Vasopressin: a homeostatic effector in the febrile process.

This review compares the physiological changes which accompany infection and fever with the effects of the peptide, arginine vasopressin (AVP). AVP may act as a neuromodulator, a releasing factor, or a hormone to induce responses which are opposite to those homeostatic changes accompanying fever. Since AVP is released into blood and brain during fever, it is hypothesized that AVP contributes to the maintenance of homeostasis in the infected organism.

Salivary glands, their hormones, and thermoregulation.

The effects of the removal of the submandibular glands (sialadenectomy) on the fever induced by bacterial lipopolysaccharide (LPS) were examined. Thermally sensitive radiotransmitters were implanted into the abdomens of adult male Sprague-Dawley rats that experienced at this time either a sham operation or a sialadenectomy, and one week later body temperatures were recorded by telemetry in these rats when conscious. The initial fever (up to 180 min following LPS) response, following the intraperitoneal injection of 150 micrograms/kg E. coli LPS, was similar in the two groups of rats, but the second phase of the fever (240 to 420 min post-LPS) was modestly, but significantly higher (mean = 0.26 degree C) in sialadenectomized rats. A submandibular gland peptide (compound T; 100 micrograms/kg), given one-half hour before the LPS, did not affect the early fever, but suppressed the late-phase fever by 0.37 degree C (mean). The submandibular glands, which form an integral part of the neuroendocrine mechanisms responsible for attenuating the responses of the immune system to inflammatory stimuli, also appear to modulate thermogenic responses to these stimuli.

Some historical perspectives on thermoregulation.

In this paper, selected historical aspects of thermoregulation and fever are presented as background to the application of molecular biology to thermoregulation. Temperature-sensing mechanisms, coordination of thermal information, thermoregulatory circuitry, efferent responses to thermal stimuli, set point mechanisms, and some of the mechanisms and consequences of fever and hyperthermia are highlighted. Neurotransmitters used in thermoregulatory circuits are also discussed. An attempt is made to include information from comparative physiological sources. Possible future avenues of research in the light of recent new technologies are also presented.

Peripheral blood flow during rewarming from mild hypothermia in humans.

During the initial stages of rewarming from hypothermia, there is a continued cooling of the core, or after-drop in temperature, that has been attributed to the return of cold blood due to peripheral vasodilatation, thus causing a further decrease of deep body temperature. To examine this possibility more carefully, subjects were immersed in cold water (17 degrees C), and then rewarmed from a mildly hypothermic state in a warm bath (40 degrees C). Measurements of hand blood flow were made by calorimetry and of forearm, calf, and foot blood flows by straingauge venous occlusion plethysmography at rest (Ta = 22 degrees C) and during rewarming. There was a small increase in skin blood flow during the falling phase of core temperature upon rewarming in the warm bath, but none in foot blood flow upon rewarming at room air, suggesting that skin blood flow seems to contribute to the after-drop, but only minimally. Limb blood flow changes during this phase suggest that a small muscle blood flow could also have contributed to the after-drop. It was concluded that the after-drop of core temperature during rewarming from mild hypothermia does not result from a large vasodilatation in the superficial parts of the periphery, as postulated. The possible contribution of mechanisms of heat conduction, heat convection, and cessation of shivering thermogenesis were discussed.

Indomethacin-induced antipyresis in the rat: role of vasopressin receptors.

Infusion of 15 micrograms/microliters (approximately 120 micrograms/kg/h) of indomethacin within the ventral septal area of the rat brain significantly reduced a centrally induced prostaglandin E1 (PGE1) hyperthermia when compared with infusions of artificial cerebrospinal fluid. A bolus injection of a V1 receptor antagonist, d(CH2)5Try(Me)AVP, (200, 2000, or 20,000 pmol) within the ventral septal area had no effect of body temperature alone but did suppress the PGE1-induced fever. Similar bolus injections of the V1 receptor antagonist within the ventral septal area failed to alter the antipyretic action of indomethacin on the hyperthermia resulting from centrally administered PGE1. Central injections of a V2 receptor antagonist failed to alter either the PGE1-induced fever or the indomethacin-evoked antipyresis. The results suggest that the V1 receptor antagonist may exert non-specific neurodepressant effects which may interfere with the expression or production of PGE1 hyperthermia and may further mask any contribution of arginine vasopressin to the antipyretic effects of indomethacin.

Effect of prostaglandin, pyrogen and noradrenaline, injected into the hypothalamus, on thermoregulation in newborn lambs.

Thirteen newborn lambs were implanted stereotaxically with an array of 4 guide tubes positioned bilaterally so that their tips lay above various hypothalamic loci. At postnatal ages 50-70 h, rectal temperature was monitored, and bilateral 1 microliter injections were made into the hypothalamus. Prostaglandin E1 (0.2 microgram) and prostaglandin E2 (0.2-2.0 microgram) did not cause fever on any occasion though injections were made into 44 sites throughout the hypothalamus. Nevertheless, lambs that did not develop fever following central injection were often, if sensitized by bacterial pyrogen given earlier able to develop fever after intravenous injection of bacterial pyrogen. Infusion of a bacterial pyrogen (S. abortus equi, 0.2 microgram) into these same sites caused fever only when injections were made into the anterior hypothalamic/preoptic area (AH/POA). Eight lambs were placed in a 10 degrees C environment and noradrenaline was injected. Rectal temperature fell by 0.5-1.4 degrees C after 7 bilateral injections into the AH/POA, but 9 injections into other hypothalamic areas caused little temperature change. When 6 lambs were placed at a temperature of 30 degrees C and noradrenaline was injected, no consistent temperature changes were observed after microinjection into the AH/POA or other parts of the hypothalamus.

Vasopressin may mediate febrile convulsions.

The possibility that arginine vasopressin (AVP) is involved in the etiology of febrile convulsions was investigated by experiments on hyperthermia-induced convulsions in rats. Homozygous Brattleboro rats, which genetically lack AVP, and Long Evans rats, which were passively immunized by intracerebroventricular anti-AVP antiserum, either convulsed at higher body temperatures than untreated Long Evans rats or did not convulse at all. This indicates that a lack of AVP increases the threshold for the convulsions. High blood levels of AVP in hyperthermic convulsing rats compared to hyperthermic non-convulsive rats support the hypothesis that AVP may mediate febrile convulsions.

Modulation of brown adipose tissue-mediated thermogenesis by lesions to the nucleus tractus solitarius in the rat.

Given that relatively little is known regarding the central control of brown adipose tissue (BAT)-mediated thermogenesis the present study assessed whether the direct pharmacological stimulation of beta- or alpha-adrenergic receptors located on the brown adipocytes would result in a typical thermogenic response following electrolytic lesions to the nucleus tractus solitarius (NTS). Bilateral electrolytic lesions to the NTS in the rat effectively disrupted the baroreceptor reflex arc. It was observed that the metabolic and temperature responses to either norepinephrine (1, 5, or 25 micrograms/kg/min) or to the beta-agonist isoproterenol (0.5 micrograms/kg/min) were significantly attenuated in the NTS-lesioned rats relative to the control animals with an intact baroreflex. Conversely, the cardiovascular effects of norepinephrine or of the alpha-agonist phenylephrine (10 micrograms/kg/min) were enhanced in the NTS-lesioned animals. The results suggest that the functional capacity of the brown adipocytes was reduced following NTS lesions and points to an alteration in the ability of beta-receptors to respond to pharmacological stimulation with a typical thermogenic response.

Changes in the hypothalamic mechanisms involved in the control of body temperature induced by the early thermal environment.

The experiments reported in this study were designed to investigate the influence of the early thermal environment on the functional properties of certain putative thermoregulatory neurotransmitters within the hypothalamus of the Sprague-Dawley rat. The effects on body temperature of serotonin, dopamine, carbachol, PGE2 and endotoxin when microinjected into the anterior hypothalamic/preoptic region of the brain have been examined in warm-reared, control and warm-acclimated animals. Serotonin and PGE2 are shown to have different effects on body temperature in warm-reared as compared to warm-acclimated and control animals. The thermoregulatory effects of intrahypothalamic dopamine are shown to be changed by the normal acclimation process, while carbachol and endotoxin have similar effects on the body temperature of all 3 groups of animals. These data suggest that the thermal environment may significantly affect the roles which specific neurotransmitters play in the control of body temperature.

Vasopressin perfusion within the medial amygdaloid nucleus attenuates prostaglandin fever in the urethane-anaesthetized rat.

The antipyretic effect of arginine vasopressin (AVP) introduced into the ventral septal area (VSA) by push-pull perfusion was investigated in the urethane-anaesthetized rat. In addition, experiments were carried out to determine whether AVP could suppress fever when similarly perfused within the medial amygdaloid nucleus (meA). During push-pull perfusion of artificial cerebrospinal fluid within the VSA or meA, PGE1 injected intracerebroventricularly evoked fevers with respective magnitudes of 1.3 +/- 0.2 degrees C and 1.4 +/- 0.3 degrees C above baseline. Perfusion of AVP (6.5 micrograms/ml) within the VSA had significantly reduced the magnitude of PGE1 fever to 0.3 +/- 0.3 degrees C above baseline, while having no significant effect on afebrile colonic temperature. Perfusion of AVP (6.5 micrograms/ml) within the meA had significantly attenuated the magnitude of PGE1 fever to 0.7 +/- 0.2 degrees C above baseline, while having no significant effect on afebrile colonic temperature. These results support further the utility of the urethane-anaesthetized rat model for future investigations of the central control of fever and antipyresis. In addition, these data are consistent with the hypothesis that AVP may act within the meA as an endogenous antipyretic.

The effectiveness of arginine vasopressin and sodium salicylate as antipyretics in the Brattleboro rat.

The infusion of either 30 micrograms/microliters (approx. 100 micrograms/kg/h) of sodium salicylate or 10 ng/microliters (10(-5) M) arginine vasopressin within the ventral septal area of the Brattleboro rat brain reduced a centrally induced prostaglandin E1 (PGE1) hyperthermia when compared with infusions of artificial cerebrospinal fluid. Conversely, the infusion of a related peptide, oxytocin (10 ng/microliters (10(-5) M), or 33 ng/kg/h) failed to alter the rise in core temperature following the PGE1 injection. These results suggest that the vasopressin receptors reported to be present in the Brattleboro rat may respond normally to exogenously administered vasopressin, thus allowing for the antipyretic action. Moreover, the antipyretic effects of sodium salicylate suggest that aspirin-like drugs may induce the release of alpha-melanocyte-stimulating hormone which, in turn, attenuates the PGE1-evoked fever. Given recent evidence, however, which suggests that the Brattleboro rat may contain vasopressin both peripherally and within the brain, the antipyretic action of sodium salicylate may be alternatively explained through the endogenous release of vasopressin.

Vasopressin: its role in antipyresis and febrile convulsion.

When pyrogenic substances are injected intravenously into experimental animals, a sequence of events is set in motion which involves the hypothalamus and perhaps other portions of the diencephalon to produce a febrile response. We now present evidence that the brain produces its own endogenous antipyretic which may serve as a means of controlling the extent of the fever. When arginine vasopressin is perfused through the lateral septal area of the hypothalamus of the sheep, fever is suppressed. Vasopressin alone does not lower normal body temperature when perfused through this region of the brain. In addition, evidence is provided to indicate that vasopressin is released within the lateral septal area during the febrile response. It is concluded that, in fever, arginine vasopressin may be released in the lateral septal area of the brain and serve as an endogenous antipyretic. Results indicate that, following an initial application of vasopressin into the brain itself, a subsequent similar administration of vasopressin produces seizure-like activity. Therefore, it is suggested that this release of arginine vasopressin may contribute to the production of febrile convulsion.

Antipyresis: its effect on mortality rate of bacterially infected rabbits.

The effect of an antipyretic drug administered directly into the preoptic-anterior hypothalamus was measured in order to investigate the role of fever on mortality of bacterially infected mammals. New Zealand white rabbits (Oryctolagus cuniculus) were injected intravenously with Pasteurella multocida and either sodium salicylate or a control solution was infused directly into the preoptic-anterior hypothalamus. Both groups developed fevers, but the fever of the rabbits infused with the antipyretic was reduced by 50% during the initial stage of infection. Hypothalamic sodium salicylate infusions produced a lower average fever than control infusions over an initial 5 hour period of infection, reducing average 5 hour fevers from 1.56 degrees C to 0.72 degrees C. All of the infected rabbits infused with sodium salicylate died whereas only 29% of the infected control rabbits died. Rabbits receiving sodium salicylate alone did not die. The increased mortality could possibly be the result of a fulminating infection caused by rapidly multiplying bacteria during the initial, attenuated phase of the febrile course in the salicylate-treated rabbits.

Measurement of intracranial pressure in the unanesthetized rabbit.

A method is described for the measurement of intracranial pressure in the unanesthetized, minimally restrained rabbit utilizing a modified subarachnoid screw system. The pressures are transmitted from within the cranium via a flexible saline filled catheter to a fixed external pressure transducer. An index of the relative vertical position of the animal's skull as compared to the fixed transducer is given by means of a second open-ended pressure measuring catheter, the open end of which is fixed to the subarachnoid screw assembly on the animal's skull. The system was found to be a reliable method of measurement of intracranial pressures in the minimally restrained rabbit, and could easily be adapted to other animal species. The method is currently being used to assess the effects of fever on intracranial pressures.

Effects of antipyresis on bacterial numbers in infected rabbits.

A previous investigation demonstrated that infusion of an antipyretic drug into the preoptic anterior hypothalamus (PO/AH) of rabbits reduced the fever usually seen during the initial stages of infection. This was followed by an increased fever and an increased mortality rate [32]. The work reported here investigated the hypothesis that the increased mortality was the result of decreased killing and/or increased multiplication of bacteria during the initial, attenuated phase of the febrile course in the antipyretic-treated rabbits. Rabbits were injected intravenously with Pasteurella multocida and either sodium salicylate or a control solution was infused directly into the PO/AH. Infusion of sodium salicylate reduced the mean fever 4 hours after injection of bacteria from 2.07 +/- 0.28 degrees C (S.E.M.) to 0.62 +/- 0.43 degrees C. Rabbits with reduced fevers had decreased blood leucocyte counts and greater numbers of bacteria in lung and liver samples. No differences were seen in reticuloendothelial clearance of carbon, hematocrit, or intracellular viability of bacteria when antipyretics were administered. This increase in bacterial numbers corresponds well to the increased mortality found in previous studies in animals with reduced fevers.

Induced changes in intracranial pressure in the anesthetized rat and rabbit.

Intracranial pressure (ICP) was measured continuously in anesthetized, free-breathing, adult, male Sprague-Dawley rats and New Zealand White rabbits by means of a subarachnoid screw technique. The effect upon ICP of changing the volumes within the cranium by infusion of artificial cerebrospinal fluid into the lateral cerebral ventricle at various rates was examined. Results obtained demonstrated some of the elastic and compensatory aspects of cerebrospinal fluid dynamics. The effects upon ICP of the intravenous administration of urea, mannitol, acetazolamide, dimethyl sulfoxide, norepinephrine, epinephrine, isoproterenol, nitroglycerin, papaverine, histamine, angiotension II, pitressin, sodium nitroprusside, diazoxide, lidocaine, sodium pentobarbitone, as well as inhalation of amyl nitrate and carbon dioxide were examined in anesthetized rats. The effect upon ICP of the intravenous infusion of urea, as well as the bolus intravenous administration of epinephrine and pitressin was examined in the anesthetized rabbit. Results obtained from these animals demonstrate the action of these experimental interventions upon ICP as measured by means of the subarachnoid screw technique.

Fever and intracranial pressures.

The effect of fever upon intracranial pressures was determined in the rabbit and cat. In the unanesthetized rabbit and cat, cerebrospinal fluid (CSF) pressure was measured via direct cannulation of the lateral cerebral ventricle. Intracranial pressure (ICP) was measured in the rabbit by a subarachnoid screw technique. In all cases, intravenous administration of bacterial pyrogen extracted from Salmonella abortus equi resulted in significant differences from controls in physiological variables measured during the initial "chill" phase of the fever. There was an increase in body temperature, a fall in CSF or ICP pulse rate, an increase in pulse pressure amplitude, and a small increase in mean CSF or ICP. In addition, venous and arterial blood pressures increased significantly and, consistent with heat conservation, there was a fall in respiratory rate as well as cutaneous vasoconstriction in the ears. The arterial carbon dioxide tension was unchanged during the prodrome but fell significantly during the chill and flush phases and rose again during defervescence. The results suggest that in these animals there is a slight increase in pressures within the cranium during the "chill" phase of a pyrogen induced fever, resulting from changes occurring in many body systems during this phase of the fever.

Alterations in body temperature elicited by intrahypothalamic administration of tetrodotoxin, ouabain and A23187 ionophore in the conscious cat.

Ouabain, tetrodotoxin, and calcium selective ionophore (A23187) were administered bilaterally into the hypothalamus of the unrestrained, fully conscious cat, while body temperature and other indicators of thermoregulatory responses were monitored continuously. Posterior hypothalamic microinjection of 2.0 to 10.0 ng or tissue perfusion with 1.1 X 10(-7) to 1.1 X 10(-8) M ouabain elicited dose dependent increases in body temperature accompanied by pinnae vasoconstriction, shivering and postural changes consistent with heat conservation. Tetrodotoxin, microinjected in doses of 0.5 and 5.0 ng or tissue perfusions with 7.8 X 10(-9) to 7.8 X 10(-7) M in the posterior hypothalamus elicited dose dependent falls in body temperature. However, tetrodotoxin microinjected into the anterior hypothalamic region elicited only increases in temperature. The calcium selective ionophore, A23187, at least at the concentrations used in this study, did not appear to produce any consistent effects on thermoregulation. These data support the hypothesis that the ionic milieu of the posterior hypothalamic region is essential in the maintenance of body temperature. Further, they suggest that increasing the [Ca++]/[Na+] acts in a manner similar to a depression in the firing frequency of a distinct population of cells, which may in turn determine in some way the "set-point" for body temperature. There is no evidence to support the concept that increasing the [Ca++]/[Na+] causes an increased release of the synaptic contents of the region.

A method for continuous blood sampling during cold water immersion.

A technique, consisting of a pre-calibrated, catheter-peristaltic pump combination, for continuous blood sampling was tested using six volunteers during a 20 min immersion in cold water at 14.7 +/- 0.9 degrees C. The device offered the advantage of continued collection of blood samples from an antecubital vein during the experiment with little discomfort for the subjects and in sufficient volume for assay of plasma constituents eg. catecholamines.

Neurotransmitter effects on body temperature are modified with increasing age.

This study reports effects on body temperature, in two different age groups of Sprague Dawley rats, of intracerebroventricular (ICV) administration of prostaglandin E2, noradrenaline, serotonin, dopamine, and carbachol. Young animals (3-5 months) developed fevers in response to administration of prostaglandin E2 (+ 1.02 +/- 0.26 degrees C), while no significant changes in colonic temperature were observed in the older (15-18 months) group of rats. Noradrenaline (10.0 micrograms), caused a decrease in colonic temperature in the younger group of animals (-2.02 +/- 0.70 degrees C), but had no significant effects on the body temperature of the older group. Similarly, differences between the temperature responses of the young as compared with the older group of animals were observed following ICV administration of carbachol, dopamine and serotonin. These data suggest that the roles of these substances in the hypothalamic control of body temperature may be modified with increasing age.