Centrally Acting Humoral Factors in the Control of Vasopressin Release

The Neurahypophysis: Structure, Func,tion cind Control. Progress in Bruin Reseorch, Vol. 6 0 , edited b y B.A. Cross und G . Leng

0/Y83Elsevier Science Publishers B.V.

Centrally Acting Humoral Factors in the Control of Vasopressin Release L. SHARE Deportment (fPhysiology and Biophysics. University of Tennessrr Crnter .for the Hrcil~hScieircrs. Memnphis TN 38/63 (U.S.A.)

INTRODUCTION The major physiological stimuli for vasopressin release are reductions in arterial blood pressure and blood volume and an increase in plasma osmolality. Changes in blood volume and pressure are sensed by receptors in the cardiovascular system (Share and Grosvenor, 1974), and vasopressin release is modified by neural pathways coursing through the central nervous system to the supraoptic and paraventricular nuclei of the anterior hypothalamus. There is also evidence that osmoreceptors, that sense changes in plasma osmolality , are separated from the magnocellular neurosecretory cells of the anterior hypothalamus by at least one synapse (Bridges and Thorn, 1970; Sladek, 1980). It is evident, then, that vasopressin secretion is under neural control. Consequently, neurotransmitters and neuromodulators, acting either at synapses in the central neural pathways that control vasopressin release or directly on the neurosecretory neurones, can affect vasopressin secretion. This review will focus upon recent studies of the central actions of catecholamines, prostaglandins, and vasopressin itself, o n vasopressin release. NOR ADRENALINE The heavy noradrenergic innervation of vasopressin neurones in the supraoptic and paraventricular nuclei (Sladek et a]. , 1980) suggests that noradrenaline has an important function as a neurotransmitter in the control of vasopressin secretion. Reports of the central actions of noradrenaline on the release of vasopressin have been controversial. There have been a number of reports that vasopressin release is stimulated by the central application of noradrenaline (Bhargava et al., 1972; Bridges et al., 1976; Hisada et al., 1977; Hoffman et al., 1977; Milton and Paterson, 1974; Kuhn, 1974; Olsson, 1970; Urano and Kobayashi, 1978 ;Vandeputte-Van Messom and Peeters, 1975). On the other hand, Beal and Bligh ( I 980) suggested that centrally administered noradrenaline inhibited vasopressin release, and Moss et al. (1971) and Barker et al. (1971) observed that direct application of noradrenaline to neurosecretory cells in the supraoptic and paraventricular nuclei inhibited their electrical activity, indicating, presumably, an inhibition of secretion. This controversy could be due largely to methodological problems. Only Bhargava et al. (1972) and Milton and Paterson (1 974) measured plasma levels of vasopressin; in the other studies, changes in urine flow were used as an index of changes in the plasma vasopressin concentration. As [425]

426 intracerebroventricular (i.c.v.) injection of vasopressin lowers blood pressure (e.g. Kobinger, 1978), the reduction in urine flow following central administration of noradrenaline could be due to the reduction in blood pressure rather than to an increase in the plasma vasopressin concentration. In many of the experiments cited above, arterial blood pressure was not measured. To clarify the role of noradrenaline in the control of vasopressin release, the following experiments (Kimura et al., 1981a) were carried out in dogs, sedated with morphine and anaesthetized with a mixture of chloralose and urethane, in which a cannula was placed in a lateral cerebral ventricle. Vasopressin was measured with a sensitive and specific radioimmunoassay (Crofton et al., 1978,1980), and arterial blood pressure and heart rate were monitored. The i.c.v. infusion of noradrenaline at 0.7,uglkg per min for 20 min resulted in a sustained fall in mean arterial blood pressure. This fall in blood pressure, which ordinarily would result in an increased release of vasopressin (Share and Grosvenor, 1974), was accompanied by a profound fall in the plasma vasopressin concentration (Fig. 1 ) that continued for 55 min after the infusion of noradrenaline was stopped, and that reached a level that was only 11 % of the pre-infusion value. Although noradrenaline is considered to have predominantly a-adrenergic activity centrally, with littlep-adrenergic effect, the responses to i.c.v. clonidine, a relatively pure a-adrenergic agonist, were also determined. The effects of clonidine on mean arterial blood pressure and the plasma vasopressin concentration (Fig. 1) were virtually identical to those of noradrenaline.

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To confirm that the inhibition of vasopressin secretion by noradrenaline was due to its a-adrenergic activity, the effects of pretreatment with the a-adrenoreceptor antagonist phenoxybenzamine were determined. Phenoxybenzamine, at a dose of 100,ug/kg, was injected i.c.v. 90 min before the start of the i.c.v. infusion of noradrenaline or its saline vehicle. Treatment with phenoxybenzamine alone was without effect on mean arteiial blood pressure, but produced a small reduction in plasma vasopressin (Fig. 2). Although phenoxybenzamine completely blocked the effect of i.c.v. noradrenaline on blood pressure, it inhibited the effect of noradrenaline on vasopressin release by only approximately 50 % (Fig. 2). The reason for the failure of phenoxybenzamine to block completely the effect of noradrenaline on vasopressin secretion is not certain.

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Further evidence that the central actions of noradrenaline on the secretion of vasopressin are due to its a-adrenergic activity is found in the observation that the i.c.v. infusion of the p-adrenergic agonist isoprenaline, at 0.7,uuglkg per min for 20 min, was without effect on the plasma vasopressin concentration (Fig. 1 ) . Thus, in the anaesthetized dog, the central action of noradrenaline is to inhibit vasopressin release, and this action is due to a-adrenergic activity. The data, however, do not make it possible to distinguish between activation of a I- and a,-adrenoreceptors. In view of the heavy noradrenergic innervation of the magnocellular vasopressin neurones of the anterior hypothalamus, it is likely that this is the primary site of action of noradrenaline to inhibit vasopressin release. This view is supported by the observation by Armstrong et al. (1 982) that

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noradrenaline inhibited the release of vasopressin from the hypothalamo-neurohypophysial complex in vitro. Physiologically, inhibition of vasopressin secretion results from activation of arterial baroreceptors and left atrial stretch receptors (Share and Grosvenor, 1974). It is, then, reasonable to conjecture that the noradrenergic neurones that innervate vasopressin perikarya in the supraoptic and paraventricular nuclei are the rostra1 terminations of this pathway.

DOPAMINE Dopamine neurones project to the supraoptic and paraventricular nuclei, the median eminence, and the posterior pituitary (Palkovits, I98 I ) , but the role of these neurones in the control of vasopressin secretion is highly controversial. There are reports that dopamine increases (Bridges et a]., 1976; Milton and Paterson, 1973; Urano and Kobayashi, 1978), decreases (Barker et al., 197 1; Forsling et al., I98 1 ; Johnston et al., 197.5 ; Lightman and Forsling, 1980; Passo et al., 198 1; Wolny et al., I974), or has little or no effect on (Bhargava et al., 1972 ; Hoffman et al., 1977 ; Olsson, 1970) vasopressin secretion. These reports are based upon in vitro and in vivo studies, and in most of the latter, plasma vasopressin levels were not measured (the exceptions are the reports by Bhargava et al. ( 1972) and Lightman and Forsling ( 1 980)). We therefore studied the effects of dopamine, administered centrally, on vasopressin secretion under carefully controlled conditions (Kimura et al., 198 1b). Dogs were anaesthetized and prepared in the manner described above for the study of i .c.v. noradrenaline. The infusion of dopamine i.c.v. at 1.2Spglkg per min for 20 min resulted in a small transient reduction in mean arterial blood pressure. The plasma vasopressin concentration, however. fell 44 %, beginning 25 min after the end of the dopamine infusion (Fig. 3). The findings were quite different when bromocriptine mesylate, a specific dopamine agonist, was infused 1.c.v. at 0.25pgikg per min for 20min. There was a larger sustained fall in mean arterial blood pressure, which did not begin until after the bromocriptine infusion was completed, and a marked increase in the plasma vasopressin concentration (Fig. 3). As the increase in plasma vasopressin occurred before the fall in blood pressure, the increased secretion of vasopressin was due to a central action of the bromocriptine, rather than as a consequence of the fall in blood pressure. There are several explanations for the apparently paradoxical findings that dopamine and its specific agonist, bromocriptine, had opposite effects. The inhibition of vasopressin release by dopamine could have been due to its inherenta-adrenergic activity (e.g. Goldberg et al., 1978) or to its conversion to noradrenaline (Glowinski and Iversen, 1966), and, as we have shown (Kimura et al., 1981a),a-adrenergic agonists act centrally to inhibit the release of vasopressin. Although bromocriptine has somea-adrenergic antagonistic activity, it seems more likely that the stimulation of vasopressin release by bromocriptine was due primarily to its dopaminergic agonistic activity. These findings may also partly expIain the diverse reports of the effects of dopamine on vasopressin release. Thus, the specific experimental conditions may determine whether the a-adrenergic or dopaminergic activity of exogenous dopamine predominates, and therefore, whether vasopressin secretion is inhibited or stimulated. As there are three dopamine pathways within the hypothalamus (Palkovits, 198l), it is also possible that dopamine neurones inhibit the release of vasopressin at one site, e.g. the posterior pituitary (Forsling et al., 198 1 ; Passo et al., I98 I ) , and stimulate the release of vasopressin at another site, perhaps the perikarya of the vasopressin cells.

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The physiological significance of the hypothalamic and neurohypophysial dopamine pathways in the control of vasopressin secretion is conjectural. Dehydration results in an increased dopamine content of the posterior pituitary (Alper et al., 1980; Holzbauer et al., 1978), which suggests that dopamine pathways may be involved in the osmotic control of vasopressin secretion. Brooks and Claybaugh ( 1982) found that the dopamine antagonist haloperidol blocked the stimulation of vasopressin release by angiotensin 11, and suggested that dopamine may be involved in angiotensin-mediated vasopressin secretion.

PROSTAGLANDINS The evidence indicates that centrally generated prostaglandins can serve as humoral mediators in the control of vasopressin secretion. Yamamoto et al. (1976) found that perfusion of the cerebral ventricles in the anaesthetized dog with artificial CSF containing prostaglandin (PC) E, resulted in a marked, sustained increase in plasma vasopressin (Fig. 4). Consistent with this observation are the reports that prostaglandins of the E series, given centrally

430 (Andersson and Leksell, 1975 ; Leksell, 1978) or into a common carotid artery (Vilhardt and Hedqvist, 1970), inhibit a water diuresis. It has also been reported that PGF,, PGH, and arachidonic acid decrease urine flow when given centrally (Leksell, 1978 ; Fujimoto et al., 1980). Fujimoto and Hisada (1978) observed that, in the ethanol-anaesthetized rat, PGE, i.c.v. caused first a diuresis and then an antidiuresis, but this report is difficult to interpret in the absence of measurement of the plasma vasopressin levels.

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The demonstration that exogenous, centrally administered prostaglandins affect vasopressin release does not necessarily indicate that endogenous brain prostaglandins participate in the control of vasopressin secretion. There is, however, evidence that this may indeed be the case. First, PGE, i.c.v. and hypertonic NaCl i.c.v. interact synergistically in inhibiting a water diuresis in the conscious goat (Andersson and Leksell, 1975). Second, the stimulation of vasopressin release by i.c.v angiotensin I1 was blunted by blockade of prostaglandin biosynthesis by i.c.v. indomethacin (Fig. 5; Yamamoto et al., 1978). However, the most convincing demonstration that brain prostaglandins have a role in the control of vasopressin release is found in the report by Hoffman et al. (1982). These investigators found that, in the dog, the stimulation of vasopressin release by i.v. infusion of hypertonic NaCl was almost completely blocked by the central administration of indomethacin (Fig. 6). Centrally administered indomethacin alone was without effect on basal plasma vasopressin levels (Yamamoto eta]., 1978 ;Hoffman et al., 1982). These data suggest that brain prostaglandins of the E series play an important role in the osmotic control of vasopressin release, perhaps as modulators of input from osmoreceptors to neurosecretory cells. This locus of action for the prostaglandins is supported by the work of Ishikawa et al. (1981) with explants of the hypothalamo-neurohypophysial complex in organ culture. The addition of PGE, to the incubation medium increased the release of vasopressin into the incubation medium ; the addition of indomethacin to the

43 I incubation medium reduced substantially the ability of angiotensin I1 and hypertonic saline to stimulate the release of vasopressin into the medium. Whether brain prostaglandins participate in other components of the control of vasopressin release remains to be determined.

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432 VASOPRESSIN There is reason to believe that vasopressin can act centrally to inhibit its release from the posterior pituitary into the peripheral circulation. Bhargava et al. (1977) reported that the i.c.v. injection of Pitressin in anaesthetized dogs resulted in a reduction in the concentration of vasopressin in blood. There is some concern about this work, however. First, very large doses of vasopressin were necessary; the i.c.v. bolus injection of 10 mU of Pitressin produced only a 10 % reduction in the blood vasopressin concentration. Second, the Pitressin was dissolved in 0.9 % NaCl and administered in relatively large volumes (up to 0.5 ml). Finally, the Pitressin was probably a mixture of arginine- and lysine-vasopressins. Somewhat similar findings have been obtained by Nashold et al. (1963), who found that the i.c.v. injection of huge doses (10-15 U) of lysine-vasopressin increased urine flow in cats. As there was an accompanying increase in osmolar clearance, it is not certain that the increased urine flow was due to a fall in plasma vasopressin. Because of these problems we (Wang et al., I982a) re-examined the effects of the central administration of vasopressin on vasopressin release. In anaesthetized dogs, pure synthetic arginine-vasopressin dissolved in artificial CSF was infused i.c.v. at rates of 10, 20 and SOpUlmin (IOpYmin) for 90 min. Concentrations of vasopressin in plasma and CSF were monitored during the 90 min infusion and for 120 min thereafter. The concentration of vasopressin in CSF increased slowly during the vasopressin infusion, and decreased slowly after the end of the infusion, with a half-life of roughly 1-2 h. The maximum vasopressin levels achieved in the CSF were 32 5 , 8 3 f5 , and 13 1 IL 13pUlml for infusion rates of 1 0 , 2 0 and SOpUirnin, respectively. There was little or no effect on mean arterial blood pressure and heart rate, but there were slow progressive reductions in plasma vasopressin concentrations, which continued for a considerable time after the vasopressin infusion was discontinued (Fig. 7).

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The maximum CSF vasopressin concentration obtained when vasopressin was infused i.c.v. at 10pUlmin was similar to that found in CSF after severe haemorrhage (Wang et al., 198 1) or the i.c.v. infusion of hypertonic artificial CSF (Wang et al., 1982b). Furthermore, if the

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vasopressin diffused from the CSF to a site of action removed from the borders of the cerebral ventricles, the concentration at that site would have been relatively low. Thus, the concentrations of vasopressin in CSF achieved in these experiments are physiologically reasonable. These data suggest, then, that centrally released vasopressin may act under physiological or pathophysiological conditions to inhibit the release of vasopressin into the peripheral circulation. The available data do not answer the question of whether centrally released vasopressin is transported to its site of action via the CSF, or whether it is released at its site of action from the axonal endings of vasopressin cells. In view of the sluggish turnover of vasopressin in CSF, the latter seems to be more likely. The central site of action for vasopressin is also not certain. Vasopressin could act directly on the neurosecretory cells in the anterior hypothalamus, as it has been shown that the microelectrophoretic application of vasopressin to cells in the supraoptic nucleus inhibits the electrical activity of these cells (Nicoll and Barker, 197 1). Vasopressin may also act at brain centres remote from the anterior hypothalamus, and these centres could, in turn, inhibit the neurosecretory cells in the paraventricular and supraoptic nuclei. There is an anatomical and functional basis for this route of action. Parvocellular vasopressin neurones project from the anterior hypothalamus to centres in the medulla concerned with blood pressure regulation (e.g. Sofroniew and Schrell, 198 1) and which are, presumably, way-stations in the neural pathway which subserves baroreceptor control of vasopressin release. In addition, centrally administered vasopressin affects the activity of catecholamine neurones in several brain regions which have neural projections to the anterior hypothalamus (Tanaka et al., 1977). SUMMARY AND CONCLUSIONS Thus, noradrenaline, dopamine, prostaglandins of the E series and vasopressin itself, can act centrally to affect the release of vasopressin from the posterior pituitary into the circulating blood. In addition, there is evidence that other centrally acting humoral agents, e.g. acetylcholine, angiotensin I1 and the opioids, also influence vasopressin secretion. The failure to review the data relating to these latter agents reflects a limitation of space rather than a lack of importance. These agents may act as neurotransmitters at synapses on the neurosecretory cells in the supraoptic and paraventricular nuclei, or at interneuronal synapses in the neural systems that control vasopressin release. Some of these agents, e.g. the prostaglandins, may act as neuromodulators, modifying the response to a stimulus of some element in the neural control system for vasopressin release. A given agent, e.g. dopamine, may act in several different neural pathways that innervate the supraoptic and paraventricular nuclei and the neurohypophysis. Thus, the effects of such an agent, when it is administered centrally, could vary according to the experimental conditions. Considerable work remains to be done to identify the humoral agents that act centrally on vasopressin release, and to characterize carefully their actions, their sites of action, and their role in the control of vasopressin secretion. REFERENCES Alper, R.H., Demarest, K.T. and Moore, K.E. (1980) Dehydration selectively increases dopamine synthesis in tuberohypophyseal dopaminergic neurons. Nuurorndocrinology , 3 1 : 1 12-1 15. Anderson, B. and Leksell, L.G. (1975) Effects on fluid balance of intraventricular infusions of prostaglandin E , Actu physiol. scand., 93: 286288.

434 Armstrong, W.E., Sladek, C.D. and Sladek, J.R. (1982) Characterization of noradrenergic control of vasopressin release by the organ-cultured rat hypothalamo-neurohypophyseal system. Endocrinology, I 1 1 : 273-279. Barker, J.L., Crayton, J. W. and Wicoll, R.A. (1971) Noradrenaline and acetylcholine responses of supraoptic neurosecretory cells. J . Physiol. (Lond.), 2 I8 : 19-32. Beal, A.M. and Bligh, J. (1980) Diuretic effect of intraventricular and intravenous infusions of noradrenaline in conscious sheep. Quart. J . exp. Physiol., 65: 321-333. Bhargava, K.P., Kulshrestha, V.K. and Srivastava, Y.P. (1972) Central cholinergic and adrenergic mechanisms in the release of antidiuretic hormone. Brit. J . Pharmacol., 44: 617-627. Bhargava, K.P., Kulshrestha, V.K. and Srivastava, Y.P. ( I 977) Central mechanism of vasopressin-induced changes in antidiuretic hormone release. Brir. J . Pharmacol., 60: 77-81, Bridges, T. E. and Thorn, N.A. 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(1977) Antidiuresis of centrally administered amines and peptides and release of antidiuretic hormone from isolated rat neurohypophysis. J a p . J . Pharmacol., 27: 153-161. Hoffman, P.K., Share, L., Crofton, J.T. and Shade, R.E. (1982) The effect of intracerebroventricuhrindomethacin on osmotically stimulated vasopressin release. Neuroert[focririology, 34 : 132-1 39. Hoffman, W.E., Phillips, M.I. and Schmid, P. (1977) The role of catecholamines in central antidiuretic and pressor mechanisms. Neuruphurmncology , 16 : 563-569. Holzbauer, M., Shaman, D.F. and Godden, U. (1978) Observations on the function of the dopaminergic nerves innervating the pituitary gland. Neuroscience, 3 : 1251-1262. Ishikawa, S., Toshikazu, S. and Yoshida, S. ( I 98 1) The effect of prostaglandins on the release of arginine vasopressin from the guinea pig hypothalamo-neurohypophyseal complex in organ culture. Endoc,rinology, 108 : 193-1 98. Johnston, C.I., Hutchinson, J.S., Morris, B.J. and Dax, E.M. 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