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Role of TRPV1 in thermoregulation
Abstracts / Autonomic Neuroscience: Basic and Clinical 192 (2015) 1–55
067047 increases core body temperature, which, at 26 °C of ambient temperature, is accompanied by increase in oxygen consumption (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) is inhibited by TRPV4 antagonist. These results suggest that TRPV4 channel is involved in the recruitment of behavioural and autonomic warmthdefense responses in order to regulate core body temperature. Financial Support: Fapesp and CNPq.
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effects of CIH/H, we selectively expressed excitatory DREADDs in PVN OXT neurons, and implanted animals with telemetry devices to monitor blood pressure (BP) and EKG activity. Selective chronic activation of PVN OXT neurons decreased resting BP and HR, and more importantly chronic PVN OXT neuron activation prevented the elevations in BP and HR that with CIH/H. These results indicate excitation of parvocellular PVN fibers releases OXT at brainstem CVN targets, decreases resting BP and HR, and prevent the elevations in BP and HR that occur after 21 days of CIH/H. doi:10.1016/j.autneu.2015.07.418
doi:10.1016/j.autneu.2015.07.416 32.2 What roles do afferents play in efferent vagal autonomic regulation? 31.4 Role of TRPV1 in thermoregulation A. Gomtsyan Global Pharmaceutical Research and Development, Abbvie Inc., USA Transient receptor potential vanilloid-1 (TRPV1) is the founding member of larger family of TRP ion channels. As a molecular integrator of multiple physical and chemical stimuli, TRPV1 plays important role in numerous biological processes including thermoregulation. In fact, involvement of TRPV1 in thermoregulation and thermosensation is so prominent that it is hindering a development of safe drugs targeting other functions of TRPV1 such as emergence and the maintenance of pain. This presentation will review our current understanding of thermoregulatory function of TRPV1 based on mechanistic studies conducted by using pharmacological and genetic tools. doi:10.1016/j.autneu.2015.07.417
Symposium 32: Mechanisms For Restoring Autonomic Sympathetic/Parasympathetic Balance: Can It Be Beneficial In Gastrointestinal And Cardiovascular Diseases?
M.C. Andresen Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR USA A common feature across parasympathetic regulation of visceral organs like the heart is the presence of full reflex pathways with as few as two central neurons. Neurons of the solitary tract nucleus (NTS) receive directly synaptic terminals from primary viscerosensory afferents and these afferents belong to two broad phenotypic classes – neurons with either myelinated or unmyelinated axons. Although these sensory terminals all release glutamate as their primary transmitter, the release of glutamate is highly regulated by presynaptic mechanisms. For example, the neuropeptides vasopressin and oxytocin that are synthesized in the hypothalamus oppositely regulated glutamate release at NTS second order neurons. The segregation of viscerosensory phenotype is absolute for aortic baroreceptors and likely other viscerosensory afferents – myelinated afferents contact different neurons than do unmyelinated afferents. The ramifications of the segregation of afferent inputs to second, higher order, and projection neurons will be discussed as well as the presence of a separate pool of glutamate vesicles devoted to calcium entry associated with Transient Receptor Potential Vanilloid Type 1 receptors as a new form of tonic “afferent” presence driving brainstem circuits.
doi:10.1016/j.autneu.2015.07.419 32.1 Can oxytocin increase parasympathetic activity to the heart and treat cardiovascular diseases? H. Jameson, E. Cauley, D. Mendelowitz Department of Pharmacology and Physiology, George Washington University, Washington, DC, USA New promising work has indicated oxytocin (OXT) receptor activation is blunted in cardiovascular diseases (CVDs) and OXT receptor activation may be a novel target to increase parasympathetic activity to the heart and treat cardiac autonomic imbalance. This study tests the hypotheses that the release of OXT from hypothalamic paraventricular (PVN) neurons onto cardiac vagal neurons (CVNs) is diminished with chronic intermittent hypoxia-hypercapnia (CIH/H), an animal model of Obstructive Sleep Apnea (OSA) and furthermore that selective activation of PVN OXT neurons can reduce adverse cardiovascular consequences that occur with CIH/H. Optogenetic stimulation of channelrhodopsin expressing PVN fibers evoked large transient increases in Ca2+ in CHO cells stably transfected to express the human recombinant OXT receptor and the red fluorescent calcium indicator, R-GECO1, dispersed adjacent to CVNs. The release of OXT onto CVNs upon photoactivation of PVN fibers was blunted in animals exposed to 21 days of CIH/H. To examine if restoration of OXT neuron activity can prevent the in vivo cardiovascular
32.3 What is responsible for the elevated hypothalamic drive to sympathetic neurons in cardiovascular diseases? J.E. Stern Department of Physiology, Medical College of Georgia, GA Regents University, USA Accumulating evidence supports altered hypothalamic neuronal activity as a major factor contributing to increased sympathetic drive in major cardiovascular diseases, including hypertension and heart failure. Numerous precise underlying mechanisms have been distinctly proposed to contribute to hypothalamic-driven sympathetic activity. These include, among others, enhanced excitatory (glutamate, angiotensin II) and blunted inhibitory (GABA, nitric oxide) synaptic mechanisms, altered intrinsic ion channel function, as well as a pro-inflammatory glia microenvironment (gliosis, microglia cell activation). However, to what extent these seemingly disparate mechanisms are causally and functionally interrelated remains at present unknown. I will present a set of recent studies from our group in which we present a mechanistic functional link between Angiotensin II, glutamate and the potassium channel IA in the regulation of sympathetic-related neuronal activity in
067047 increases core body temperature, which, at 26 °C of ambient temperature, is accompanied by increase in oxygen consumption (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) is inhibited by TRPV4 antagonist. These results suggest that TRPV4 channel is involved in the recruitment of behavioural and autonomic warmthdefense responses in order to regulate core body temperature. Financial Support: Fapesp and CNPq.
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effects of CIH/H, we selectively expressed excitatory DREADDs in PVN OXT neurons, and implanted animals with telemetry devices to monitor blood pressure (BP) and EKG activity. Selective chronic activation of PVN OXT neurons decreased resting BP and HR, and more importantly chronic PVN OXT neuron activation prevented the elevations in BP and HR that with CIH/H. These results indicate excitation of parvocellular PVN fibers releases OXT at brainstem CVN targets, decreases resting BP and HR, and prevent the elevations in BP and HR that occur after 21 days of CIH/H. doi:10.1016/j.autneu.2015.07.418
doi:10.1016/j.autneu.2015.07.416 32.2 What roles do afferents play in efferent vagal autonomic regulation? 31.4 Role of TRPV1 in thermoregulation A. Gomtsyan Global Pharmaceutical Research and Development, Abbvie Inc., USA Transient receptor potential vanilloid-1 (TRPV1) is the founding member of larger family of TRP ion channels. As a molecular integrator of multiple physical and chemical stimuli, TRPV1 plays important role in numerous biological processes including thermoregulation. In fact, involvement of TRPV1 in thermoregulation and thermosensation is so prominent that it is hindering a development of safe drugs targeting other functions of TRPV1 such as emergence and the maintenance of pain. This presentation will review our current understanding of thermoregulatory function of TRPV1 based on mechanistic studies conducted by using pharmacological and genetic tools. doi:10.1016/j.autneu.2015.07.417
Symposium 32: Mechanisms For Restoring Autonomic Sympathetic/Parasympathetic Balance: Can It Be Beneficial In Gastrointestinal And Cardiovascular Diseases?
M.C. Andresen Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR USA A common feature across parasympathetic regulation of visceral organs like the heart is the presence of full reflex pathways with as few as two central neurons. Neurons of the solitary tract nucleus (NTS) receive directly synaptic terminals from primary viscerosensory afferents and these afferents belong to two broad phenotypic classes – neurons with either myelinated or unmyelinated axons. Although these sensory terminals all release glutamate as their primary transmitter, the release of glutamate is highly regulated by presynaptic mechanisms. For example, the neuropeptides vasopressin and oxytocin that are synthesized in the hypothalamus oppositely regulated glutamate release at NTS second order neurons. The segregation of viscerosensory phenotype is absolute for aortic baroreceptors and likely other viscerosensory afferents – myelinated afferents contact different neurons than do unmyelinated afferents. The ramifications of the segregation of afferent inputs to second, higher order, and projection neurons will be discussed as well as the presence of a separate pool of glutamate vesicles devoted to calcium entry associated with Transient Receptor Potential Vanilloid Type 1 receptors as a new form of tonic “afferent” presence driving brainstem circuits.
doi:10.1016/j.autneu.2015.07.419 32.1 Can oxytocin increase parasympathetic activity to the heart and treat cardiovascular diseases? H. Jameson, E. Cauley, D. Mendelowitz Department of Pharmacology and Physiology, George Washington University, Washington, DC, USA New promising work has indicated oxytocin (OXT) receptor activation is blunted in cardiovascular diseases (CVDs) and OXT receptor activation may be a novel target to increase parasympathetic activity to the heart and treat cardiac autonomic imbalance. This study tests the hypotheses that the release of OXT from hypothalamic paraventricular (PVN) neurons onto cardiac vagal neurons (CVNs) is diminished with chronic intermittent hypoxia-hypercapnia (CIH/H), an animal model of Obstructive Sleep Apnea (OSA) and furthermore that selective activation of PVN OXT neurons can reduce adverse cardiovascular consequences that occur with CIH/H. Optogenetic stimulation of channelrhodopsin expressing PVN fibers evoked large transient increases in Ca2+ in CHO cells stably transfected to express the human recombinant OXT receptor and the red fluorescent calcium indicator, R-GECO1, dispersed adjacent to CVNs. The release of OXT onto CVNs upon photoactivation of PVN fibers was blunted in animals exposed to 21 days of CIH/H. To examine if restoration of OXT neuron activity can prevent the in vivo cardiovascular
32.3 What is responsible for the elevated hypothalamic drive to sympathetic neurons in cardiovascular diseases? J.E. Stern Department of Physiology, Medical College of Georgia, GA Regents University, USA Accumulating evidence supports altered hypothalamic neuronal activity as a major factor contributing to increased sympathetic drive in major cardiovascular diseases, including hypertension and heart failure. Numerous precise underlying mechanisms have been distinctly proposed to contribute to hypothalamic-driven sympathetic activity. These include, among others, enhanced excitatory (glutamate, angiotensin II) and blunted inhibitory (GABA, nitric oxide) synaptic mechanisms, altered intrinsic ion channel function, as well as a pro-inflammatory glia microenvironment (gliosis, microglia cell activation). However, to what extent these seemingly disparate mechanisms are causally and functionally interrelated remains at present unknown. I will present a set of recent studies from our group in which we present a mechanistic functional link between Angiotensin II, glutamate and the potassium channel IA in the regulation of sympathetic-related neuronal activity in