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Zena L.A.,São Paulo State University | Zena L.A.,Wright State University | Zena L.A.,National Institute of Science and Technology in Comparative Physiology INCT Fisiologia Comparada | Fonseca E.M.,São Paulo State University | And 11 more authors.
Journal of Experimental Biology | Year: 2016

Savannah monitor lizards (Varanus exanthematicus) are unusual among ectothermic vertebrates in maintaining arterial pH nearly constant during changes in body temperature in contrast to the typical stat regulating strategy of most other ectotherms. Given the importance of pH in the control of ventilation, we examined the CO2/H+ sensitivity of neurons from the locus coeruleus (LC) region of monitor lizard brainstems.Whole-cell patch-clamp electrophysiology was used to recordmembrane voltage in LCneurons in brainstemslices. Artificial cerebral spinal fluid equilibrated with80%O2, 0.0-10.0%CO2, balance N2, was superfused across brainstem slices. Changes in firing rate of LCneuronswere calculated fromaction potential recordings to quantify the chemosensitive response to hypercapnic acidosis. Our results demonstrate that the LC brainstem region contains neurons that can be excited or inhibited by, and/or are not sensitive to CO2 in V. exanthematicus. While few LC neurons were activated by hypercapnic acidosis (15%), a higher proportion of the LC neurons responded by decreasing their firing rate during exposure to high CO2 at 20C (37%); this chemosensitive response was no longer exhibited when the temperaturewas increased to 30C. Further, the proportion of chemosensitive LC neurons changed at 35C with a reduction in CO2-inhibited (11%) neurons and an increase in CO2-activated (35%) neurons. Expressing a high proportion of inhibited neurons at low temperature may provide insights into mechanisms underlying the temperature-dependent pH-stat regulatory strategy of savannah monitor lizards. © 2016. Published by The Company of Biologists Ltd.


Biancardi V.,São Paulo State University | Biancardi V.,National Institute of Science and Technology in Comparative Physiology INCT Fisiologia Comparada | Bicego K.C.,São Paulo State University | Bicego K.C.,National Institute of Science and Technology in Comparative Physiology INCT Fisiologia Comparada | And 2 more authors.
Experimental Physiology | Year: 2014

Locus coeruleus (LC) noradrenergic neurons are chemosensitive to CO2 and pH in mammals and amphibians and are involved in the CO2-related drive to breathe. Purinergic neuromodulation in the LC is of particular interest because ATP acts as a neuromodulator in brainstem regions involved in cardiovascular and respiratory regulation, such as the LC. ATP acting on LC P2 receptors influences the release of noradrenaline. Thus, the goal of the present study was to investigate the role of LC purinergic neuromodulation of ventilatory and cardiovascular responses in normocapnic and hypercapnic conditions in unanaesthetized male Wistar rats. We assessed the purinergic modulation of cardiorespiratory systems by microinjecting an ATP P2X receptor agonist [α,β-methylene ATP (α,β-meATP), 0.5 or 1 nmol in 40 nl] and two non-selective P2 receptor antagonists [pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), 0.5 or 1 nmol in 40 nl; and suramin, 1 nmol in 40 nl] into the LC. Pulmonary ventilation (measured by plethysmography), mean arterial pressure (MAP) and heart rate (HR) were determined before and after unilateral microinjection (40 nl) of α,β-meATP, PPADS, suramin or 0.9% saline (vehicle) into the LC. These measurements were made during a 60 min exposure to normocapnic conditions or a 30 min exposure to 7% CO2. Subsequently, animals undergoing pharmacological treatment were subjected to a 30 min exposure to normocapnic conditions as a recovery period. In normocapnic conditions, α,β-meATP did not affect any parameter, whereas PPADS decreased respiratory frequency and increased MAP and HR. Suramin increased MAP and HR but did not change ventilation. Moreover, hypercapnic conditions induced an increase in ventilation and a decrease in HR in all groups. In hypercapnic conditions, α,β-meATP increased ventilation but did not change cardiovascular parameters, whereas PPADS increased MAP but did not alter ventilation, and suramin increased both ventilation and MAP. Thus, our data suggest that purinergic signalling, specifically through P2 receptors, in the LC plays an important role in cardiorespiratory control in normocapnic and hypercapnic conditions in unanaesthetized rats. © 2013 The Authors.


Incheglu J.M.,São Paulo State University | Incheglu J.M.,National Institute of Science and Technology in Comparative Physiology INCT Fisiologia Comparada | Bicego K.C.,São Paulo State University | Bicego K.C.,National Institute of Science and Technology in Comparative Physiology INCT Fisiologia Comparada | And 2 more authors.
Respiratory Physiology and Neurobiology | Year: 2016

The locus coeruleus (LC) is a pontine noradrenergic nucleus that acts as a central chemoreceptor to CO2/pH and has been implicated in the cognitive aspects of stress responses. This participation is in part mediated by the action of corticotropin-releasing factor (CRF), which when released in these situations increases the firing frequency of LC noradrenergic neurons. Nevertheless, the role of CRF1 receptors in the LC in breathing and temperature control is unknown. Therefore, we tested the involvement of CRF1 receptors located in the LC in room air ventilation and the ventilatory response induced by hypercapnia (7% CO2) in rats. To this end, we injected CRF-R1-selective antagonists (antalarmin-1.2 and 2.4 mmol/0.1 μL or CP-376395-5 nmol/0.1 μL) into the LC of male Wistar rats. Pulmonary ventilation (VE) and body temperature (Tb, dataloggers) were measured in air, followed by 7% CO2 in unanesthetized rats. Antalarmin (higher dose) and CP-376395 in the LC caused an increase in VE during normocapnia and hypercapnia, due to an increase in tidal volume. There were no differences in Tb between groups under normocapnia and hypercapnia. The results suggest that CRF acting on CRF1 receptors in the LC exerts a tonic inhibitory role in ventilation. © 2016 Elsevier B.V.


Vizin R.C.L.,Federal University of ABC | Scarpellini C.S.,São Paulo State University | Scarpellini C.S.,National Institute of Science and Technology in Comparative Physiology INCT Fisiologia Comparada | Ishikawa D.T.,Federal University of ABC | And 9 more authors.
Acta Physiologica | Year: 2015

Aim: In this study, we aimed at investigating the involvement of the warmth-sensitive channel - TRPV4 (in vitro sensitive to temperatures in the range of approx. 24-34 °C) - on the thermoregulatory mechanisms in rats. Methods: We treated rats with a chemical selective agonist (RN-1747) and two antagonists (RN-1734 and HC-067047) of the TRPV4 channel and measured core body temperature, metabolism, heat loss index and preferred ambient temperature. Results: Our data revealed that chemical activation of TRPV4 channels by topical application of RN-1747 on the skin leads to hypothermia and this effect was blocked by the pre-treatment with the selective antagonist of this channel. Intracerebroventricular treatment with RN-1747 did not cause hypothermia, indicating that the observed response was indeed due to activation of TRPV4 channels in the periphery. Intravenous blockade of this channel with HC-067047 caused an increase in core body temperature at ambient temperature of 26 and 30 °C, but not at 22 and 32 °C. At 26 °C, HC-067047-induced hyperthermia was accompanied by increase in oxygen consumption (an index of thermogenesis), while chemical stimulation of TRPV4 increased tail heat loss, indicating that these two autonomic thermoeffectors in the rat are modulated through TRPV4 channels. Furthermore, rats chemically stimulated with TRPV4 agonist choose colder ambient temperatures and cold-seeking behaviour after thermal stimulation (28-31 °C) was inhibited by TRPV4 antagonist. Conclusion: Our results suggest, for the first time, that TRPV4 channel is involved in the recruitment of behavioural and autonomic warmth-defence responses to regulate core body temperature. © 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

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