Contribuição da neurotransmissão glutamatérgica na região rostroventrolateral do bulbo (RVLM) para as respostas cardiovasculares e autonômicas induzidas pelo fator de necrose tumoral alfa (TNF-α) no núcleo paraventricular do hipotálamo (PVN)
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2022-10-31
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Universidade Federal de Goiás
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Neurogenic hypertension is characterized by a chronic elevation of blood pressure (BP) associated with exacerbation of sympathetic nerve activity (SNA). In this sense, the neuroinflammation, marked by the presence of pro-inflammatory cytokines (PIC) in the central nervous system (CNS), can be related to increased sympathetic drive and arterial hypertension (AH) development. Furthermore, the presence of tumor necrosis factor alpha (TNF-α) in sympathetic premotor neurons that compose the rostral ventrolateral medulla (RVLM) and hypothalamic paraventricular nucleus (PVN) is associated with hypertensive phenotype. However, the pathways and mechanisms by which TNF-α act in the CNS remain under investigation. Thus, the present study investigated the cardiovascular and autonomic effects promoted by TNF-α administration in the PVN and the participation of glutamatergic neurotransmission and N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the RVLM in these responses. For this, Wistar and spontaneously hypertensive rats (SHR) (270 - 300g) were anesthetized with urethane (400 mg/mL, intravenous - i.v.) associated with α-chloralose (40 mg/mL, i.v.) and instrumented to mean arterial pressure (MAP), heart rate (HR) and splanchnic sympathetic nervous activity (SSNA) recordings. The animals were organized into five groups and subjected to unilateral nanoinjections (50 nL) in the RVLM as follows: I. Wistar subjected to vehicle nanoinjections (Ringer's solution, normotensive SHAM group, n=5); II. SHR subjected to vehicle nanoinjections (Ringer's solution, hypertensive SHAM group, n=7); III. SHR subjected to kynurenic acid nanoinjections (KYN, 50 mM, glutamate receptor antagonist, hypertensive GLU group, n=6); IV. SHR subjected to 2-amino-5-phosphonovaleric acid nanoinjections (AP5, 24 nmol/50 nL, NMDA receptor antagonist, hypertensive NMDA group, n=7) and V. SHR subjected to 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f] quinoxaline nanoinjections (NBQX, 5.2 nmol/50 nL, AMPA receptor antagonist, hypertensive AMPA group, n=6). Then, all groups were subjected to ipsilateral TNF-α nanoinjections (0.6 pmol/50 nL, 50 nL) in the PVN. Nanoinjections of vehicle, KYN, AP5 or NBQX in RVLM did not change baseline values of MAP, HR and SSNA. In the normotensive SHAM group, TNF-α nanoinjections into the PVN induced an ANSE increase after 50 min of TNF-α nanoinjections, without modifying the MAP and HR. In contrast, in the hypertensive SHAM group, TNF-α nanoinjections in the PVN promoted a progressive splanchnic sympathoexcitation initiated 20 min after the TNF-α nanoinjections. After 50 min of TNF-α nanoinjections, a pressor response was observed, without changing HR, in the hypertensive SHAM group. Previous inhibition of RVLM glutamatergic neurotransmission did not alter the pressor response induced by TNF-α in hypertensive animals and did not change the HR. However, abolished the splanchnic sympathoexcitation observed after TNF-α. Additionally, NMDA or AMPA receptors previous inhibition in RVLM was not able to change the TNF-α-induced late increase in MAP and the HR in hypertensive animals. However, attenuated the splanchnic sympatoexcitation generated after the TNF-α nanoinjections. These results suggest that cardiovascular and autonomic changes promoted by TNF-α in the PVN are exacerbated in hypertensive animals and that the integrity of glutamatergic neurotransmission and NMDA and AMPA receptors in the RVLM are essential for the sympathoexcitatory response induced by TNF-α in the PVN in SHR.
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NAVES, L. M. Contribuição da neurotransmissão glutamatérgica na região rostroventrolateral do bulbo (RVLM) para as respostas cardiovasculares e autonômicas induzidas pelo fator de necrose tumoral alfa (TNF-α) no núcleo paraventricular do hipotálamo (PVN). 2022. 59 f. Tese (Doutorado em Ciências Biológicas) - Universidade Federal de Goiás, Goiânia, 2022.