vasopressin--1-(1-mercaptocyclohexaneacetic-acid)-2-(o--methyl-l-tyrosine)-8-l-arginine- and Fever

Antipyretic properties have been ascribed to arginine vasopressin (AVP), and the site where its antipyretic effects are mediated in the brain was identified as the ventrolateral septum of the limbic system. In guinea pigs, the majority of AVP projections to the septum originate from parvocellular neurons of the hypothalamic paraventricular nucleus (PVN). Electrical stimulation of the PVN with 10-s trains of current pulses (duration 1 ms, frequency 20 Hz, amplitude 8 V, current 0.205 +/- 0.017 mA) reduced the febrile response to an intramuscular injection of 20 micrograms/kg lipopolysaccharide (LPS from Escherichia coli, 0111: B4) by 54% compared with unstimulated animals. This reduction in fever by electrical PVN stimulation was partly reversed by a simultaneous intraseptal microinfusion of the vasopressinergic V1-receptor antagonist d(CH2)5[Tyr(Met)2]AVP at a concentration of 10(-5) mol for 6 h with an infusion speed of 0.1 microliter/min. We further investigated the effects of intraseptal microinfusions or systemic infusions of the gamma-melanocyte-stimulating hormone (gamma-MSH), a derivative of the proopiomelanocortin, on LPS-induced fever. Intraseptal microinfusions of gamma-MSH at a concentration of 10(-5) mol/l for 6 h with an infusion speed of 0.1 microliter/min caused a 38% reduction in fever. A significantly greater 57% reduction in fever was observed when the intraseptal microinfusion of gamma-MSH was combined with electrical stimulation of the PVN (for parameters see above). A systemic infusion of 0.261 mumol gamma-MSH for 6 h reduced LPS fever to approximately 50% compared with animals infused with vehicle (0.9% saline).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Body Temperature; Brain; Brain Mapping; Electric Stimulation; Escherichia coli; Fever; Guinea Pigs; Infusions, Intra-Arterial; Infusions, Parenteral; Lipopolysaccharides; Male; Melanocyte-Stimulating Hormones; Neurons; Paraventricular Hypothalamic Nucleus; Stereotaxic Techniques

Previous investigations on the antipyretic properties of arginine vasopressin have used bacterial endotoxins or pyrogens to induce fever. Because these experimental models of fever fail to mimic all aspects of the responses to infection, we felt it was important to examine the role of endogenously released vasopressin as a neuromodulator in febrile thermoregulation during infection. Therefore the present study examines the effects of chronic infusion of a V1-receptor antagonist or saline (via osmotic minipumps into the ventral septal area of the brain) on a fever induced by injection of live bacteria. Telemetry was used for continuous measurement of body temperature in the awake unhandled rat. Animals infused with the V1-antagonist exhibited fevers that were greater in duration compared with those of saline-infused animals. These results support the hypothesis that vasopressin functions as an antipyretic agent or fever-reducing agent in brain. Importantly, they suggest that endogenously released vasopressin may play a role as a neuromodulator in natural fever.

Topics: Animals; Arginine Vasopressin; Body Temperature Regulation; Brain; Drinking; Eating; Escherichia coli Infections; Fever; Infusion Pumps; Male; Rats; Rats, Sprague-Dawley; Vasopressins

Experiments were undertaken to characterize a possible receptor mediating antipyretic action of arginine vasopressin (AVP) within the medial amygdaloid nucleus (meA) in the conscious rat. Additional experiments were directed at determining whether the action of endogenously released AVP can be revealed in the meA during fever in the conscious rat. These objectives were achieved using vasopressin analogues directed against vasopressor (V1a) and antidiuretic (V2) receptors. Bilateral injection of AVP (40 pmol) into the meA of conscious rats suppressed fever evoked by intracerebroventricular (icv) administration of prostaglandin E1 (PGE1, 50 ng). The V2 receptor agonist 1-desamino-8-D-AVP (40 pmol) injected into the meA evoked only moderate antipyresis compared with AVP, possibly because of interaction of this agonist with V1a receptors. The antipyretic effect of AVP was blocked when injection of the peptide was preceded by a bilateral injection of the V1a antagonist 1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)-2-(O-methyl)tyrosine AVP [d(CH2)5Tyr(Me)AVP, 400 pmol] into the meA. Injection of d(CH2)5Tyr(Me)AVP alone into the meA was without significant effect on afebrile core temperature. Injection of d(CH2)5Tyr(Me)AVP or 1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)-2-D-valine,4-valine AVP (a V2 antagonist) alone into the meA before icv PGE1 resulted in fevers that were not significantly different from artificial cerebrospinal fluid controls. These data are consistent with the possibility that AVP might act within the meA to evoke antipyresis via receptors that resemble V1a (vasopressor) receptors. However, the action of AVP endogenously released into the meA does not appear to be an absolute requisite in the normal modulation of PGE1 fever.

Topics: Alprostadil; Amygdala; Angiotensin Receptor Antagonists; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arginine Vasopressin; Deamino Arginine Vasopressin; Fever; Injections, Intraventricular; Male; Rats; Receptors, Angiotensin; Receptors, Vasopressin; Vasopressins

Repeated daily intravenous injections of bacterial endotoxin induce a refractory state to their usual pyrogenic effects. The neuropeptide arginine vasopressin (AVP) has been implicated in natural fever suppression and may be involved in the process of pyrogenic tolerance to intravenous endotoxin. This study was conducted to test this hypothesis. Tolerance was induced by two successive daily intravenous injections of Escherichia coli endotoxin (50 micrograms/kg) into conscious unrestrained rats. This tolerance was maintained, unaltered, after a third or fourth subsequent injection. However, bilateral administration of an AVP V1-receptor antagonist (0.43-4.3 nmol) into the ventral septal area (VSA) of the rat brain markedly enhanced the thermoregulatory response to a third or fourth endotoxin challenge compared with saline controls. The effect of the V1 antagonist was dose related. In contrast, an AVP V2 antagonist (0.43 nmol) bilaterally injected into the VSA did not affect the tolerant reaction to endotoxin. Furthermore, neither saline nor the V1 antagonist significantly affected core temperature when administered within the VSA without subsequent endotoxin. These results are consistent with the hypothesis that AVP acts as an endogenous antipyretic within the VSA during fever. Moreover, the data suggest a possible role for centrally acting vasopressin during pyrogenic tolerance to E. coli endotoxin.

Topics: Animals; Arginine Vasopressin; Body Temperature Regulation; Drug Tolerance; Endotoxins; Escherichia coli; Fever; Male; Rats; Rats, Inbred Strains; Septum Pellucidum; Vasopressins

Recent evidence has suggested that the endogenous antipyretic arginine vasopressin (AVP) may participate in drug-induced antipyresis. This study sought to further those investigations by comparing the effects of two other antipyretic drugs, sodium salicylate and acetaminophen, administered intraperitoneally, during AVP V1-receptor blockade within the ventral septal area (VSA) of the rat brain. During endotoxin-evoked fever, V1-receptor blockade within the VSA of the conscious unrestrained rat significantly antagonized the antipyretic effects of salicylate. The effects of the V1-antagonist on salicylate-induced antipyresis were dose related. In contrast, the antipyresis elicited by acetaminophen was unaffected by VSA V1-antagonist pretreatment. Neither saline nor the V1-antagonist microinjected into the VSA of febrile or nonfebrile rats had any significant effects on the normal progression of endotoxin fever or normal core temperature, respectively. These data suggest that the mechanism of action of salicylate-induced antipyresis includes activation of AVP V1-type receptors within the VSA, as has been shown for indomethacin. However, the lack of effect of the V1-antagonist on antipyresis induced by acetaminophen indicates that not all antipyretic drugs act through the same mechanism in the brain.

Topics: Acetaminophen; Animals; Arginine Vasopressin; Brain; Endotoxins; Fever; Male; Rats; Rats, Inbred Strains; Receptors, Angiotensin; Receptors, Vasopressin; Salicylates; Salicylic Acid

Infusion of sodium salicylate (50.0 or 100.0 micrograms/microliters) into the ventral septal area (VSA) of the rat brain suppressed Prostaglandin-E1-induced hyperthermia. Infusion of artificial cerebrospinal fluid (aCSF) or 10.0 micrograms doses of salicylate did not. The suppression of intracerebroventricularly-induced (icv) Prostaglandin E1 (PGE1) hyperthermia was not due to a hypothermic action of salicylate since salicylate infusions given during cold exposure (10.0 degrees C) did not lower core body temperatures. A possible interaction between salicylate and endogenous arginine vasopressin (AVP) was investigated. Infusion of both salicylate (50.0 micrograms/microliters) and either AVP antiserum or AVP antagonist into the VSA resulted in PGE hyperthermias occurring at levels which were not different from control levels as opposed to enhanced hyperthermia (antiserum or antagonist alone) or suppressed hyperthermia (salicylate alone). These results are consistent with the notion that sodium salicylate infusions within the VSA enhance AVP action and thus bring about the attenuation of PGE-induced hyperthermia.

Topics: Alprostadil; Animals; Arginine Vasopressin; Fever; Infusions, Parenteral; Male; Rats; Rats, Inbred Strains; Septum Pellucidum; Sodium Salicylate

Central microinjection or infusion of an arginine vasopressin (AVP) V1-receptor antagonist within the brain of the conscious, unrestrained, and febrile rat inhibited or abolished the antipyretic effects of peripherally administered indomethacin (Indo). The degree of Indo-induced antipyresis was determined by 2-h thermal indexes (degree C.h) calculated from the time of Indo injection. Microinjection of saline or V1-receptor antagonist within the ventral septal area (VSA) of the rat brain immediately followed by intraperitoneal Indo evoked antipyretic responses of -1.63 +/- 0.17 and -0.24 +/- 0.09 degrees C.h, respectively (P less than 0.01). Infusion of the VSA with saline or V1-receptor antagonist before and after Indo resulted in thermal indexes of -1.35 +/- 0.16 and 0.13 +/- 0.30 degree C.h, respectively (P less than 0.01). Central microinjection of a V2-receptor antagonist did not significantly effect Indo-induced antipyresis compared with paired saline controls. Neither saline nor the V1-receptor antagonist affected nonfebrile body temperature when microinjected into the VSA. These data indicate the importance of AVP V1-receptors within the VSA in mediating the potent fever-reducing properties of the antipyretic drug Indo. Furthermore, these data call into question whether prostaglandin synthesis inhibition is a sufficient explanation of drug-induced antipyresis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arginine Vasopressin; Body Temperature; Brain; Fever; Indomethacin; Injections; Male; Rats; Rats, Inbred Strains; Receptors, Angiotensin; Receptors, Vasopressin; Septum Pellucidum; Time Factors

1. Infusion of prostaglandin E1 (PGE1) into a lateral cerebral ventricle of the rat evoked a rise in core temperature which could be attenuated by electrical stimulation of the bed nucleus of the stria terminalis (BST). Electrical stimulation of the BST in the absence of PGE1 did not alter body temperature in the afebrile rat. 2. When the intracerebroventricular (I.C.V.) infusion of PGE1 was preceded by a bilateral injection of saline or vasopressin V2 antagonist d(CH2)5D-ValVAVP into the ventral septal area (VSA), electrical stimulation of the BST suppressed the PGE1 hyperthermia. However, when the vasopressin V1 antagonist d(CH2)5Tyr(Me)AVP was injected into the VSA prior to I.C.V. infusion of PGE1, electrical stimulation of the BST did not alter the hyperthermic response to PGE1. 3. These actions were site specific in that the suppression of PGE1 hyperthermia was observed only when the electrode tips were located in the area of the BST. Similarly, the V1 antagonist only blocked the effect of electrical stimulation when injected into the VSA. 4. When the vasopressin V1 antagonist was injected into the VSA, the PGE1 fever was prolonged when compared to the controls with saline. 5. Injection of saline, vasopressin V1 and V2 antagonist into the VSA, without PGE1 or BST stimulation, did not evoke any significant change in the core temperature of the rats. 6. These data are consistent with the hypothesis that vasopressin may function within the brain as an endogenous antipyretic and that vasopressin may act in a BST-VSA neuronal pathway concerned with endogenous antipyresis.

Topics: Animals; Arginine Vasopressin; Electric Stimulation; Fever; Male; Prostaglandins E; Rats; Rats, Inbred Strains; Thalamus

These experiments sought to determine the role of arginine vasopressin (AVP) in the inability of newborns to produce a fever. Our data demonstrate that the AVP analog, [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid)-2-(O-methyl) tyrosine]arginine vasopressin (M-AVP), administered centrally to adult rats, prevented the antipyretic action of centrally injected AVP. Behaviorally thermoregulating 3-day-old rat pups failed to respond to endoxin with a fever, similar to neonates of other species, but when central AVP antipyretic receptors were blocked by pretreatment with M-AVP, the pups were able to raise their body temperature to febrile levels. The antipyretic drug, indomethacin, prevented these fevers. We conclude that endogenous AVP is a physiologically important antipyretic substance in the brain of the newborn rat.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Arginine Vasopressin; Body Temperature Regulation; Brain; Endotoxins; Fever; Indomethacin; Male; Rats; Rats, Inbred Strains

1. Infusion of human purified interleukin-1 into a lateral cerebral ventricle of the rat evoked a rise in core temperature which was abolished by heating the interleukin-1. 2. When the intracerebroventricular infusion of interleukin-1 was preceded by a bilateral injection of saline into the ventral septal area, the resulting febrile response was not different from that induced by interleukin-1 alone. However, when the vasopressin V1 antagonist, d(CH2)5Tyr(Me)AVP, was injected into the ventral septal area prior to interleukin-1, a fever was evoked which was significantly greater in magnitude and duration. This enhancement of fever by the V1 antagonist was dose related. 3. Injection of either saline or the V1 antagonist into the ventral septal area, in the absence of interleukin-1, did not evoke any consistent alteration in the core temperature of the rats. 4. The vasopressin V2 antagonist, d(CH2)5-D-ValVAVP, was injected into the ventral septal area to determine the effect of another vasopressin analogue on the fever evoked by interleukin-1. The V2 antagonist did not alter the time course of interleukin-1-induced fever or alter core temperature in the afebrile rat. 5. These data are consistent with the hypothesis that endogenous vasopressin, released in the ventral septal area, may be involved in limiting fever. In addition, these results indicate that the central receptor mediating the antipyretic action of vasopressin may resemble the V1 subtype of peripheral vasopressin receptor.

Topics: Animals; Arginine Vasopressin; Body Temperature; Fever; Interleukin-2; Male; Rats; Time Factors; Vasopressins