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. 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 +/- 6.4p > 0.05)HF (nu) (VEH: 75.1 +/- 3.7 vs. IVA: 69.2 +/- 5.8p > 0.05), any cardiovascular reflexes, neither the tonic autonomic control of the HR (tonic sympathovagal indexVEH: 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.Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Fundacao de Amparo a Pesquisa de Minas Gerais (FAPEMIG)Universidade Federal de Ouro Preto (UFOP)Universidade Federal do Triangulo Mineiro (UFTM), BrazilUniv Fed Ouro Preto, Inst Exact & Biol Sci, Dept Biol Sci, Lab Cardiovasc Physiol, Ouro Preto, BrazilUniv Fed Ouro Preto, CBIOL NUPEB, Grad Program Biol Sci, Ouro Preto, BrazilUniv Fed Minas Gerais, Inst Biol Sci, Dept Physiol & Biophys, Lab Hypertens, Belo Horizonte, MG, BrazilUniv Fed Sao Paulo, Inst Sci & Technol, Biomed Engn Lab, Sao Jose Dos Campos, BrazilUniv Uberaba, Dept Physiol, Uberaba, BrazilUniv Milan, Osped Maggiore Policlin, IRCCS Ca Granda Fdn, Dept Clin Sci & Community Hlth, Milan, ItalyFed Univ Trianaulo Pvlineiro, Inst Biol & Nat Sci, Dept Physiol, Uberaba, BrazilUniv Fed Sao Paulo, Inst Sci & Technol, Biomed Engn Lab, Sao Jose Dos Campos, BrazilCNPq: 400851/2014-8Web of Scienc

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. 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

Heart rate and arterial pressure variability in the experimental renovascular hypertension model in rats

This study was conducted in one kidney, one clip (1K1C) Goldblatt hypertensive rats to evaluate vascular and cardiac autonomic control using different approaches: 1) evaluation of the autonomic modulation of heart rate (HR) and systolic arterial pressure (SAP) by means of autoregressive power spectral analysis 2) assessment of the cardiac baroreflex sensitivity; and 3) double blockade with methylatropine and propranolol. The 1K1C group developed hypertension and tachycardia. The 1K1C group also presented reduction in variance as well as in LF (0.23 +/- 0.1 vs. 1.32 +/- 0.2 ms(2)) and HF (6.6 +/- 0.49 vs. 15.1 +/- 0.61 ms(2)) oscillations of pulse interval. Autoregressive spectral analysis of SAP showed that 1K1C rats had an increase in variance and LF band (13.3 +/- 2.7 vs. 7.4 +/- 1.01 mmHg(2)) in comparison with the sham group. The baroreflex gain was attenuated in the hypertensive 1K1C (- 1.83 +/- 0.05 bpm/mmHg) rats in comparison with normotensive sham (-3.23 +/- 0.06 bpm/MmHg) rats. The autonomic blockade caused an increase in the intrinsic HR and sympathetic predominance on the basal HR of 1K1C rats. Overall, these data indicate that the tachycardia observed in the 1K1C group may be attributed to intrinsic cardiac mechanisms (increased intrinsic heart rate) and to a shift in the sympathovagal balance towards cardiac sympathetic over-activity and vagal suppression associated to depressed baroreflex sensitivity. Finally, the increase in the LF components of SAP also suggests an increase in sympathetic activity to peripheral vessels. (c) 2008 Elsevier B.V. All rights reserved

Effect of the duration of daily aerobic physical training on cardiac autonomic adaptations

The present study has investigated in conscious rats the influence of the duration of physical training sessions on cardiac autonomic adaptations by using different approaches; 1) double blockade with methylatropine and propranolol; 2) the baroreflex sensitivity evaluated by alternating bolus injections of phenylephrine and sodium nitroprusside; and 3) the autonomic modulation of HRV in the frequency domain by means of spectral analysis. The animals were divided into four groups: one sedentary group and three training groups submitted to physical exercise (swimming) for 15, 30, and 60 min a day during 10 weeks. All training groups showed similar reduction in intrinsic heart rate (IHR) after double blockade with methylatropine and propranolol. However, only 30-min and 60-min physical training presented an increase in the vagal autonomic component for determination of basal heart rate (HR) in relation to group sedentary. Spectral analysis of HR showed that the 30-min and 60-min physical training presented the reduction in low-frequency oscillations (LF = 0.20-0.75 Hz) and the increase in high-frequency oscillations (HF = 0.75-2.5 Hz) in normalized units. These both groups only showed an increased baroreflex sensitivity to tachycardiac responses in relation to group sedentary, however when compared, the physical training of 30-min exhibited a greater gain. In conclusion, cardiac autonomic adaptations, characterised by the increased predominance of the vagal autonomic component, were not proportional to the duration of daily physical training sessions. In fact, 30-minute training sessions provided similar cardiac autonomic adaptations, or even more enhanced ones, as in the case of baroreflex sensitivity compared to 60-minute training sessions. (C) 2010 Elsevier B.V. All rights reserved.FAPESPFAEP