Centrally acting adrenomedullin in the long-term potentiation of sympathetic vasoconstrictor activity induced by intermittent hypoxia in rats

Autor(es)

Zoccal, Daniel B. ^[1] ; Colombari, Debora S. A. ^[1] ; Colombari, Eduardo ^[1] ; Flor, Karine C. ^[1] ; da Silva, Melina P. ^[2] ; Costa-Silva, Joao H. ^{[2, 3]} ; Machado, Benedito H. ^[2] ; Moraes, Davi J. A. ^[2] ; Murphy, David ^[4] ; Paton, Julian F. R. ^{[5, 6]}

Afiliação do(s) autor(es)

^[1] Sao Paulo State Univ UNESP, Sch Dent, Dept Physiol & Pathol, Araraquara - Brazil

^[2] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Physiol, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Fed Univ Pernambuco UFPE, Acad Ctr Vitoria, Vitoria De Santo Antao, PE - Brazil

^[4] Univ Bristol, Bristol Med Sch Translat Hlth Sci, Dorothy Hodgkin Bldg, Bristol BS1 3NY, Avon - England

^[5] Univ Bristol, Sch Physiol Pharmacol & Neurosci, Biomed Sci, Bristol BS8 1TD, Avon - England

^[6] Univ Auckland, Fac Med & Hlth Sci, Dept Physiol, Pk Rd, Auckland - New Zealand

• Tipo de documento: Artigo Científico
• Fonte: Experimental Physiology; v. 104, n. 9, p. 1371-1383, SEP 2019.
• Citações Web of Science: 2

Resumo

Adrenomedullin in the rostral ventrolateral medulla (RVLM) has been shown to increase sympathetic activity whereas the antagonism of its receptors inhibited this autonomic activity lowering blood pressure in conditions of hypertension. Given that hypoxia is a stimulant for releasing adrenomedullin, we hypothesized that the presence of this peptide in the RVLM associated with chronic intermittent hypoxia (CIH) would cause sympathetic overdrive. Juvenile male rats (50-55 g) submitted to CIH (6% oxygen every 9 min, 8 h day(-1) for 10 days) were studied in an arterially perfused in situ preparation where sympathetic activity was recorded. In control rats (n=6), exogenously applied adrenomedullin in the RVLM raised baseline sympathetic activity when combined with episodic activation of peripheral chemoreceptors (KCN 0.05%, 5 times every 5 min). This sympathoexcitatory response was markedly amplified in rats previously exposed to CIH (n=6). The antagonism of adrenomedullin receptors in the RVLM caused a significant reduction in sympathetic activity in the CIH group (n=7), but not in controls (n=8). The transient reflex-evoked sympathoexcitatory response to peripheral chemoreceptor stimulation was not affected by either adrenomedullin or adrenomedullin receptor antagonism in the RVLM of control and CIH rats. Our findings indicate that CIH sensitizes the sympathoexcitatory networks within the RVLM to adrenomedullin, supporting its role as an excitatory neuromodulator when intermittent hypoxia is present. These data reveal novel state-dependent mechanistic insights into the generation of sympathetic overdrive and provide potential guidance on possible unique approaches for controlling sympathetic discharge in diseases such as sleep apnoea and neurogenic hypertension. (AU)

• Processo FAPESP: 13/06077-5 - Alterações nas redes neurais envolvidas na geração e controle das atividades simpática e respiratória em diferentes modelos experimentais de hipóxia
• Beneficiário: Benedito Honorio Machado
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/23467-7 - Fisiopatologia experimental: mecanismos centrais de controle cardiovascular e respiratório envolvidos em modelos experimentais de hipertensão e obesidade
• Beneficiário: Eduardo Colombari
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/10484-5 - Caracterização eletrofisiológica e molecular dos neurônios envolvidos na geração do ritmo e do padrão respiratório de ratos durante o desenvolvimento pós-natal
• Beneficiário: Davi José de Almeida Moraes
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores