No abstract

Systemic inflammation (SI) is a leading cause of hospital death. Although fever and hypothermia are listed as symptoms in every definition of SI, how SI affects thermoregulatory behavior is unclear. SI is often modeled by systemic administration of bacterial lipopolysaccharide (LPS) to rats. When rats are not allowed to regulate their body temperature (Tb) behaviorally, LPS causes either fever or hypothermia, and the direction of the response is determined by LPS dose and ambient temperature (Ta). However, in many studies in which rats were allowed to regulate Tb behaviorally (by selecting their preferred Ta in a thermogradient apparatus), they consistently expressed warmth-seeking behavior and developed fever. We hypothesized that SI can cause not only warmth-seeking behavior but also cold-seeking behavior; we then tested this hypothesis by studying LPS-induced thermoregulatory behavior in adult Wistar rats. A multichannel thermogradient apparatus, implantable data loggers and infrared thermography were used; multiple control experiments were conducted; and the ability of the apparatus to reliably register the changes in rats' preferred Ta induced by thermal (external cooling or heating) or chemical (TRPV1 or TRPM8 agonist) stimuli was confirmed. The rats responded to a low dose of LPS (10 microg/kg i.v.) with warmth-seeking behavior and a polyphasic fever, but to a high dose (5 mg/kg i.v.) with marked cold-seeking behavior and hypothermia followed by warmth-seeking behavior and fever. This is the first well-controlled study to report SI-associated cold-seeking behavior in rats. Cold-seeking behavior is likely to be an important defense response in severe SI.

Hypoxia elicits an array of compensatory responses in animals ranging from protozoa to mammals. Central among these responses is anapyrexia, the regulated decrease of body temperature. The importance of anapyrexia lies in the fact that it reduces oxygen consumption, increases the affinity of hemoglobin for oxygen, and blunts the energetically costly responses to hypoxia. The mechanisms of anapyrexia are of intense interest to physiologists. Several substances, among them lactate, adenosine, opioids, and nitric oxide, have been suggested as putative mediators of anapyrexia, and most appear to act in the central nervous system. Moreover, there is evidence that the drop in body temperature in response to hypoxia, unlike the ventilatory response to hypoxia, does not depend on the activation of peripheral chemoreceptors. The current knowledge of the mechanisms of hypoxia-induced anapyrexia are reviewed.

Systemic inflammation is a leading cause of hospital death. Mild systemic inflammation is accompanied by warmth-seeking behavior (and fever), whereas severe inflammation is associated with cold-seeking behavior (and hypothermia). Both behaviors are adaptive. Which brain structures mediate which behavior is unknown. The involvement of hypothalamic structures, namely, the preoptic area (POA), paraventricular nucleus (PVH), or dorsomedial nucleus (DMH), in thermoregulatory behaviors associated with endotoxin (lipopolysaccharide [LPS])-induced systemic inflammation was studied in rats. The rats were allowed to select their thermal environment by freely moving in a thermogradient apparatus. A low intravenous dose of Escherichia coli LPS (10 µg/kg) caused warmth-seeking behavior, whereas a high, shock-inducing dose (5,000 µg/kg) caused cold-seeking behavior. Bilateral electrocoagulation of the PVH or DMH, but not of the POA, prevented this cold-seeking response. Lesioning the DMH with ibotenic acid, an excitotoxin that destroys neuronal bodies but spares fibers of passage, also prevented LPS-induced cold-seeking behavior; lesioning the PVH with ibotenate did not affect it. Lesion of no structure affected cold-seeking behavior induced by heat exposure or by pharmacological stimulation of the transient receptor potential (TRP) vanilloid-1 channel (“warmth receptor”). Nor did any lesion affect warmth-seeking behavior induced by a low dose of LPS, cold exposure, or pharmacological stimulation of the TRP melastatin-8 (“cold receptor”). We conclude that LPS-induced cold-seeking response is mediated by neuronal bodies located in the DMH and neural fibers passing through the PVH. These are the first two landmarks on the map of the circuitry of cold-seeking behavior associated with endotoxin shock.

Our hypothesis is that oxytocin (OT) causes natriuresis by activation of renal NO synthase that releases NO followed by cGMP that mediates the natriuresis. To test this hypothesis, an inhibitor of NO synthase, L-nitroarginine methyl ester (NAME), was injected into male rats. Blockade of NO release by NAME had no effect on natriuresis induced by atrial natriuretic peptide (ANP). This natriuresis presumably is caused by cGMP because ANP also activates guanylyl cyclase, which synthesizes cGMP from GTP. The 18-fold increase in sodium (Na ؉ ) excretion induced by OT (1 g) was accompanied by an increase in urinary cGMP and preceded by 20 min a 20-fold increase in NO 3 ؊ excretion. NAME almost completely inhibited OT-induced natriuresis and increased NO 3 ؊ excretion; however, when the dose of OT was increased 10-fold, a dose that markedly increases plasma ANP concentrations, NAME only partly inhibited the natriuresis. We conclude that the natriuretic action of OT is caused by a dual action: generation of NO leading to increased cGMP and at higher doses release of ANP that also releases cGMP. OT-induced natriuresis is caused mainly by decreased tubular Na ؉ reabsorption mediated by cGMP. In contrast to ANP that releases cGMP in the renal vessels and the tubules, OT acts on its receptors on NOergic cells demonstrated in the macula densa and proximal tubules to release cGMP that closes Na ؉ channels. Both ANP-and OT-induced kaliuresis also appear to be mediated by cGMP. We conclude that cGMP mediates natriuresis and kaliuresis induced by both ANP and OT.Atrial natriuretic peptide (ANP) and oxytocin (OT) are natriuretic hormones that play a fundamental role in the regulation of extracellular fluid volume. The natriuretic action of ANP has been explained by its combination with ANP A receptors on kidney cells that convert GTP into cGMP by activating particulate guanylate cyclase (GC). This form of GC (GC A ) is the cell surface receptor for ANP (1). In contrast, OT is a potent natriuretic peptide and OT receptors occur in the kidney, but the mechanism of OT-induced natriuresis is not clearly understood (2-7).The release of ANP that follows blood volume expansion is partly mediated by renal and arterial baroreceptor input to the brain stem that stimulates OT release from the neurohypophysis. Circulating OT binds to its receptors in the right atrium and stimulates ANP release from atrial myocytes (8,9). Because the injection of OT evoked concomitant release of ANP and natriuresis (10), the natriuretic action of OT might be mediated by the release of ANP that activates renal GC A receptors localized in glomeruli, their afferent and efferent arterioles, and the tubules (11). ANP selectively dilates preglomerular vessels and constricts efferent arterioles, thereby increasing the filtration fraction (FF). If the glomerular filtration rate (GFR) and tubular reabsorption of sodium (Na ϩ ) remain constant, this increase in FF would provide an increased filtered load (FL) of Na ϩ , resulting in natriuresis (12).In addition t...