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Chronic Treatment with Ivabradine Does Not Affect Cardiovascular Autonomic Control in Rats

A low resting heart rate (HR) would be of great benefit in cardiovascular diseases. Ivabradine—a novel selective inhibitor of hyperpolarization-activated cyclic nucleotide gated (HCN) channels- has emerged as a promising HR lowering drug. Its effects on the autonomic HR control are little known. Thi...

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Autores principales: Silva, Fernanda C., Paiva, Franciny A., Müller-Ribeiro, Flávia C., Caldeira, Henrique M. A., Fontes, Marco A. P., de Menezes, Rodrigo C. A., Casali, Karina R., Fortes, Gláucia H., Tobaldini, Eleonora, Solbiati, Monica, Montano, Nicola, Dias Da Silva, Valdo J., Chianca, Deoclécio A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960883/
https://www.ncbi.nlm.nih.gov/pubmed/27507948
http://dx.doi.org/10.3389/fphys.2016.00305
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author Silva, Fernanda C.
Paiva, Franciny A.
Müller-Ribeiro, Flávia C.
Caldeira, Henrique M. A.
Fontes, Marco A. P.
de Menezes, Rodrigo C. A.
Casali, Karina R.
Fortes, Gláucia H.
Tobaldini, Eleonora
Solbiati, Monica
Montano, Nicola
Dias Da Silva, Valdo J.
Chianca, Deoclécio A.
author_facet Silva, Fernanda C.
Paiva, Franciny A.
Müller-Ribeiro, Flávia C.
Caldeira, Henrique M. A.
Fontes, Marco A. P.
de Menezes, Rodrigo C. A.
Casali, Karina R.
Fortes, Gláucia H.
Tobaldini, Eleonora
Solbiati, Monica
Montano, Nicola
Dias Da Silva, Valdo J.
Chianca, Deoclécio A.
author_sort Silva, Fernanda C.
collection PubMed
description A low resting heart rate (HR) would be of great benefit in cardiovascular diseases. Ivabradine—a novel selective inhibitor of hyperpolarization-activated cyclic nucleotide gated (HCN) channels- has emerged as a promising HR lowering drug. Its effects on the autonomic HR control are little known. This study assessed the effects of chronic treatment with ivabradine on the modulatory, reflex and tonic cardiovascular autonomic control and on the renal sympathetic nerve activity (RSNA). Male Wistar rats were divided in 2 groups, receiving intraperitoneal injections of vehicle (VEH) or ivabradine (IVA) during 7 or 8 consecutive days. Rats were submitted to vessels cannulation to perform arterial blood pressure (AP) and HR recordings in freely moving rats. Time series of resting pulse interval and systolic AP were used to measure cardiovascular variability parameters. We also assessed the baroreflex, chemoreflex and the Bezold-Jarish reflex sensitivities. To better evaluate the effects of ivabradine on the autonomic control of the heart, we performed sympathetic and vagal autonomic blockade. As expected, ivabradine-treated rats showed a lower resting (VEH: 362 ± 16 bpm vs. IVA: 260 ± 14 bpm, p = 0.0005) and intrinsic HR (VEH: 369 ± 9 bpm vs. IVA: 326 ± 11 bpm, p = 0.0146). However, the chronic treatment with ivabradine did not change normalized HR spectral parameters LF (nu) (VEH: 24.2 ± 4.6 vs. IVA: 29.8 ± 6.4; p > 0.05); HF (nu) (VEH: 75.1 ± 3.7 vs. IVA: 69.2 ± 5.8; p > 0.05), any cardiovascular reflexes, neither the tonic autonomic control of the HR (tonic sympathovagal index; VEH: 0.91± 0.02 vs. IVA: 0.88 ± 0.03, p = 0.3494). We performed the AP, HR and RSNA recordings in urethane-anesthetized rats. The chronic treatment with ivabradine reduced the resting HR (VEH: 364 ± 12 bpm vs. IVA: 207 ± 11 bpm, p < 0.0001), without affecting RSNA (VEH: 117 ± 16 vs. IVA: 120 ± 9 spikes/s, p = 0.9100) and mean arterial pressure (VEH: 70 ± 4 vs. IVA: 77 ± 6 mmHg, p = 0.3293). Our results suggest that, in health rats, the long-term treatment with ivabradine directly reduces the HR without changing the RSNA modulation and the reflex and tonic autonomic control of the heart.
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spelling pubmed-49608832016-08-09 Chronic Treatment with Ivabradine Does Not Affect Cardiovascular Autonomic Control in Rats Silva, Fernanda C. Paiva, Franciny A. Müller-Ribeiro, Flávia C. Caldeira, Henrique M. A. Fontes, Marco A. P. de Menezes, Rodrigo C. A. Casali, Karina R. Fortes, Gláucia H. Tobaldini, Eleonora Solbiati, Monica Montano, Nicola Dias Da Silva, Valdo J. Chianca, Deoclécio A. Front Physiol Physiology A low resting heart rate (HR) would be of great benefit in cardiovascular diseases. Ivabradine—a novel selective inhibitor of hyperpolarization-activated cyclic nucleotide gated (HCN) channels- has emerged as a promising HR lowering drug. Its effects on the autonomic HR control are little known. This study assessed the effects of chronic treatment with ivabradine on the modulatory, reflex and tonic cardiovascular autonomic control and on the renal sympathetic nerve activity (RSNA). Male Wistar rats were divided in 2 groups, receiving intraperitoneal injections of vehicle (VEH) or ivabradine (IVA) during 7 or 8 consecutive days. Rats were submitted to vessels cannulation to perform arterial blood pressure (AP) and HR recordings in freely moving rats. Time series of resting pulse interval and systolic AP were used to measure cardiovascular variability parameters. We also assessed the baroreflex, chemoreflex and the Bezold-Jarish reflex sensitivities. To better evaluate the effects of ivabradine on the autonomic control of the heart, we performed sympathetic and vagal autonomic blockade. As expected, ivabradine-treated rats showed a lower resting (VEH: 362 ± 16 bpm vs. IVA: 260 ± 14 bpm, p = 0.0005) and intrinsic HR (VEH: 369 ± 9 bpm vs. IVA: 326 ± 11 bpm, p = 0.0146). However, the chronic treatment with ivabradine did not change normalized HR spectral parameters LF (nu) (VEH: 24.2 ± 4.6 vs. IVA: 29.8 ± 6.4; p > 0.05); HF (nu) (VEH: 75.1 ± 3.7 vs. IVA: 69.2 ± 5.8; p > 0.05), any cardiovascular reflexes, neither the tonic autonomic control of the HR (tonic sympathovagal index; VEH: 0.91± 0.02 vs. IVA: 0.88 ± 0.03, p = 0.3494). We performed the AP, HR and RSNA recordings in urethane-anesthetized rats. The chronic treatment with ivabradine reduced the resting HR (VEH: 364 ± 12 bpm vs. IVA: 207 ± 11 bpm, p < 0.0001), without affecting RSNA (VEH: 117 ± 16 vs. IVA: 120 ± 9 spikes/s, p = 0.9100) and mean arterial pressure (VEH: 70 ± 4 vs. IVA: 77 ± 6 mmHg, p = 0.3293). Our results suggest that, in health rats, the long-term treatment with ivabradine directly reduces the HR without changing the RSNA modulation and the reflex and tonic autonomic control of the heart. Frontiers Media S.A. 2016-07-26 /pmc/articles/PMC4960883/ /pubmed/27507948 http://dx.doi.org/10.3389/fphys.2016.00305 Text en Copyright © 2016 Silva, Paiva, Müller-Ribeiro, Caldeira, Fontes, de Menezes, Casali, Fortes, Tobaldini, Solbiati, Montano, Dias Da Silva and Chianca. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Silva, Fernanda C.
Paiva, Franciny A.
Müller-Ribeiro, Flávia C.
Caldeira, Henrique M. A.
Fontes, Marco A. P.
de Menezes, Rodrigo C. A.
Casali, Karina R.
Fortes, Gláucia H.
Tobaldini, Eleonora
Solbiati, Monica
Montano, Nicola
Dias Da Silva, Valdo J.
Chianca, Deoclécio A.
Chronic Treatment with Ivabradine Does Not Affect Cardiovascular Autonomic Control in Rats
title Chronic Treatment with Ivabradine Does Not Affect Cardiovascular Autonomic Control in Rats
title_full Chronic Treatment with Ivabradine Does Not Affect Cardiovascular Autonomic Control in Rats
title_fullStr Chronic Treatment with Ivabradine Does Not Affect Cardiovascular Autonomic Control in Rats
title_full_unstemmed Chronic Treatment with Ivabradine Does Not Affect Cardiovascular Autonomic Control in Rats
title_short Chronic Treatment with Ivabradine Does Not Affect Cardiovascular Autonomic Control in Rats
title_sort chronic treatment with ivabradine does not affect cardiovascular autonomic control in rats
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960883/
https://www.ncbi.nlm.nih.gov/pubmed/27507948
http://dx.doi.org/10.3389/fphys.2016.00305
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