Central mechanisms involved in the sympathoexcitation in response to hypoxia

• Grant number: 04/03285-7
• Support Opportunities: Research Projects - Thematic Grants
• Start date: September 01, 2004
• End date: August 31, 2009
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Benedito Honorio Machado
• Grantee: Benedito Honorio Machado
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Hypoxia is a possible physiological and pathophysiological situation that play a major role in the activation of the peripheral chemoreceptors, which produces the correspondent autonomic, respiratory and behavioural responses in arder to provide the system with the appropriated leveI of oxigen in the arterial blood. The acute chemoreflex activation produces the necessary increased in the sympathetic nerve activity to provide the cardiovascular system with the leveI of vascular resistance required to increase the arterial blood flow to the upper part of the body and preserve the central nervous system of any hypoxic situation. However, the chronic activation of the peripheral chemoreceptors in physiopathological circunstances such as the chronic intermitent hypoxia may result in a persisten increase in the leveI of the sympathetic outflow, which may result in arterial hypertension, i.e., another physiopathological situation. The main focos of this project is the study of several aspects of the neurotransmission of the chemoreflex in different areas of the brain involved with the generation and modulation of the sympathetic nerve activity. Among several neurotransmitters systems, we will evaluated the possible role of glutamatergic and purinergic systems in the processing of the sympathoexcitatory component of the chemoretlex in the nucleus tractus solitaty (NTS), bulbo rostral ventrolateral (R VLM) and the paraventricular nucleus of the hypothalamus (PVN), due to a series of previous experimental evidences about the possible involvement of these systems. In this project experimental hypoxia will be induced by two different ways: a) acute cytotoxic hypoxia will be obtained by intravenous injection of potassium cyanide and b) hypoxic hypoxia will be obtained by lowering the pO2 to 6% for short period of time (30 sec) during 8 hours a dar during 35 days in order to reproduce the experimental model of the chronic intermitent hypoxia. The neurotransmission of the sympathoexcitatory component of the chemoretlex activated by the acute or chronic hypoxia will be evaluated in the NTS, RVLM and PVN by different experimental methods, which includes pharmacological, eletrophysiological and immunohistochemistry approachees. The evaluation of the neurochemical mechanisms involved in the processing of the sympathoexcitatory component of the chemoreflex, in different areas of the brain, will help us to understand the role of L-glutamate and excitatory aminoacid receptors as well as the role of ATP and P2 receptors in the generation and modulation of the sympathetic activity at the brainstem leveI. The data to be obtained will be also important for understanding the neural mechanisms involved in the abnormal increase of the sympathetic activity observed in pathophysiological situations such as the sleep obstructive apnoea and heart failure. In the development of this project we will combine the use of techniques of microinjections into the central nervous system in awake rats, used in our laboratory in the last 16 reaIs, with new methods recently introduced in our laboratory with financial support from FAPESP, which includes the electrophysiology [working heart-brainstem preparation (grant 2001/11190-8) and patch-clamp (grant 1995/4685-8)] and immunocitochemistry for the different types of receptors involved in the processing of the sympathoexcitatory component of the chemoreflex at different levels (grant 2001/01252-6). As previously emphasized, the studies will be also performed in the model. of intermitent hypoxia, in which the animals are submitted to the activation of the chemoretlex during 8 hours a day dyring 35 days. The Oxycycler system used for inducing the chronic intermitent hypoxia and introduced in our laboratory last year was also supported by the financial support from FAPESP (grant 2001./11190-8). The present project contain the main directions of our laboratory for the next 4 years and it is based upon our previous experience with the pharmacological studies of the brainstem areas in awake and anesthetized rats as well as our more recent experiences with electrophysiology and immunocitochemistry and 2 major experimental models will be used: the acute (KCN) and the chronic activation of the peripheral. chemoreceptors. The experiments to be performed as well as the different experimental protocols to be used are divided in 13 sub-projects, which are divided in functional and pharmacological (7), electrophysiological (4) and imunohistochemical approaches (2). These different sub-projects are presented in details in the sequence of this proposal. (AU)

Scientific publications

(23)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ZOCCAL, DANIEL B.; PABLO HUIDOBRO-TORO, J.; MACHADO, BENEDITO H.. Chronic intermittent hypoxia augments sympatho-excitatory response to ATP but not to l-glutamate in the RVLM of rats. AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL, v. 165, n. 2, p. 156-162, DEC 7 2011. (04/03285-7)

MOLKOV, YAROSLAV I.; ZOCCAL, DANIEL B.; MORAES, DAVI J. A.; PATON, JULIAN F. R.; MACHADO, BENEDITO H.; RYBAK, ILYA A.. Intermittent hypoxia-induced sensitization of central chemoreceptors contributes to sympathetic nerve activity during late expiration in rats. Journal of Neurophysiology, v. 105, n. 6, p. 3080-3091, JUN 2011. (04/03285-7)

OLIVA, WALDYR M.; GRANJEIRO, ERICA M.; BONGAMBA, LENI G. H.; MENDES, RICARDO A.; MACHADO, BENEDITO H.. Dopamine microinjected into brainstem of awake rats affects baseline arterial pressure but not chemoreflex responses. AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL, v. 155, n. 1-2, p. 73-81, JUN 24 2010. (04/03285-7)

GRANJEIRO, ERICA M.; MACHADO, BENEDITO H.. NO in the caudal NTS modulates the increase in respiratory frequency in response to chemoreflex activation in awake rats. Respiratory Physiology & Neurobiology, v. 166, n. 1, p. 32-40, MAR 31 2009. (04/03285-7)

ACCORSI-MENDONCA, DANIELA; BONAGAMBA, LENI G. H.; LEAO, RICARDO M.; MACHADO, BENEDITO H.. Are l-glutamate and ATP cotransmitters of the peripheral chemoreflex in the rat nucleus tractus solitarius ?. Experimental Physiology, v. 94, n. 1, p. 38-45, JAN 1 2009. (04/03285-7)

CRUZ, J. C.; BONAGAMBA, L. G. H.; MACHADO, B. H.; BIANCARDI, V. C.; STERN, J. E.. INTERMITTENT ACTIVATION OF PERIPHERAL CHEMORECEPTORS IN AWAKE RATS INDUCES Fos EXPRESSION IN ROSTRAL VENTROLATERAL MEDULLA-PROJECTING NEURONS IN THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS. Neuroscience, v. 157, n. 2, p. 463-472, NOV 19 2008. (04/03285-7)

BRAGA, VALDIR A.; ANTUNES, VAGNER R.; MACHADO, BENEDITO H.. Autonomic and respiratory responses to microinjection of l-glutamate into the commissural subnucleus of the NTS in the working heart-brainstem preparation of the rat. Brain Research, v. 1093, n. 1, p. 150-160, June 2006. (04/03285-7)

BRAGA, VALDIR A.; MACHADO, BENEDITO H.. Chemoreflex sympathoexcitation was not altered by the antagonism of glutamate receptors in the commissural nucleus tractus solitarii in the working heart-brainstem preparation of rats. Experimental Physiology, v. 91, n. 3, p. 551-559, May 2006. (04/03285-7)

BRAGA, VALDIR A.; SORIANO, RENATO N.; BRACCIALLI, ALEX L.; PAULA, PATRÍCIA M. DE; BONAGAMBA, LENI G. H.; PATON, JULIAN F. R.; MACHADO, BENEDITO H.. Involvement of L-glutamate and ATP in the neurotransmission of the sympathoexcitatory component of the chemoreflex in the commissural nucleus tractus solitarii of awake rats and in the working heart-brainstem preparation. JOURNAL OF PHYSIOLOGY-LONDON, v. 581, n. 3, p. 1129-1145, 2007. (04/03285-7)

BRAGA, VALDIR A.; SORIANO, RENATO N.; MACHADO, BENEDITO H.. Sympathoexcitatory response to peripheral chemoreflex activation is enhanced in juvenile rats exposed to chronic intermittent hypoxia. Experimental Physiology, v. 91, n. 6, p. 1025-1031, Nov. 2006. (04/03285-7)

CRUZ, JOSIANE DE CAMPOS; BONAGAMBA, LENI G. H.; STERN, JAVIER E.; MACHADO, BENEDITO H.. Fos expression in the NTS in response to peripheral chemoreflex activation in awake rats. AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL, v. 152, n. 1-2, p. 27-34, JAN 15 2010. (04/03285-7)

ACCORSI-MENDOCA, D.; CASTANIA, J. A.; BONAGAMBA, L. G. H.; MACHADO, B. H.; LEAO, R. M.. SYNAPTIC PROFILE OF NUCLEUS TRACTUS SOLITARIUS NEURONS INVOLVED WITH THE PERIPHERAL CHEMOREFLEX PATHWAYS. Neuroscience, v. 197, p. 107-120, DEC 1 2011. (04/03285-7)

ACCORSI-MENDON{\K{I}}A‚ D.; ALMADO‚ C.E.L.; DAGOSTIN‚ A.L.A.; MACHADO‚ B.H.; LEÃO‚ R.M.. Inhibition of spontaneous neurotransmission in the nucleus of solitary tract of the rat by the cannabinoid agonist WIN 55212-2 is not via CB1 or CB2 receptors. Brain Research, v. 1200, p. 1-9, 2008. (04/03285-7)

BRACCIALLI‚ A.L.; BONAGAMBA‚ L.G.H.; MACHADO‚ B.H.. Glutamatergic and purinergic mechanisms on respiratory modulation in the caudal NTS of awake rats. Respiratory Physiology & Neurobiology, v. 161, n. 3, p. 246-252, 2008. (04/03285-7)

CRUZ, JOSIANE C.; BONAGAMBA, LENI G. H.; MACHADO, BENEDITO H.. Modulation of arterial pressure by P2 purinoceptors in the paraventricular nucleus of the hypothalamus of awake rats. AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL, v. 158, n. 1-2, p. 79-85, DEC 8 2010. (04/03285-7)

GRANJEIRO, ERICA M.; PAJOLLA, GISELA P.; ACCORSI-MENDONCA, DANIELA; MACHADO, BENEDITO H.. Interaction of purinergic and nitrergic mechanisms in the caudal nucleus tractus solitarii of rats. AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL, v. 151, n. 2, p. 117-126, DEC 3 2009. (04/03285-7)

ZOCCAL, DANIEL B.; BONAGAMBA, LENI G. H.; PATON, JULIAN F. R.; MACHADO, BENEDITO H.. Sympathetic-mediated hypertension of awake juvenile rats submitted to chronic intermittent hypoxia is not linked to baroreflex dysfunction. Experimental Physiology, v. 94, n. 9, p. 972-983, SEP 1 2009. (04/03285-7)

CRUZ, JOSIANE C.; MACHADO, BENEDITO H.. GABA and nitric oxide in the PVN are involved in arterial pressure control but not in the chemoreflex responses in rats. AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL, v. 146, n. 1-2, p. 47-55, MAR 12 2009. (04/03285-7)

PAJOLLA, GISELA P.; ACCORSI-MENDONCA, DANIELA; LUNARDI, CLAURE N.; BENDHACK, LUSIANE M.; MACHADO, BENEDITO H.; LLEWELLYN-SMITH, IDA J.. Immunoreactivity for neuronal NOS and fluorescent indication of NO formation in the NTS of juvenile rats submitted to chronic intermittent hypoxia. AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL, v. 148, n. 1-2, p. 55-62, JUN 15 2009. (04/03285-7)

PAJOLLA, GISELA P.; ACCORSI-MENDONCA, DANIELA; RODRIGUES, GERSON J.; BENDHACK, LUSIANE M.; MACHADO, BENEDITO H.; LUNARDI, CLAURE N.. Fluorescent indication that nitric oxide formation in NTS neurons is modulated by glutamate and GABA. NITRIC OXIDE-BIOLOGY AND CHEMISTRY, v. 20, n. 3, p. 207-216, APR 15 2009. (04/03285-7)

ZOCCAL, DANIEL B.; BONAGAMBA, LENI G. H.; OLIVEIRA, FABÍOLA R. T.; ANTUNES-RODRIGUES, JOSÉ; MACHADO, BENEDITO H.. Increased sympathetic activity in rats submitted to chronic intermittent hypoxia. Experimental Physiology, v. 92, n. 1, p. 79-85, Jan. 2007. (04/03285-7)

WEISSHEIMER, KARIN VIANA; MACHADO, BENEDITO H.. Inhibitory modulation of chemoreflex bradycardia by stimulation of the nucleus raphe obscurus is mediated by 5-HT3 receptors in the NTS of awake rats. AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL, v. 132, n. 1/2, p. 27-36, Mar. 2007. (04/03285-7)

ALMADO‚ C.E.L.; MACHADO‚ B.H.. Respiratory and autonomic responses to microinjection of NMDA and AMPA into the commissural subnucleus of the NTS of awake rats. Brain Research, v. 1063, n. 1, p. 59-68, 2005. (04/03285-7)