Rostral ventrolateral medullary catecholaminergic neurones mediate irregular breathing pattern in volume overload heart failure rats

Camilo Toledo, David C. Andrade, Hugo S. Díaz, Katherin V. Pereyra, Karla G. Schwarz, Esteban Díaz-Jara, Luiz M. Oliveira, Ana C. Takakura, Thiago S. Moreira, Harold D. Schultz, Noah J. Marcus, Rodrigo Del Rio

Research output: Contribution to journalArticle

Abstract

Key points: A strong association between disordered breathing patterns, elevated sympathetic activity, and enhanced central chemoreflex drive has been shown in experimental and human heart failure (HF). The aim of this study was to determine the contribution of catecholaminergic rostral ventrolateral medulla catecholaminergic neurones (RVLM-C1) to both haemodynamic and respiratory alterations in HF. Apnoea/hypopnoea incidence (AHI), breathing variability, respiratory–cardiovascular coupling, cardiac autonomic control and cardiac function were analysed in HF rats with or without selective ablation of RVLM-C1 neurones. Partial lesion (∼65%) of RVLM-C1 neurones reduces AHI, respiratory variability, and respiratory–cardiovascular coupling in HF rats. In addition, the deleterious effects of central chemoreflex activation on cardiac autonomic balance and cardiac function in HF rats was abolished by ablation of RVLM-C1 neurones. Our findings suggest that RVLM-C1 neurones play a pivotal role in breathing irregularities in volume overload HF, and mediate the sympathetic responses induced by acute central chemoreflex activation. Abstract: Rostral ventrolateral medulla catecholaminergic neurones (RVLM-C1) modulate sympathetic outflow and breathing under normal conditions. Heart failure (HF) is characterized by chronic RVLM-C1 activation, increased sympathetic activity and irregular breathing patterns. Despite studies showing a relationship between RVLM-C1 and sympathetic activity in HF, no studies have addressed a potential contribution of RVLM-C1 neurones to irregular breathing in this context. Thus, the aim of this study was to determine the contribution of RVLM-C1 neurones to irregular breathing patterns in HF. Sprague–Dawley rats underwent surgery to induce volume overload HF. Anti-dopamine β-hydroxylase–saporin toxin (DβH-SAP) was used to selectively lesion RVLM-C1 neurones. At 8 weeks post-HF induction, breathing pattern, blood pressures (BP), respiratory–cardiovascular coupling (RCC), central chemoreflex function, cardiac autonomic control and cardiac function were studied. Reduction (∼65%) of RVLM-C1 neurones resulted in attenuation of irregular breathing, decreased apnoea–hypopnoea incidence (11.1 ± 2.9 vs. 6.5 ± 2.5 events h−1; HF+Veh vs. HF+DβH-SAP; P < 0.05) and improved cardiac autonomic control in HF rats. Pathological RCC was observed in HF rats (peak coherence >0.5 between breathing and cardiovascular signals) and was attenuated by DβH-SAP treatment (coherence: 0.74 ± 0.12 vs. 0.54 ± 0.10, HF+Veh vs. HF+DβH-SAP rats; P < 0.05). Central chemoreflex activation had deleterious effects on cardiac function and cardiac autonomic control in HF rats that were abolished by lesion of RVLM-C1 neurones. Our findings reveal that RVLM-C1 neurones play a major role in irregular breathing patterns observed in volume overload HF and highlight their contribution to cardiac dysautonomia and deterioration of cardiac function during chemoreflex activation.

Original languageEnglish (US)
Pages (from-to)5799-5820
Number of pages22
JournalJournal of Physiology
Volume597
Issue number24
DOIs
StatePublished - Dec 1 2019

Fingerprint

Respiration
Heart Failure
Neurons
Dopamine
Apnea
Incidence
Primary Dysautonomias
Hemodynamics

Keywords

  • RVLM-C1
  • autonomic imbalance
  • breathing disorders
  • cardiac dysfunction
  • heart failure

ASJC Scopus subject areas

  • Physiology

Cite this

Toledo, C., Andrade, D. C., Díaz, H. S., Pereyra, K. V., Schwarz, K. G., Díaz-Jara, E., ... Del Rio, R. (2019). Rostral ventrolateral medullary catecholaminergic neurones mediate irregular breathing pattern in volume overload heart failure rats. Journal of Physiology, 597(24), 5799-5820. https://doi.org/10.1113/JP278845

Rostral ventrolateral medullary catecholaminergic neurones mediate irregular breathing pattern in volume overload heart failure rats. / Toledo, Camilo; Andrade, David C.; Díaz, Hugo S.; Pereyra, Katherin V.; Schwarz, Karla G.; Díaz-Jara, Esteban; Oliveira, Luiz M.; Takakura, Ana C.; Moreira, Thiago S.; Schultz, Harold D.; Marcus, Noah J.; Del Rio, Rodrigo.

In: Journal of Physiology, Vol. 597, No. 24, 01.12.2019, p. 5799-5820.

Research output: Contribution to journalArticle

Toledo, C, Andrade, DC, Díaz, HS, Pereyra, KV, Schwarz, KG, Díaz-Jara, E, Oliveira, LM, Takakura, AC, Moreira, TS, Schultz, HD, Marcus, NJ & Del Rio, R 2019, 'Rostral ventrolateral medullary catecholaminergic neurones mediate irregular breathing pattern in volume overload heart failure rats', Journal of Physiology, vol. 597, no. 24, pp. 5799-5820. https://doi.org/10.1113/JP278845
Toledo, Camilo ; Andrade, David C. ; Díaz, Hugo S. ; Pereyra, Katherin V. ; Schwarz, Karla G. ; Díaz-Jara, Esteban ; Oliveira, Luiz M. ; Takakura, Ana C. ; Moreira, Thiago S. ; Schultz, Harold D. ; Marcus, Noah J. ; Del Rio, Rodrigo. / Rostral ventrolateral medullary catecholaminergic neurones mediate irregular breathing pattern in volume overload heart failure rats. In: Journal of Physiology. 2019 ; Vol. 597, No. 24. pp. 5799-5820.
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T1 - Rostral ventrolateral medullary catecholaminergic neurones mediate irregular breathing pattern in volume overload heart failure rats

AU - Toledo, Camilo

AU - Andrade, David C.

AU - Díaz, Hugo S.

AU - Pereyra, Katherin V.

AU - Schwarz, Karla G.

AU - Díaz-Jara, Esteban

AU - Oliveira, Luiz M.

AU - Takakura, Ana C.

AU - Moreira, Thiago S.

AU - Schultz, Harold D.

AU - Marcus, Noah J.

AU - Del Rio, Rodrigo

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N2 - Key points: A strong association between disordered breathing patterns, elevated sympathetic activity, and enhanced central chemoreflex drive has been shown in experimental and human heart failure (HF). The aim of this study was to determine the contribution of catecholaminergic rostral ventrolateral medulla catecholaminergic neurones (RVLM-C1) to both haemodynamic and respiratory alterations in HF. Apnoea/hypopnoea incidence (AHI), breathing variability, respiratory–cardiovascular coupling, cardiac autonomic control and cardiac function were analysed in HF rats with or without selective ablation of RVLM-C1 neurones. Partial lesion (∼65%) of RVLM-C1 neurones reduces AHI, respiratory variability, and respiratory–cardiovascular coupling in HF rats. In addition, the deleterious effects of central chemoreflex activation on cardiac autonomic balance and cardiac function in HF rats was abolished by ablation of RVLM-C1 neurones. Our findings suggest that RVLM-C1 neurones play a pivotal role in breathing irregularities in volume overload HF, and mediate the sympathetic responses induced by acute central chemoreflex activation. Abstract: Rostral ventrolateral medulla catecholaminergic neurones (RVLM-C1) modulate sympathetic outflow and breathing under normal conditions. Heart failure (HF) is characterized by chronic RVLM-C1 activation, increased sympathetic activity and irregular breathing patterns. Despite studies showing a relationship between RVLM-C1 and sympathetic activity in HF, no studies have addressed a potential contribution of RVLM-C1 neurones to irregular breathing in this context. Thus, the aim of this study was to determine the contribution of RVLM-C1 neurones to irregular breathing patterns in HF. Sprague–Dawley rats underwent surgery to induce volume overload HF. Anti-dopamine β-hydroxylase–saporin toxin (DβH-SAP) was used to selectively lesion RVLM-C1 neurones. At 8 weeks post-HF induction, breathing pattern, blood pressures (BP), respiratory–cardiovascular coupling (RCC), central chemoreflex function, cardiac autonomic control and cardiac function were studied. Reduction (∼65%) of RVLM-C1 neurones resulted in attenuation of irregular breathing, decreased apnoea–hypopnoea incidence (11.1 ± 2.9 vs. 6.5 ± 2.5 events h−1; HF+Veh vs. HF+DβH-SAP; P < 0.05) and improved cardiac autonomic control in HF rats. Pathological RCC was observed in HF rats (peak coherence >0.5 between breathing and cardiovascular signals) and was attenuated by DβH-SAP treatment (coherence: 0.74 ± 0.12 vs. 0.54 ± 0.10, HF+Veh vs. HF+DβH-SAP rats; P < 0.05). Central chemoreflex activation had deleterious effects on cardiac function and cardiac autonomic control in HF rats that were abolished by lesion of RVLM-C1 neurones. Our findings reveal that RVLM-C1 neurones play a major role in irregular breathing patterns observed in volume overload HF and highlight their contribution to cardiac dysautonomia and deterioration of cardiac function during chemoreflex activation.

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