Biomedical subjects

Luiz G S Branco

Publications and source records attributed to Luiz G S Branco.

At least 19 recordsLinked to original sources

PubMed2006

Neural substrate of cold-seeking behavior in endotoxin shock.

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 microg/kg) caused warmth-seeking behavior, whereas a high, shock-inducing dose (5,000 microg/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.

Animals↗

PubMed2006

Role of the peripheral heme oxygenase-carbon monoxide pathway on the nociceptive response of rats to the formalin test: evidence for a cGMP signaling pathway.

The aim of the present study was to investigate the role of the peripheral heme oxygenase (HO)-carbon monoxide (CO) pathway on nociceptive response of rats to the formalin experimental model of pain. Animals were handled and adapted to the experimental environment for a few days before the formalin test was applied. For the formalin test, 50 microl of a 1% formalin solution was used and injected subcutaneously in the dorsal surface of the right hind paw. Following injections, animals were observed for 1 h, and flinching behavior was measured as the nociceptive response. Twenty minutes before the test rats were pretreated with podal injections with the HO inhibitor, zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) or heme-lysinate, which is known to induce the HO pathway. Control animals were treated with vehicles. We observed a significant increase on nociceptive response of rats treated with ZnDPBG, and a drastic reduction of flinching nociceptive behavioral response in the heme-lysinate and CO treated animals. Among the three different HO products, CO seems to account for the heme-lysinate effect because the injection of the gas attenuated the flinching response whereas biliverdine and deferoxanine (an iron chelator) failed to cause any significant change. Furthermore, CO seems to act via cGMP, since methylene blue (a soluble guanylate cyclase inhibitor) prevented the reduction of the flinching nociceptive behavioral response caused by heme-lysinate. These findings strongly indicate that CO is the HO pathway product that plays an antinociceptive role during the formalin test, acting via cGMP.

Animals↗

PubMed2006

nNOS is involved in behavioral thermoregulation of newborn rats during hypoxia.

The present study was undertaken to investigate the role of nitric oxide (NO) pathway in the behavioral thermoregulation of newborn rats in cold and hypoxia. We predicted that injection of L-NAME (non-selective NO synthase (NOS) inhibitor) and SMTC (neuronal NOS (nNOS) inhibitor) would restore the huddling behavior and eliminate the reduction of Tb caused by hypoxia. Experiments were performed on Wistar rat pups of 7-9 days old. We measured Tb and analyzed the huddling behavior by means of the calculation of the total surface area occupied by 5 pups and the number of single pups grouped in the center of a chamber at 20 degrees C, before and after L-NAME, SMTC or their respective vehicles (D-NAME and saline) s.c. injections. Subsequently, the pups were exposed to hypoxia (10% O(2)) during 30 min, whereas control animals were kept under normoxia. The experiments were monitored by a digital camera. All animals were hypothermic when exposed to 20 degrees C. There was no significant difference in Tb, total area and number of single pups in normoxia after treatments. During hypoxia, the drop in Tb was higher in control groups, and this effect was attenuated by L-NAME and SMTC injections. Hypoxia increased the area occupied by the pups in saline, D-NAME and L-NAME groups, while SMTC attenuated this response. The data indicate that NO pathway is involved in the inhibition of huddling behavior and in the reduction of Tb caused by hypoxia, but plays no role during normoxia. Furthermore, NO seems to arise from the nNOS isoform.

Animals↗

PubMed2006

Role of the locus coeruleus carbon monoxide pathway in endotoxin fever in rats.

Carbon monoxide (CO) has been identified as a diffusible signaling messenger in the brain, capable of altering body temperature by stimulating soluble guanylate cyclase (sGC). However, its site of action remains unclear. Locus coeruleus (LC) is rich not only in sGC but also in heme oxygenase (HO; the enzyme that catalyses the metabolism of heme to CO, along with biliverdin and free iron). Therefore, the possible role of the HO-CO-cGMP pathway in the lipopolysaccharide (LPS)-induced fever regulation by LC neurones was investigated. Induction of the HO pathway using heme-lysinate (7.6 nmol, intra-LC) attenuated the febrile response, and this effect could be prevented by pretreatment with ODQ (an sGC inhibitor; given intracerebroventricularly, 1.3 nmol). Moreover, ZnDPBG (an HO inhibitor; 5 nmol, intra-LC) augmented the febrile response. Taken together, these data suggest that CO in the LC produced by the HO pathway and acting via cGMP plays an antipyretic role during LPS-fever in rats.

Animals↗

PubMed2006

New role of the trigeminal nerve as a neuronal pathway signaling brain in acute periodontitis: participation of local prostaglandins.

The systemic induction of cytokines and prostaglandins plays a key role in the development of fever. However, whether fever is triggered by local injection of lipopolysaccharide (LPS) and the involvement of locally produced prostaglandins in periodontal tissue has never been assessed. Thus, we tested the hypothesis that the trigeminal nerve is a neuronal pathway that signals the brain during acute periodontitis, and this response involves prostaglandin induction. Rats were given a gingival intra-pouch injection of sterile saline or Escherichia coli lipopolysaccharide, at doses of 10 and 100 microg/kg. Some animals were pre-treated with the local anesthetic mepivacaine or had the peripheral branches of the trigeminal nerves transected. Another group of animals were pre-treated (locally or systemically) with the nonselective inhibitor of cyclooxygenases diclofenac. Body core temperature (T (b)) was measured by means of biotelemetry before and after injections. LPS elicited a dose-dependent increase in T (b), which was abolished by mepivacaine, bilateral transection of the peripheral branches of the trigeminal nerve, or local treatment with diclofenac. The results indicate that there is an activation of periodontal nerves to induce fever by LPS. It also shows that local formation of prostaglandins plays a role in fever development. Moreover, immunohistochemistry detected c-fos expression in the subnucleus caudalis of spinal trigeminal nucleus and in the preoptic area of the hypothalamus 2 and 3 h after LPS injection, further confirming the role of trigeminal nerve signaling brain in acute periodontitis.

Animals↗

PubMed2006

Central heme oxygenase-carbon monoxide pathway participates in the lipopolysaccharide-induced tolerance in rats.

Recently, heme oxygenase-carbon monoxide (HO-CO) pathway has been reported to be involved in the development of lipopolysaccharide (LPS) fever. However, no information exists about its participation in LPS tolerance, which is defined by an attenuation of the febrile response to repeated administrations of LPS. Thus, we tested the hypothesis that HO-CO pathway plays a role in endotoxin tolerance, which was induced by means of three consecutive LPS intraperitoneal injections (i.p.) at 24-h intervals. Body temperature (Tb) was measured by biotelemetry. Induction of the HO pathway using intracerebroventricular (i.c.v.) heme lysinate reversed tolerance, and this effect could be prevented by pretreatment with ODQ [a soluble guanylate cyclase (sGC) inhibitor; i.c.v.]. These results indicate that HO-CO pathway seems to be down-regulated during LPS tolerance, and that CO is the HO product that can prevent LPS tolerance, acting via cGMP. In further support, either biliverdine or iron (the others HO products; i.c.v.) had no effect in LPS-induced tolerance.

Animals↗

PubMed2006

Physiology of temperature regulation: comparative aspects.

Few environmental factors have a larger influence on animal energetics than temperature, a fact that makes thermoregulation a very important process for survival. In general, endothermic species, i.e., mammals and birds, maintain a constant body temperature (Tb) in fluctuating environmental temperatures using autonomic and behavioural mechanisms. Most of the knowledge on thermoregulatory physiology has emerged from studies using mammalian species, particularly rats. However, studies with all vertebrate groups are essential for a more complete understanding of the mechanisms involved in the regulation of Tb. Ectothermic vertebrates-fish, amphibians and reptiles-thermoregulate essentially by behavioural mechanisms. With few exceptions, both endotherms and ectotherms develop fever (a regulated increase in Tb) in response to exogenous pyrogens, and regulated hypothermia (anapyrexia) in response to hypoxia. This review focuses on the mechanisms, particularly neuromediators and regions in the central nervous system, involved in thermoregulation in vertebrates, in conditions of euthermia, fever and anapyrexia.

Animals↗

PubMed2006

Locus coeruleus is a central chemoreceptive site in toads.

The locus coeruleus (LC) has been suggested as a CO2 chemoreceptor site in mammals. This nucleus is a mesencephalic structure of the amphibian brain and is probably homologous to the LC in mammals. There are no data available for the role of LC in the central chemoreception of amphibians. Thus the present study was designed to investigate whether LC of toads (Bufo schneideri) is a CO2/H+ chemoreceptor site. Fos immunoreactivity was used to verify whether the nucleus is activated by hypercarbia (5% CO2 in air). In addition, we assessed the role of noradrenergic LC neurons on respiratory and cardiovascular responses to hypercarbia by using 6-hydroxydopamine lesion. To further explore the role of LC in central chemosensitivity, we examined the effects of microinjection of solutions with different pH values (7.2, 7.4, 7.6, 7.8, and 8.0) into the nucleus. Our main findings were that 1) a marked increase in c-fos-positive cells in the LC was induced after 3 h of breathing a hypercarbic gas mixture; 2) chemical lesions in the LC attenuated the increase of the ventilatory response to hypercarbia but did not affect ventilation under resting conditions; and 3) microinjection with acid solutions (pH = 7.2, 7.4, and 7.6) into the LC elicited an increased ventilation, indicating that the LC of toads participates in the central chemoreception.

Acids↗

PubMed2006

Cold-seeking behavior as a thermoregulatory strategy in systemic inflammation.

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.

Animals↗

PubMed2005

Respiratory and body temperature modulation by adenosine A1 receptors in the anteroventral preoptic region during normoxia and hypoxia.

The present study was undertaken to investigate adenosine as a simultaneous mediator of hypoxia-induced hyperventilation and regulated hypothermia in the anteroventral preoptic region (AVPO), the thermointegrative region of the central nervous system (CNS). Accordingly, we predicted that injection of aminophylline and DPCPX, non-selective and A(1) receptor antagonists, respectively, into the AVPO would exacerbate the ventilatory response and lessen the drop in body temperature (T(b)) caused by hypoxia. We measured ventilation (V ) and T(b) of conscious Wistar rats before and after AVPO injection of aminophylline (1 and 10 microg/100 nL) or DPCPX (17.5 and 175 ng/100 nL), or their respective vehicles, followed by 30 min of hypoxia (7% O(2)). Vehicles and the lower doses of both antagonists had no effect on V and T(b) during normoxia or hypoxia. The higher doses of aminophylline and DPCPX increased (P<0.05) the hypoxia-induced hyperventilation, whereas the drop in T(b) elicited by hypoxia was attenuated (P<00.05) by DPCPX only. This higher DPCPX dose also increased T(b) during normoxia. The present data is consistent with the notion that adenosine plays an inhibitory role in respiratory and metabolic regulation, in a way that A(1) receptors stimulation in the AVPO inhibits ventilatory drive during hypoxia and tonically modulates basal T(b).

Adaptation, Physiological↗

PubMed2005

Serotoninergic receptors in the anteroventral preoptic region modulate the hypoxic ventilatory response.

Hypothalamus is a site of integration of the hypoxic and thermal stimuli on breathing and there is evidence that serotonin (5-HT) receptors in the anteroventral preoptic region (AVPO) mediate hypoxic hypothermia. Once 5-HT is involved in the hypoxic ventilatory response (HVR), we investigated the participation of the 5-HT receptors (5-HT1, 5-HT2 and 5-HT7) in the AVPO in the HVR. To this end, pulmonary ventilation (V(E)) of rats was measured before and after intra-AVPO microinjection of methysergide (a 5-HT1 and 5-HT2 receptor antagonist), WAY-100635 (a 5-HT1A receptor antagonist) and SB-269970 (a 5-HT7 receptor antagonist), followed by 60 min of hypoxia exposure (7% O2). Intra-AVPO microinjection of vehicles or 5-HT antagonists did not change V(E) during normoxic conditions. Exposure of rats to 7% O2 evoked typical hypoxia-induced hyperpnea after vehicle microinjection, which was not affected by methysergide. WAY-100635 and SB-269970 treatment caused an increased HVR, due to a higher tidal volume. Therefore, the current data provide the evidence that 5-HT acting on 5-HT1A and 5-HT7 receptors in the AVPO exert an inhibitory modulation on the HVR.

Analysis of Variance↗

PubMed2005

Vasopressin release during endotoxaemic shock in mice lacking inducible nitric oxide synthase.

We tested the hypothesis that nitric oxide (NO) arising from the action of inducible nitric oxide synthase (iNOS) is responsible for the deficiency in vasopressin (AVP) release and consequent hypotension during endotoxaemic shock. Wild-type (WT) and iNOS knockout mice (iNOS(-/-)) were given either saline or Escherichia coli lipopolysaccharide (LPS, 1.0 mg/kg i.v., final volume 0.03 ml). Mean arterial blood pressure (MAP) was measured and plasma AVP levels determined before and after LPS or saline injection. In WT mice, MAP was significantly lower 2 h after LPS administration and remained low for the remainder of the 6-h observation period. AVP plasma levels were increased at the 2nd and 4th h of the experiment, returning thereafter to basal levels. Conversely, LPS injection in iNOS iNOS(-/-) mice elicited a sustained increase in plasma AVP concentration and attenuated the fall in blood pressure. These data indicate that NO arising from the iNOS plays an important inhibitory role in AVP release during endotoxaemia and may be responsible for the hypotension occurring during this vasodilatory shock.

Animals↗

PubMed2005

Glutamatergic receptors of the rostral ventrolateral medulla are involved in the ventilatory response to hypoxia.

Rostral ventrolateral medulla (RVLM) is a region in the brainstem that is involved in the physiologic responses to hypoxia (i.e. hyperventilation and regulated hypothermia) and contains l-glutamate receptors. Therefore, we examined the effects of blocked of glutamatergic receptors in the RVLM on hypoxic hyperventilation and regulated hypothermia. Ventilation (V(E)) and body temperature (T(b)) were measured before and after bilaterally microinjection of kynurenic acid (KYN, 5 nmol/100 nl, an ionotropic glutamatergic receptors antagonist) and alpha-methyl-4-carboxyphenylglycine (MCPG, 10 nmol/100 nl, a metabotropic glutamatergic receptors antagonist) into the RVLM, followed by a 60-min period of hypoxia exposure. Control rats received microinjection of saline (vehicle). KYN or MCPG into the RVLM did not change V(E) and T(b) under normoxia, but reduced the hypoxic hyperventilation due to a lower tidal volume, although regulated hypothermia persisted. These data suggest that glutamatergic receptors in the RVLM are involved in the ventilatory response to hypoxia, exercising an excitatory modulation of the RVLM neurons, but play no role in hypoxia-induced hypothermia.

Animals↗

PubMed2005

Involvement of serotoninergic receptors in the anteroventral preoptic region on hypoxia-induced hypothermia.

Hypoxia causes a regulated decrease in body temperature (Tb). There is circumstantial evidence that the neurotransmitter serotonin (5-HT) in the anteroventral preoptic region (AVPO) mediates this response. However, which 5-HT receptor(s) is (are) involved in this response has not been assessed. Thus, we investigated the participation of the 5-HT receptors (5-HT1, 5-HT2, and 5-HT7) in the AVPO in hypoxic hypothermia. To this end, Tb of conscious Wistar rats was monitored by biotelemetry before and after intra-AVPO microinjection of methysergide (a 5-HT1 and 5-HT2 receptor antagonist, 0.2 and 2 microg/100 nL), WAY-100635 (a 5-HT(1A) receptor antagonist, 0.3 and 3 microg/100 nL), and SB-269970 (a 5-HT7 receptor antagonist, 0.4 and 4 micro/100 nL), followed by 60 min of hypoxia exposure (7% O2). During the experiments, the mean chamber temperature was 24.6 +/- 0.7 degrees C (mean +/- SE) and the mean room temperature was 23.5 +/- 0.8 degrees C (mean +/- SE). Intra-AVPO microinjection of vehicle or 5-HT antagonists did not change Tb during normoxic conditions. Exposure of rats to 7% of inspired oxygen evoked typical hypoxia-induced hypothermia after vehicle microinjection, which was not affected by both doses of methysergide. However, WAY-100635 and SB-269970 treatment attenuated the drop in Tb in response to hypoxia. The effect was more pronounced with the 5-HT7 antagonist since both doses (0.4 and 4 microg/0.1 microL) were capable of attenuating the hypothermic response. As to the 5-HT(1A) antagonist, the attenuation of hypoxia-induced hypothermia was only observed at the higher dose. Therefore, the present results are consistent with the notion that 5-HT acts on both 5-HT(1A) and 5-HT7 receptors in the AVPO to induce hypothermia, during hypoxia.

Animals↗

PubMed2004

Evidence for thermoregulation by dopamine D1 and D2 receptors in the anteroventral preoptic region during normoxia and hypoxia.

Hypoxia causes a regulated decrease in body temperature (Tb), a response that has been called anapyrexia. Stimulation of dopamine receptors in the central nervous system (CNS) reduces Tb in rats, and dopamine D1 and D2 receptors seem to be involved in this response. Thus, we predicted that injection of SCH 23390 and haloperidol, D1 and partly D2 receptor antagonists, respectively, into the anteroventral preoptic region (AVPO, the thermointegrative region of the CNS) would lessen the hypoxia-induced anapyrexia. We measured Tb of conscious Wistar rats before and after injection of SCH 23390 (50 and 100 ng/100 nl) or haloperidol (50 e 500 ng/100 nl) or their respective vehicles (saline and DMSO 5%) into the AVPO followed by 30 min of hypoxia (7% O2). Vehicles and the lower doses of SCH 23390 and haloperidol had no effect on Tb during normoxia or hypoxia. The higher doses of SCH 23390 and haloperidol attenuated (P<0.05) the drop in Tb elicited by hypoxia. However, this higher haloperidol dose also increased Tb during normoxia. The present data is consistent with the notion that dopamine is an important thermoregulatory neurotransmitter in a way that D2 receptors are mainly involved with maintenance of Tb in euthermia, while D1 receptors are activated to induce hypoxic anapyrexia in the AVPO.

Analysis of Variance↗

PubMed2004

Role of nitric oxide in tolerance to lipopolysaccharide in mice.

The injection of repeated doses of lipopolysaccharide (LPS) results in attenuation of the febrile response, which is called endotoxin tolerance. We tested the hypothesis that nitric oxide (NO) arising from inducible NO synthase (iNOS) plays a role in endotoxin tolerance, using not only pharmacological trials but also genetically engineered mice. Body core temperature was measured by biotelemetry in mice treated with NG-monomethyl-L-arginine (L-NMMA, 40 mg/kg; a nonselective NO synthase inhibitor) or aminoguanidine (AG, 10 mg/kg; a selective iNOS inhibitor) and in mice deficient in the iNOS gene (iNOS KO) mice. Tolerance to LPS was induced by means of three consecutive LPS (100 microg/kg) intraperitoneal injections at 24-h intervals. In wild-type mice, we observed a significant reduction of the febrile response to repeated administration of LPS. Injection of L-NMMA and AG markedly enhanced the febrile response to LPS in tolerant animals. Conversely, iNOS-KO mice repeatedly injected with LPS did not become tolerant to the pyrogenic effect of LPS. These data are consistent with the notion that NO modulates LPS tolerance in mice and that iNOS isoform is involved in NO synthesis during LPS tolerance.

Adaptation, Physiological↗

PubMed2004

Nucleus isthmi and control of breathing in amphibians.

Despite recent advances, the mechanisms of neurorespiratory control in amphibians are far from understood. One of the brainstem structures believed to play a key role in the ventilatory control of anuran amphibians is the nucleus isthmi (NI). This nucleus is a mesencephalic structure located between the roof of the midbrain and the cerebellum, which differentiates during metamorphosis; the period when pulmonary ventilation develops in bullfrogs. It has been recently suggested that the NI acts to inhibit hypoxic and hypercarbic drives in breathing by restricting increases in tidal volume. This data is similar to the influence of two pontine structures of mammals, the locus coeruleus and the nucleus raphe magnus. The putative mediators for this response are glutamate and nitric oxide. Microinjection of kynurenic acid (an ionotropic receptor antagonist of excitatory amino acids) and l-NAME (a non-selective NO synthase inhibitor) elicited increases in the ventilatory response to hypoxia and hypercarbia. This article reviews the available data on the role of the NI in the control of ventilation in amphibians.

Amphibians↗

PubMed2004

Nitric oxide pathway in the nucleus raphe magnus modulates hypoxic ventilatory response but not anapyrexia in rats.

Nucleus raphe magnus (NRM) is one of the cellular groups of the brainstem that is involved in the physiologic responses to hypoxia and contains nitric oxide (NO) synthase. In the present study, we assessed the role of NO pathway in the NRM on the hypoxic ventilatory response (HVR) and anapyrexia (a regulated decrease in body temperature). To this end, pulmonary ventilation (VE) and body temperature (Tb) of male Wistar rats were measured before and after microinjection of N-monomethyl-L-arginine (L-NMMA, a nonselective nitric oxide synthase inhibitor, 12.5 microg/0.1 microl) into the NRM, followed by hypoxia. Control rats received microinjection of saline. Under resting conditions, L-NMMA treatment did not affect pulmonary VE or Tb. Typical hypoxia-induced hyperventilation and anapyrexia were observed after saline treatment. L-NMMA into the NRM reduced the HVR but did not affect hypoxia-induced anapyrexia. In conclusion, the present study indicates that NO in the NRM is involved in HVR, exerts an inhibitory modulation on the NRM neurons but does not mediate hypoxia-induced anapyrexia.

Animals↗