sign in sign up
<<
Home , Gastrointestinal hormone, Hormone, Secretin

J Clin Pathol: first published as 10.1136/jcp.s1-8.1.63 on 1 January 1978. Downloaded from

J. clin. Path., 33, Suppl. (Ass. Clin. Path.), 8, 63-67

Vasoactive intestinal (VIP) *

M. G. BRYANT From the Department ofMedicine, RoyalPostgraduate Medical School, Du Cane Road, London W12 OHS.

In 1969, Said and Mutt reported the extraction from , increased flow of alkaline pancreatic normal lung of a peptide which was capable juice and small intestinal juice with increased cyclic of causing gradual but prolonged peripheral AMP content (Makhlouf and Said, 1975), overlap . This finding led them to search for markedly with the actions of the other three . similar vasoactive substances in extracts of other Thus VIP was included as a member of the metabolically active organs and, in 1970, they family ofhormonal peptides and, in 1974, it appeared described the isolation of a potent peripheral and in a list of 'candidate of the gut' compiled splanchnic vasodilatory peptide from hog small by Grossman et al. (1974). intestine, which they named Vasoactive Intestinal In the eight or so years since its discovery, a great Peptide (VIP) (Said and Mutt, 1970 a, b). Subsequent deal of information has been amassed about VIP. purification of VIP allowed determination of its With the development of highly sensitive and specific amino-acid sequence, which showed it to be a radioimmunoassays for VIP, it has been possible to straight chain of 28 amino-acid residues with basic study its distribution in the body and its mode of properties because of a predominance of release. However, with this growth in knowledge copyright. and lysine residues (Said and Mutt, 1972). Compari- controversy developed as to whether VIP fulfilled son of the amino-acid sequence of VIP with those of the classical criteria for a or whether it the classical hormones secretin and pancreatic acted locally as a paracrine substance or even as a showed a considerable degree of homology or neuromodulatory substance. (Fig. 1). Thus, these three peptides, together with the This has now been resolved in favour of the latter, more recently discovered -dependent as discussed below. releasing polypeptide (GIP), were thought to be Perhaps one of the first indications that VIP http://jcp.bmj.com/ related and it was suggested that they were perhaps might not be a hormone was obtained -from its derived from a common ancestral peptide. Further distribution in the gut. Unlike the other members of weight was added to these suggestions by the fact the , which are located in discrete that the many biological effects of VIP, which regions of the upper (secretin) and include systemic vasodilation, glycogenolysis (Kerins (glucagon), VIP appeared to have a much and Said, 1973), lipolysis (Frandsen and Moody, wider distribution. High concentrations of VIP were'

1973), inhibition of production found throughout the length of the gut from the on September 26, 2021 by guest. Protected (Makhlouf and Said, 1975), stimulation of oesophagus to the rectum, including the pancreas myocardial contractility (Said et al., 1972), insulin (Bloom et al., 1975; Said, 1975) (Fig. 2). A similar * is [unsuitable for VIP estimations as the level falls distribution of VIP-producing endocrine cells was during the time taken for the clot to form and retract. also observed by some authors (Polak et al., 1974; Plasma should be frozen immediately after collection-Ed. Buffa et al., 1977) (Fig. 2). Others, however, (Larsson

1 2 3 4 5 6 7 8 9 10 11 12 14 15 16 17 18 19 20 21 a His-Ser-Asp Ala-Vol- -Thr -Asp-Asn-Tyr-Thr- Arg-Leu- Lys-Gln- Met-Alb - Val- Lys- Lys- b His-Ser- Thr-P - tu- leu.herArg-Leu -Ar Ap-Ser Ala-r Leul C- H n-ly-Thr-Phe-Thy Ser-Asp-Ty .er Lys-Tyr-Leu- Asp-5e -Arg. Ar -Ala-Gn-Asp-

d Tyr u- B erAp-y Sr le-l-Mt r -l--Gin. - -+ Fig. 1 Amino-acidsequences of(a) VIP, Tyr- Ala-Glu-fly -Thier-PAha-Met91---+Ys-lie -nr (b) secretin, (c) pancreatic glucagon, 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 (d) GIP (allporcine). a Tyr- Leu-Asn-Ser- lle - Leu-Asn (NH2) b Leu-Leu-9n-gy -Val (NH2) c Ph GinTrLeL-Met-Asn-Thr d Phe-\bl AsnITrp- .Leu-Ala-Gki-Ghn- Lys-Gly-Lys-Lys- Ser-Asp-Trp- Lys-His- Asn-lle - Thr-Ghn 63 J Clin Pathol: first published as 10.1136/jcp.s1-8.1.63 on 1 January 1978. Downloaded from

64 M. G. Bryant circulation by other agents. Instillation of into the in sufficient quantity to stimulate the release of secretin also results in a significant increase in plasma VIP concentrations from a basal level of 1.7 to a peak at 6 minutes of 6*6 pmol/l, a rise which is sustained for at least 30 minutes (Ebeid et al., 1977a; Bloom et al., 1978). Similarly, the intraduodenal administra- tion of hypertonic saline (6 %, 3 %) and phenylamine in the dog also results in the release of VIP (Ebeid et al., 1977a). An intravenous infusion of calcium gluceptate (Ebeid et al., 1977b), and, in pigs, electrical stimulation of the vagus are other pro- cedures which result in a considerable release of VIP (Schaffalitzky de Muckadell et al., 1977). It is particularly interesting that in the latter much higher VIP concentrations were attained in portal than in systemic blood, perhaps confirming previous reports that the is one of the major sites of degradation of VIP. Similarly, in the pig, higher systemic levels are produced by an infusion of VIP into the systemic veins than when the same GO 1-10 11l-30 *>31 solution is infused into the portal vein (Fig. 3). No of cells per mm2 Degradation of VIP in the liver suggests that itscopyright. actions may be limited to the Fig. 2 Distribution of VIP cells and VIP concentration and portal circulation. Perhaps another indication in the human gastrointestinal tract. that VIP does not have an important role as a peripheral circulatory hormone is its rapid clearance et al., 1976b) were able to find VIP endocrine cells from plasma. The half life of porcine VIP has been only in the antral region of the cat and in no other reported as 0*85 minutes in the pig and 1 03 to 1 *22 minutes in (Domschke et al., 1978). This is far http://jcp.bmj.com/ species examined. more In classical endocrine theory, a hormone is rapid than that of the classical hormones produced from a discrete in response to a , pancreatic glucagon, and secretin. and is secreted into the in which it is carried to a distant target where it exerts its effect. In normal subjects, VIP does circulate but only at very low concentrations (Mitchell and Bloom, 1978). Circulating plasma VIP on September 26, 2021 by guest. Protected concentrations in 110 healthy fasting subjects, 2M showing a skew distribution, are given in Table 1. So far, however, there has been no convincing demonstration of a significant change in peripheral 100= plasma VIP concentration after ingestion of a mixed meal. This lack of response to such a physiological stimulus may well point to a non- endocrine role for VIP but it is by no means conclusive. Indeed, there have been several reports of the stimulation of VIP release into the peripheral -15 0 20 45 -10 0 20 40 60 Syst inf. Portol inf. (minutes) Table 1 Plasma VIP concentrations (pmol/l) in 110 Porcine VIP:48xlO molar healthy fasting subjects. Fig. 3 Peripheralplasma VIP concentrations attained Range 0.5-21 Mean 2.1 with an infusion of VIP (4.8 pmol/l) given into a Mode 1.5 systemic or portal vein. (From the data ofModlin Median 1.7 et al., 1978.) J Clin Pathol: first published as 10.1136/jcp.s1-8.1.63 on 1 January 1978. Downloaded from

Vasoactive intestinalpeptide (VIP) 65 In 1973, Bloom and colleagues found that (Fig. 5). In the extract there was a small peak patients with the Verner-Morrison or Watery of VIP immunoreactivity of apparently higher Diarrhoea Syndrome (see contribution by Professor molecular weight, but its significance is unknown. Welbourn, page 85) who presented with profuse Immunofluorescent studies of human and watery diarrhoea (several litres daily), hypokalaemia, intestine have demonstrated VIP in many tiny nerve and hypo- or achlorhydria had extremely high fibres in the mucosa and muscle layers (Bryant et al., circulating VIP concentrations, often in excess of 300 1976). Similarly, VIP-containing nerve fibres were pmol/1 (Fig. 4). The known biological actions of this peptide fitted very well with a causative role of VIP for the symptoms of the disease. This finding Cerebral hemisphere 27 5 :± 6.4 was later confirmed by Said and Faloona (1975). In Brain-stem 4.0 : 1.0 many cases, the source of these high concentrations Cerebellum 0.7 ± 0.03 of VIP was a pancreatic tumour composed of Table 2 VIP concentrations in rat brain (pmol/g) VIP-containing endocrine-type cells (Fig. 4). (mean i SEM) However, in a few cases (Fig. 4) the source of VIP was not an endocrine-like tumour but an abdominal ganglioneuroblastoma. This led to a search for the presence of VIP in a wide range of both animal and Pig Man human tissue. High concentrations of VIP were Organ 1 2 Organ 1 2 found in the of the rat, cat, pig, and man Hemisphere 12.4 10.1 Cerebral grey 12.1 23.2 (Bryant et al., 1976; Larsson et al., 1976b; Said and Cerebellum 1.0 0.8 Cerebellum 0.2 0.7 Medulla 4.5 7-4 Medulla 1.1 2.9 Rosenberg, 1976) and also in other organs such Pituitary 0.9 1.3 Occipital lobes 6.5 23.0 as the adrenals, urinary bladder, , and Adrenal 10.7 13.6 Frontal lobes 14.4 46.6

Pancreas 58.2 60.0 10.7 21.9 copyright. salivary (Bryant et al., 1976) (Table 2, 3). The Large bowel 92.6 90*2 Corpus callosum 0.2 0.3 bulk of VIP extracted from pig brain and gallbladder Bladder 18*2 11.6 Midbrain 3.3 5.8 behaved on gel permeation chromatography identi- Gallbladder 25.0 14.0 Pons 0-6 0.2 Salivary gland 20.8 12.0 cally to the pure intestinal VIP originally extracted Liver <0-08 <0.08 by Said and Mutt, indicating considerable similarity Plasma 7.0 24.0 Tissue concentrations in pmol/g wet tissue weight. 300. Plasma concentrations in pmol/l.

0 http://jcp.bmj.com/ * 0 0 Table 3 Representative VIP concentrations in the * S tissues of two human subjects and two pigs.

0 0

0 200- * * 0

.5 on September 26, 2021 by guest. Protected 1- E 0. 0o 0*o 2 i 0 >, 100- * S * 0 E 0 -o c

Proten. . 00 . 0 c0DO __oso c) 0 00c)c 0 c IN-N Normal VM Pseudo VM

(no tumours) 5 5 41 39 11 40 60 80 100 120 140 Fraction No Fig. 4 Plasma VIP concentrations in normal subjects, patients with the Verner-Morrison syndrome Fig. 5 Gelpermeation chromatography elution (VM), andpatients with the pseudo VM syndrome. profile of immunoreactive VIPfrom (a) porcine brain, The solid and open circles indicate pancreatic tumours (b) porcine gallbladder. The stippled area in (a) and neuroectodermal tumours, respectively. indicates pure VIP. J Clin Pathol: first published as 10.1136/jcp.s1-8.1.63 on 1 January 1978. Downloaded from

66 M. G. Bryant demonstrated in the salivary gland and in the paracrine substance. Certainly, in the case of the endocrine and exocrine pancreas (Bishop et al., Verner-Morrison syndrome, endocrine effects of Wharton et al., in preparation). Within several VIP are apparent, but it must be stressed that this is a months of the original demonstration of VIP in pathological situation. nervous tissues various independent groups using Until it is shown that VIP is released in response different antisera reported similar data. In 1977, Fuxe to a stimulus at the presynaptic junction and elicits and co-workers showed by immunocytochemical an action potential at the postsynaptic junction, and techniques the presence of VIP in nerve terminals that this action can be blocked by application of in the cerebral cortex, hypothalamus, amygdaloid specific antagonists, we can still only speculate as to nucleus, and corpus striatum. Giachetti and the functional role ofVIP. colleagues (1977) also demonstrated very elegantly by subcellular fractionation that in the cerebral cortex and hypothalamus the highest concentrations References ofVIP were in the synaptosome fraction. Bloom, S. R., Bryant, M. G., and Polak, J. M. (1975). Since the initial localisation of VIP in nerve fibres Distribution ofgut hormones (Abst.). Gut, 16, 821. in the central , it has been found in Bloom, S. R., Mitchell, S. J., Greenberg, G. R., the superior and inferior mesenteric ganglia (Hokfelt Christofides, N., Domschke, W., Domschke, S., et al., 1977), submucous and myenteric plexi of the Mitznegg, P., and Demling, L. (1978). Release of VIP, intestinal wall (Bryant et al., 1976; Larsson et al., secretin and after duodenal acidification in 1976b), cerebral vascular nerves (Larsson et al., man. Acta Hepato-Gastroenterologica, 25, 365-368. 1976a), and nerves of the female and male genital Bloom, S. R., Polak, J. M., and Pearse, A. G. E. (1973). organs (L. I. Larsson etal., unpublished observations). Vasoactive intestinal peptide and watery-diarrhoea The very wide distribution of VIP in nervous syndrome. Lancet, 2, 14-16.

Bryant, M. G., Bloom, S. R., Polak, J. M., Albuquerque,copyright. tissue, its questionable presence in true endocrine R. H., Modlin, I. M., and Pearse, A. G. E. (1976). cells, its wide spectrum of actions, and its rapid Possible dual role for vasoactive intestinal peptide as clearance time from the circulation thus differentiate and neurotransmitter this peptide from the other members of the secretin substance. Lanicet, 1, 991-993. family and obviously challenge the original belief Buffa, R., Capella, C., Solcia, E., Feigerio, B., and that VIP is a simple gastrointestinal hormone. Said, S. I. (1977). Vasoactive intestinal peptide cells in The nerve endings of the autonomic nervous the pancreas and gastro-intestinal mucosa: an immuno- system are classically divided into two types, histochemical and ultrastructural study. Histochemistry, http://jcp.bmj.com/ and each 50, 217-227. adrenergic cholinergic, type containing Domschke, S., Domschke, W., Bloom, S. R., Mitznegg, small secretory granules. Recently, ultrastructural P., Mitchell, S. J., Lux, G., Strunz, U., and Demling, L. studies have indicated a system of nerve terminals (1978). Pharmacokinetics and of within the gut with much larger, more electron dense VIP in man. In Gut Hormones, pp. 475-478, ed S. R. granules resembling those of the peptidergic system Bloom. Churchill Livingstone, Edinburgh. of the neurohypophysis, and evidence exists that Ebeid, A. M., Murray, P., and Fischer, J. E. (1977a). these consist, in part at least, of VIP-containing Vasoactive intestinal peptide: the fourth physiological on September 26, 2021 by guest. Protected nerves (see contribution by Dr Polak, page 68). It is gut hormone (Abst.). Gastroenterology, 72, A32/1055. possible then that VIP may be acting as a neuro- Ebeid, A. M., Murray, P., Soeters, P. B., and Fischer, J. E. new the (1977b). Release of VIP by calcium stimulation. transmitter substance within this division of American JournalofSurgery, 133, 140-144. autonomic nervous system. Recently, it has been Fransden, E. K., and Moody, A. J. (1973). Lipolytic shown that very high concentrations of VIP occur in action of a newly isolated vasoactive intestinal poly- nerve fibres in the neurohypophysis so that it is peptide. Hormone and Metabolic Research, 5, 196-199. possible that VIP might affect the release of Fuxe, K., Hokfelt, T., Said, S. I., and Mutt, V. (1977). or- and may have an osmo- Vasoactive intestinal polypeptide and the nervous regulatory role (Van Noorden et al., 1979). system: immunohistochemical evidence for localisation In summary, VIP immunoreactivity has been in central and peripheral , particularly intra- demonstrated in association with nerves throughout cortical neurons of the cerebral cortex. Neuroscience the . However, the evidence Letters, 5, 241-246. cir- Giachetti, A., Said, S. I., Reynolds, R. C., and Koniges, for a neurotransmitter role is still very F. C. (1977). Vasoactive intestinal polypeptide in cumstantial. An endocrine role cannot be excluded, brain: localization in and release from isolated nerve as while it would seem likely that it does not play an terminals. Proceedings of the National Academy of important part in the regulation of the peripheral Sciences ofthe USA, 74, 3424-3428. circulation, it might well act within the portal Grossman, M. I. et al. (1974). Candidate hormones of system or locally on blood vessels within the gut as a the gut. Gastroenterology, 67,730-755. J Clin Pathol: first published as 10.1136/jcp.s1-8.1.63 on 1 January 1978. Downloaded from

Vasoactive intestinalpeptide (VIP) 67 Hbkfelt, T., Elfvin, L. G., Schulzberg, M., Fuxe, K., widespread distribution in normal gastrointestinal Said, S. I., Mutt, V., and Goldstein, M. (1977). organs. Proceedings of the 57th Annual Meeting of the Immunohistochemical evidence for vasoactive intestinal Endocrine Society, New York. polypeptide neurons in sympathetic ganglia. Neuro- Said, S. I., Bosher, L. P., Spath, J. A., and Kontos, H. A. science Letters, 2, 885-896. (1972). Positive inotropic action of newly isolated Kerins, C., and Said, S. I. (1973). Hyperglycemic and vasoactive intestinal polypeptide (Abst.). Clinical glycogenolytic effects of vasoactive intestinal poly- Research, 20, 29. peptide. Proceedings of the Society for Experimental Said, S. I., and Faloona, G. R. (1975). Elevated plasma Biology andMedicine, 142, 1014-1017. and tissue levels of vasoactive intestinal polypeptide in Larsson, L. I., Edvinsson, L., Fahrenkrug, J., HAkanson, the watery-diarrhea syndrome due to pancreatic, R., Owman, C., Schaffalitzky de Muckadell, 0., and bronchogenic and other tumors. New England Journal Sundler, F. (1976a). Immunohistochemical localization ofMedicine, 293, 155-160. of a vasodilatory polypeptide in cerebrovascular Said, S. I., and Mutt, V. (1969). Long acting vasodilator nerves. Brain Research, 113,400-404. peptide from lung tissue. Nature, 224, 699-700. Larsson, L. I., Fahrenkrug, J., Schaffalitzky de Muckadell, Said, S. I., and Mutt, V. (1970a). Potent peripheral and 0., Sundler, F., Hakanson, R., and Rehfeld, J. F. splanchnic vasodilator peptide from normal gut. (1976b). Localization of vasoactive intestinal poly- Nature, 225, 863-864. peptide to central and peripheral neurons. Proceedings Said, S. I., and Mutt, V. (1970b). Polypeptide with broad of the National Academy of Sciences of the USA, 73, biological activity: isolation from small intestine. 3197-3200. Science, 169, 1217-1218. Maklouf, J. M., and Said, S. I. (1975). The effect of Said, S. I., and Mutt, V. (1972). Isolation from porcine- vasoactive intestinal peptide on digestive and hormonal intestinal wall of a vasoactive octacosapeptide related function. In Gastrointestinal Hormones, pp. 599-610, to secretin and to glucagon. European Journal of ed J. C. Thompson. University of Texas Press, Austin. Biochemistry, 28, 199-204. Mitchell, S. J., and Bloom, S. R. (1978). Measurement of Said, S. I., and Rosenberg, R. N. (1976). Vasoactive fasting and postprandial plasma VIP in man. Gut, 19, intestinal polypeptide: abundant immunoreactivity in

1043-1048. neural lines and normal nervous tissue. Science, 192, copyright. Modlin, I. M., Mitchell, S. J., and Bloom, S. R. (1978). 907-908. The systemic release and pharmacokinetics of VIP. In Schaffalitzky de Muckadell, 0. B., Fahrenkrug, J., and Gut Hormones, pp. 470-474, ed S. R. Bloom. Churchill Holst, J. J. (1977). Release of vasoactive intestinal Livingstone, Edinburgh. polypeptide by electric stimulation of the vagal nerves. Polak, J. M., Pearse, A. G. E., Garaud, J. C., and Gastroenterology, 72, 373-375. Bloom, S. R. (1974). Cellular localization of a vaso- Van Noorden, S., Polak, J. M., Bloom, S. R., and active intestinal peptide in the mammalian and avian Bryant, M. G. (1979). Vasoactive intestinal poly-

gastrointestinal tract. Gut, 15, 720-724. peptide in the pituitary pars nervosa. Neuropathology http://jcp.bmj.com/ Said, S. I. (1975). Vasoactive intestinal polypeptide: andApplied Neurobiology, 5, 149-153. on September 26, 2021 by guest. Protected