Role of vasopressin in fever regulation and suppression

428 co-localization8, to investigate the possibility of presynaptic interactions between VIP and enzymes of the cholinergic system. Recent evidence indicates that VIP has a specific regulatory action in acetylcholine biosynthesis. Acute activation of choline acetyltransferase was measured in the presence of VIP but not of several related peptides 9. VIP reduced the Km of association of choline by one half, but did not affect the kinetics of acetyl-CoA affinity for the enzyme, a significant finding in view of the action of the peptide in stimulating choline accumulation at peripheral synapses. In PNS and CNS pathways, VIP has emerged as a powerful neuro-

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effector agency, both in the control of flow in local vascular beds, and in the modulation of cholinergic transmission. Evidence that the synthesis of this peptide may be upregulated in peripheral axons during the early stages of neuronal regenerative processes 10 introduces a further potential dimension for its scope of influence. This article illustrates the importance of pursuing the complex nature of co-transmitter functions through a multidisciplinary experimental approach.

L. W, HAYNES

Department of Zoology, University of Bristol, Woodlands Road, Bristol BS8 IUG, UK.

Role of vasopressin in fever regulation and suppression The peripheral effects of arginine vasopressin (AVP) as an antidiuretic hormone and vasoactive agent have been recognized for many years, but the function of the ascending projections of AVP neurons to different brain areas 1 is still the subject of speculation. In addition to its corticotropin-releasing activity, it has been postulated that AVP acts as a neuromodulator in behavioural pathways, as a consolidator of memory and also as an endogenous antipyretic and effector in the homeostatic control of fever. Pregnant ewes 2 and guineapigs 3 show progressive loss of fever response to bacterial endotoxins before and after giving birth. Newborns of both species show similarly reduced febrile responses in the first few days of postuterine life, in spite of their fully developed abilities to produce endogenous pyrogen and to regulate their body temperature (see Ref. 4). Various lines of evidence s suggested that AVP might be the endogenous substance responsible for this afebrile period: (1) push-pull perfusion of AVP into the septal region of a non-pregnant ewe suppressed endotoxin-induced fever6, whereas similar perfusions at other brain sites had no such effect; moreover AVP antiserum or antagonistic

AVP analogues applied to the septum enhanced fevers induced by peripheral endotoxin; (2) AVP could be detected in septal perfusates from febrile animals in concentrations inversely related to fever magnitude (see Ref. 7); and (3) in the guinea-pig, immunohistochemical techniques revealed increased AVP reactivity in neurons of the medial portion of paraventricular nucleus and in terminals in the lateral septum and amygdala in pregnant animals with reduced febrile response 8. These results support the hypothesis that AVP may act as an endogenous antipyretic neuromodulator.

Significance of fever suppression in pregnancy and newborns At present, the comments on biological significance of fever suppression in near-term females and newborn animals are only speculations. Both species exhibiting this phenomenon are similar in that their offspring are highly mature at birth. The effects of anoxia during labor could be aggravated by increased body temperature and threaten the viability of these mature newborns. Also, fever in the perinatal period could lead to an impairment of surfactant maturation and thus to respiratory dysfunction, or may adversely affect the formation of a

1985,ElsevierScienceFublishersB.V.,Amsterdam 0165- 6147/85/$02.00

1985

References 1 Iversen, L. (1985) New Scientist, 30th May, pp. 11-14 2 Cuello, A.C. (1982) Co-transmission, Macmillan Press, London 3 Lundberg, J.M., Hokfelt, T., Schultzberg, M., Uvnas-Wallenstein, K., Kohler, C. and Said, S. I. (1979) Neuroscience 4, 1539-1559 4 Lundberg, J.M. (1981) Acta Physiol. Scand. suppl., 112, 1-57 5 Lundberg, M.J., Hedlund, B. and Bartfai, T. (1982) Nature (London) 295, 147-149 6 Eva, C., Meek, J. L. and Costs, E. (1985) J. PharmacoL Exp. Ther. 232, 670-674 7 Mo, N. and Dun, N. I. (1984) Neurosci. Lett. 52, 19-23 8 Eckenstein, F. and Baughman, R.W. (1984) Nature (London) 309, 153--155 9 Luine, V.N., Rostene, W., Rhodes, J. and McEwen, B. S. (1984) J. Neurochem. 42, 1131-1134 10 Anand, P., McGregor, G.P., Blank, M.A. and Bloom, S.R. (1984) Regul. Pept. 9, 321P

maternal-newborn bond (see Ref. 7). In the rabbit, whose offspring are immature at birth, this reduction in febrile response to endotoxins was not found either in the doe at term, or after injections of AVP into the septal area (see Ref. 9). However, this might be an exception, since in the rat, which also has immature offspring, AVP injections into the septal area suppressed both the endotoxininduced fever (see Ref. 7) and the increase in heat production and body temperature elicited by local cooling of the hypothalamus 1°.

AVP and fever If a central fever suppression pathway exists in the parturient animal and newborn, it could also function as a brake to prevent lethal increases in body temperature at other times. It has long been known that extreme pyrexia (41.1°C) is relatively rare in man 11, a phenomenon that has not as yet been explained. Some reports indicate the AVP is released both centrally and peripherally during fever and hyperthermia. Perfusates of the septal area in febrile sheep contain AVP2 and plasma concentrations in guinea-pigs and sheep rise during fever, reaching a maximum before the temperature peaks 12. Immunocytochemical studies have shown increased AVP reactivity in the medial part of paraventricular nucleus and in nerve fibres projecting to the septum and amygdala during the rise of fever in

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male guinea-pigs to levels similar to those in pregnant females. However, levels fell during height of fever and by the stage of fever decrease were at control levels 13. Thus, the increase in activity of the AVP system does not appear to accompany deferescence; but precedes peak body temperature. Ambient temperature also affects AVP response to endotoxin. In rabbit, blood AVP levels rose in response to endotoxin injection at 30°C (ambient), but did not change at 5°C; since the activity of thyrotropin-releasing hormone (TRH) secreting neurons increase in the cold, it was proposed that AVP neurons are inhibited by local TRH release 14. A V P and heat stress

Rats exposed to heat release AVP, and become hypothermic when AVP is administered either peripherally or into the cerebral ventricles (see Ref. 7). Both acute heat stress and prolonged moderate heat exposure increase AVP concentrations in the hypothalamic-hypophyseal axis and in some extrahypothalamic regions, particularly the septum ~s. Additional thermal dehydration during acute heat stress reduces the raised AVP level in the hypothalamus and further increases AVP concentrations in plasma and in the septum. Hypothalamic and septal AVP increases are reduced and plasma levels further increased in heat-adapted rats. This seems to reflect some changes in demands upon AVP pools by both thermoregulatory and osmoregulatory systems. Direct heating or cooling of the preoptic hypothalamus and septum increases or blocks the heat-induced increase in concentrations of AVP in blood TM. It should be noted that different pools of AVP neurons seem to be activated by different forms of stress. Whereas increase in osmolarity and decrease in blood volume, as well as anaesthesia, mainly activate descending parts of the system which release AVP into the blood 7,17, acute heat stress and fever activate parts ascending to the septum. High central AVP concentration seem to be necessary to evoke the thermoregulatory effects. Since in fever both septal and blood AVP levels are increased, it is likely that both ascending

and descending parts of the AVP system are stimulated concurrently, but it is also possible that high concentrations of AVP released centrally may leak from CSF into plasma TM. M e c h a n i s m of AVP action

Since activation of the AVP system seems to take place during fever rise, AVP may be considered to be a mediator of fever. This hypothesis apparently conflicts with the observed antipyretic action in pregnant animals. However, fever is a complex array of physiological responses 3,9,19 whose function is to restore homeostasis that has been disturbed by an infectious agent 12. The increase of temperature, which can be beneficial (see Ref. 3), is the result of many steps which finally lead to a change in thermoregulatory set point 3,9A9. AVP may interfere with early steps of this fever-inducing process. Since the AVP system is normally activated somewhat later than the fever induction, it does not normally prevent fever, although it may have a fever-limiting function. However, if activated before the application of pyrogen, which is apparently the case in pregnant animals, the fever inducing process cannot be started, or is at least significantly slowed. However, the AVP system may have a feverlimiting function, since it can activate processes that modify the rate and the height of the temperature deviation. Other brain peptides, such as adrenocorticotrophic hormone (ACTH) and its fragment c¢melanocyte stimulating hormone (c~-MSH) may also be involved in fever limitation 20. Their actions may be secondary to AVP which can release ACTH from the anterior hypophysis and consequently corticosteroids from the adrenal cortex. Corticosteroids are not only potent anti-inflammatory agents, but are also antipyretic and help to control febrile rises in body temperature. Circulating c~-MSH, in contrast to AVPTM,can penetrate the blood-brain barrier and its concentration within the septum rises at the peak of fever. Microinjections of this peptide into the region reduce fever (see Ref. 20). AVP itself seems to be a very important effector in the homeo-

static control of fever. In addition to its central effects, it has some peripheral hormonal effects which antagonize changes induced by infection 12. AVP increases water resorption in the distal tubules and collecting ducts of the kidney. The antidiuresis evoked by increased AVP plasma concentration during the rise of fever would thus alleviate the decrease in plasma volume which accompanies fever and preserve the water supply needed to compensate for increased evaporative heat loss. AVP decreases heart rate and increases blood pressure when infused. These effects would antagonize the decrease in blood pressure and the increase in heart rate that normally occur during fever. Additionally, AVP stimulates lymphocyte and leukocyte proliferation which help inactivate infectious micro-organisms and its presence seems to be necessary for the normal function of the reticulo-endothelial system which has many antimicrobial and host defence functions. Enhanced reticulo-endothelial system function may also help prevent circulatory shock resulting from infection 12. EUGEN ZEISBERGER Physiologisches Institut, Justus-Liebig-Universitiit, Aulweg 129, D-6300 Giessen, FRG.

References 1 Swanson, L. W. and Sawchenko, P. E. (1983) Annu. Rev. Neurosci. 6, 269-324 2 Cooper, K. E., Kasfing, N. W., Lederis, K. and Veale, W.L. (1979) J. Physiol. (London) 295, 33-45 3 Zeisberger, E., Merker, G. and Bl/ihser, S. (1981) Brain Res. 212, 379--392 4 Hellon, R. and Townsend, Y. (1983) Pharmacol. Ther. 19, 211-244 5 Kasting, N. W., Veale, W. L., Cooper, K. E. and Lederis, K. (1980) in Thermoregulatory Mechanisms and Their Therapeutic Implications (Cox, B., Lomax, P., Milton, A. S. and Sch6nbaum, E., eds), pp. 95-99, Karger, Basel 6 Kasting, N. W., Cooper, K. E and Veale, W. L. (1979) Experientia 35, 208-209 7 Veale, W. L., Kasting, N. W. and Cooper, K. E. (1981) Fed. Proc. 40, 2750-2753 8 Merker, G., Bl/ihser, S. and Zeisberger, E. (1980) Cell Tissue Res. 212, 47-61 9 Blatteis, C. M. (1984) in Thermal Physiology (Hales, J. R. S., ed.), pp. 539545, Raven Press, New York 10 Banet, M. andWieland, U.-E. (1985)Brain Res. Bull. 14, 113-116 11 Simon, H. B. (1980) in Fever (Lipton, J. E., ed.), pp. 213-224, Raven Press, New York 12 Kasting, N. W., Veale, W. L. and Cooper, K.E. (1982) Neurosci. Biobehav. Rev. 6, 215-222

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13 Zeisberger, E., Merker, G., Bl/ihser, S. and Krannig, M. in Proc. 6th Int. Symp.

on the Pharmacology of Thermoregulation, Jasper, Karger, Basel, (in press) 14 Riedel, W. and Gray, D. (1984) Pfliig. Arch. Eur. J. Physiol. 402, (suppl.), R41 15 Epstein, Y., Horowitz, M., Bosin, E.,

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J

Shapiro, Y., Glick, S.M. (1984) i n Thermal Physiology (Hales, J. R. S., ed.), pp. 137-140, Raven Press, New York 16 Szczepanska-Sadowska, E. (1974) Am. J. Physiol. 226, 155-161 17 Szczepanska-Sadowska, E., Gray, D. and Simon-Oppermann, Ch. (1983) Am.

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J. Physiol. 245, R549-555 18 Robinson, I. C. A. F. (1983) Prog. Brain. Res. 60, 129-145 19 Szelenyi, Z. (1983) J. Therm. Biol. 8, 185190 20 Clark, W. G. and Lipton, J.M. (1983) Pharmacol. Ther. 22, 249-297

and benzilates have been observed. For example, the dependence • "r+rLrpi,,+ + ,- of antagonist affinity on brain re.,1~_ I I L I ' k ~ . I t gion is more noticeable with tropates than with benzilates 2. It might be concluded that in most Additional c o m p l e x i t i e s in the binding of cases where binding of tertiary and quaternary amine muscarinic muscarinic r e c e p t o r antagonists receptor antagonists has been determined simultaneously, the Receptor binding studies have rements. For example, [3H]NMS is former compounds are capable of sulted in the accumulation of a capable of labeling only 65% of the labeling muscarinic receptor sites significant amount of valuable inreceptor population that is availthat are not easily accessible to the formation regarding the properties able to [3H]QNB, suggesting that latter ligands. These sites might be of muscarinic acetylcholine recep[3H]NMS might recognize only a embedded in the lipid milieu or tors in the CNS and PNS. It has subpopulation of [aH]QNB bindanother hydrophobic domain of generally been accepted that, ing sites4,5. This is reminiscent of the cell membrane. In addition, the while muscarinic agonists can disthe fact that the atypical muscardifference in binding capacity of criminate between multiple affininic receptor antagonist, pirenthese two groups of muscarinic ity states of the receptor, resulting zepine, also binds to a selective antagonists might be due to their in heterogeneity of agonist bindpopulation of [3H]QNB binding ability to recognize different coning sites 1, benzilate and tropate sites in the brain 6. Similar findings formations of the receptor. For muscarinic receptor antagonists that [3H]QNB labels double the example, it has been reported that bind to a homogeneous populanumber of receptors labeled by [3H]QNB is more efficient than tion of receptors according to the [aH]NMS in homogenates of [3H]NMS in converting the muslaw of mass action 2, with some 1321N1 astrocytoma cells have also carinic receptor into its high afregional variability in affinity3. been reported recently7. It should finity conformation s. Differentiabe noted however that contradiction between these hypotheses re0 OH tory reports have illustrated that quires further testing. Also, more [3H]QNB and [3H]NMS label the extensive experimentation with same receptor density in intact muscarinic receptor ligands bechick cardiac cells s. In addition, it longing to chemical classes other has been demonstrated that the than the benzilates and tropates is quaternary ammonium analog of required before further generaliQu/nuclidJnyl Benzilate [3H]QNB, [3H]QNB methiodide, zations are justified. binds only to half of the receptor We have also found that the population detected with [3H]QNB behavior of quaternary muscarinic in both dog ventricle homogenantagonists, when used to displace ates 9 and intact chick heart cells 10. [3H]QNB binding in rat brain o °-~1 = Much older reports suggesting a homogenates, is quite anomasimilar phenomenon can also be lous 4,s. Under these conditions, found in the literature. For unlabeled NMS and methylatroN-Methylscopolamine example, it has been shown that pine, but not their tertiary amine [3H]methylatropine binds with analogs, demonstrated very shalHowever, it has recently been prohigh affinity only to half of the low displacement curves 5. When posed that binding of antagonists sites labeled by [3H]atropine in these curves are resolved into to muscarinic receptors might not smooth muscle preparations11. high- and low-affinity componbe quite so simple. Collectively, these findings sugents, only the former correspond We have recently reported that gest that the differences in the closely to the sites labeled directly significant differences exist in the binding characteristics of [3H]by [3H]NMS (Ref. 5). Furthermore, nature of interaction of tertiary QNB and [3H]NMS might not be this anomalous receptor binding amine, e.g. [3H]quinuclidinyl due simply to the fact that they profile cannot be seen if [3H]NMS benzilate ([3H]QNB) and quaterbelong to different chemical is used as a ligand s. Similar findnary amine, e.g. [3H]N-methylgroups; these differences can also ings have been published recently scopolamine ([3H]NMS) ligands be seen when the binding of terby two other groups of investigawith the muscarinic receptors in tiary and quaternary analogs of a tors 1°,12. There are reasons to berat brain homogenates4,S. These particular ligand is examined. lieve that the high affinity muscardifferences can be revealed both in However, subtle differences in the inic receptors in rat brain labeled saturation and competition experibinding characteristics of tropates directly by [3H]NMS, or revealed

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1985,ElsevierSciencePublishersB.V.,Amsterdam 0165- 6147/85/$02.00