperprolactinaemia: Effects o f pretreatment with bromocriptine and dexamethasone. Eur. J . clin. Invest. 14: 444—448 (1984). 30 Leonard, J .F .; Bluet-Pajot, M .T.; Oliver, G ; Kordon, C : Interac tion o f vasoactive intestinal peptide (VIP) and growth hormone re-
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leasing factor (G R F ) with corticotropin releasing factor (CRF) on corticotropin secretion in vitro. Neuropeptides 1 2 : 131-133 (1988). Leung, F .C .; Chen, H .T.; Verkaik, S .J.; Steger, R.W .; Peluso, J .J .; Cam pbell, G .A .; Meites, J.: Mechanisms by which adrenalectomy and corticosterone influence prolactin release in the rat. J . endocr. 87: 131-140(1980). Loren, L ; Emson, P .C .; Fahrenkrug, J .; Bjorklund, A .; Ahumets, J .; Hakanson, R .; Sundler, F.: Distribution o f vasoactive intestinal polypeptide in the rat and mouse brain. Neuroscience 4: 1953— 1976(1979). Maletti, M .; Rotsztejn, W .H .; Carr, L .; Scherrer, H .; Retten, D .; Kordon, C ; Rosselin, G .: Interaction between estradiol and prolac tin on vasoactive intestinal peptide concentrations in the hypothala mus and in the anterior pituitary o f the female rat. Neurosci. Lett. 3 2 : 307-313 (1982). Mezey, E .; Kiss, J.Z .: Vasoactive intestinal peptide-containing neu rons in the paraventricular nucleus may participate in regulating prolactin secretion. Proc. natn. Acad. Sci. U S A 8 2 : 245-247 (1985). Minamitani, N .; Reichlin, S.: Tissue specific processing o f the pep tide histidine isoleucine (PHI) vasoactive intestinal peptide (VIP) prohormone in rat tissues (abstract). Proc. 69th Ann. Meet. Endocr. Soc. p. 198. Mitsuma, T ; Nogimori, T ; Chayd, M .: Effects o f vasoactive intesti nal polypeptide on hypothalamic-pituitary-thyroid axis in rats. En docr. exp. 18: 93-100 (1983). Morel, G .; Chayvealle, J .A .; Kerdelhne, B.; Dubois, P.M .: Ultrastructural evidence for endogenous vasoactive intestinal peptide like immunoreactivity in the pituitaiy gland. Neuroendocrinology 3 4 : 85-89 (1982). Murai, L; Reichlin, S .; Ben-Jonathan, N .: The peak phase o f the proestrus prolactin surge is blocked by either posterior pituitary lo bectomy or antisera to VIP. Endocrinolgoy 124: 1050-1055(1989). Mutt, V.: Isolation and structure o f vasoactive intestinal peptide from various species; in Said, Vasoactive intestinal peptide, pp. 1-10 (Raven Press, New York 1982). Nagy, G .; Mulchahey, J .J .; Neille, J .D .: Autocrine control o f pro lactin secretion by vasoactive intestinal peptide. Endocrinology 122: 364-366(1988). Nishizawa, M .; Hayakawa, Y .; Yanaihara, N .; Okamoto, H .: Nu cleotide sequence divergence and functional constraint in V IP pre cursor m R N A evolution between human and rat. F E B S Lett. 183: 55-59(1985). Ohtsuka, S .; Miyaka, A .; Nishizaki, T.; Tasaka, K .; Tanizama, O .: Vasoactive intestinal peptide stimulates gonadotropin-releasing hormone release from rat hypothalamus in vitro. Acta endocr. 117: 399-402(1988). Okamura, H .; Murakami, S.; Fukui, K .; Uda, K .; Kawamoto, K .; Kawashima, S .; Yanaihara, N .; Ibata, Y .: Vasoactive intestinal pep tide- and peptide histidine isoleucine amide-like immunoreactivity colocalize with vasopressin-like immunoreactivity in the canine hypothalamo-neuro-hypophyseal neuronal system. Neurosci. Lett. (59:227-232(1986). Prysor-Jones, R .A .; Silverlight, J .J .; Jenkins, J.S .: Oestradiol, va soactive intestinal peptide and fibroblast growth factor in the growth o f human pituitary tumour cells in vitro. J . Endocr. 120: 171-177(1989). Prysor-Jones, R .A .; Silverlight, J .J .; Kennedy, S .J.; Jenkins, J.S .: Vasoactive intestinal peptide and the stimulation o f lactotroph growth by oestradiol in the rats. J. Endocr. 116: 259-265 (1988).
46 Prysor-Jones, R .A .; Silverlight, J .J .; Jenkins, J.S .: Hyperprolactinaemia reduces V IP in the anterior pituitary gland o f rats. Neurosci. Lett. 8 0 : 333-338 (1987). 47 Rostene, W .H .: Neurobiological and neuroendocrine functions o f vasoactive intestinal peptide (VIP). Prog. Neurobiol. 22: 103-129 (1984). 48 Rotsztejn, W .H .; Dussaillant, M .; Nobon, F.; Rosselin, G .: Rapid glucocorticoid inhibition o f vasoactive intestinal peptide-induced cyclic A M P accumulation and prolactin release in rat pituitary cells in culture. Proc. natn. Acad. Sri. U S A 7 8: 7584-7588 (1981). 49 Rotsztejn, W .H .; Besson, J .; Briaud, B.; Gagnant, L .; Rosselin, G .; Kordon, C .: Effect o f steroids on vasoactive intestinal peptide indis crete brain regions and peripheral tissues. Neuroendocrinology 31: 287-291 (1980). 50 Rotsztejn, W .H .; Benoist, L .; Besson, J .; Béraud, G .; Bluet-Pajot, M . T.; Kordon, C .; Rosselin, G .; Duval, J .: Effect o f vasoactive in testinal peptide (VIP) on the release o f adenohypophysea! hor mones from purified cells obtained by unit gravity sedimentation: Inhibition by dexamethasone o f VIP-induced prolactin release. Neuroendocrinology 3 1 : 282-286 (1980). 51 Said, S .I.; Mutt, V.: Isolation from porcine intestinal wall o f a va soactive octacosapeptide related to secretin and to glucagon. Eur. J. Biochem. 28: 199-204 (1972). 52 Said, S .I., Mutt, V.: Polypeptide with broad biological activity: Iso lation from small intestine. Science 169: 1217-1218 (1970). 53 Said, S .I.: Vasoactive intestinal peptide (Raven Press, New York 1982). 54 Said, S .I.; Porter, J.C .: Vasoactive intestinal polypeptide: release into hypophyseal portal blood. Life Sci. 2 4 : 227-230 (1979). 55 Samson, W .K .; Bianchi, R.; Mogg, R .J.; Rivier, J .; Vale, W .; Melin, P.: Oxytocin mediates the hypothalamic action o f V IP to stimulate P R L secretion. Endocrinology 124: 812-819 (1989). 56 Samson, W .K .; Said, S .I.; Snyder, G .; M cCann, S .M .: In vitro stim ulation o f prolactin release by vasoactive intestinal peptide. Pep tides 1 : 325-332 (1980). 57 Samson, W .K .; Burton, K .P .; Reeves, J.P .; M cCann, S .M .: Vasoac tive intestinal peptide stimulates luteinizing hormone releasing hor mone release from median eminence synaptosomes. Regul. Pep tides 2 : 253-264 ( 1981). 58 Samson, W .K .; Said, S .F .; M cCann, S .M .: Radioimmunologie lo calization o f vasoactive intestinal peptide in hypothalamic and extrahypothalamic sites in the rat brain. Neurosci. Lett. 12: 265-269 (1979). 59 Samson, W .K .; Said, S .I.; Graham, J.W .; M cCann, S .M .: Vasoac tive intestinal polypeptide concentrations in median eminence o f hypothalamus. Lancet ii: 901-902 (1978). 60 Sarkar, D .K .: Evidence for prolactin feedback actions on hypotha lamic oxytocin, vasoactive intestinal peptide and dopamine secre tion. Neuroendocrinolgoy 4 9 : 520-524 (1989). 61 Segerson, T .P.; Lam , K .S .L .; Cacicedo, L .; Minamitani, N .; Fink, J.S .; Lechan, R .M .; Reichlin, S.: Thyroid hormone regulates vasoac tive intestinal peptide (VIP) m R N A levels in the rat anterior pitu itary gland. Endocrinology 125:2221-2223 (1989). 62 Shimatsu, A .; Kato, Y .; Matsushita, N .; Katakami, H .; Yanaihara, N . ; Imura, H .: Immunoreactive vasoactive intestinal polypeptide in rat hypophyseal portal blood. Endocrinology 108: 395-398 (1981). 63 Shimatsu, A .; Kato, Y .; Matsushita, N .; Katakami, H .; Ohta, H .; Yanaihara, N .; Imura, H.: Effects o f prostaglandin E l on vasoactive intestinal polypeptide release from the hypothalamus and on pro
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67 Vijayan, E .; Samson, W .K .; Said, S .I.; M cCann, S .M .: Vasoactive intestinal peptide: Evidence fora hypothalamic site o f action to re lease growth hormone, luteinizing hormone, and prolactin in con scious ovariectomised rats. Endocrinology 104: 53-57 (1979). 68 Westendorf, J .M .; Phillips, M .A .; Schonbrunn, A .: Vasoactive in testinal peptide stimulates hormone release from corticotrope cells in culture. Endocrinology 112:550-557 (1983).
Karen S .L . Lam Department o f Medicine University o f Hong Kong Hong Kong
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lactin secretion from the pituitary in rats. Endocrinology 113: 2059-2064(1983). 64 Tanimoto, K .; Tamminga, C .A .; Chase, T .N .; Nilavev, G .: Intracerebroventricular injection o f cholecystokinin octapeptide elevates plasma prolactin levels through stimulation o f vasoactive intestinal peptide. Endocrinology 121: 127-132(1987). 65 Tapia-Arancibia, L .; Arancibia S .; Bluet-Pajot, M .-T.; Enjalbert, A .; Epelbaum, J . ; Priam, M .; Kordon, C .: Effect o f vasoactive intestinal peptide (VIP) on somatostatin inhibition on pituitary growth hor mone secretion in vitro. Eur. J. Pharmacol. 6 3 : 235-236 (1980). 66 Tsukada, T.; Horovitch, S .J.; Montminy, M .R .; Mandel, G .; G o o d man, G .H .: Structure o f the human vasoactive intestinal polypep tide gene. D N A 4 : 293-300 (1985).
