Long-Term Effects of Ivabradine on Cardiac Vagal Parasympathetic Function in Normal Rats

Scridon, Alina; Halaţiu, Vasile Bogdan; Balan, Alkora Ioana; Cozac, Dan Alexandru; Moldovan, Valeriu; Bănescu, Claudia; Perian, Marcel; Șerban, Răzvan Constantin

doi:10.3389/fphar.2021.596956

Cited by 8 publications

(4 citation statements)

References 48 publications

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“…Given that chemogenetic inhibition of glutamate, which is an excitatory neurotransmitter, increased NREM sleep and decreased wakefulness in mice ( Kroeger et al, 2017 ) and more consolidated sleep in zebrafish was observed as a response to a single middle dose of ZD7288 in our study, we suggest that this effect might have been obtained due to inhibition of glutamate release. Although Ivabradine does not cross the blood brain barrier, it inhibits inward current in peripheral and autonomic somatosensory neurons ( Scridon et al, 2021 ), thereby this effect might explain shorter latency to daytime sleep immediately after drug administration. Moreover, HCN channel blocker compounds including Ivabradine ( Demontis et al, 2009 ), Zatebradine hydrochloride ( Satoh and Yamada, 2002 ) and ZD7288 ( Satoh and Yamada, 2000 ) inhibit Ih in HCN channels especially HCN1 in rod photoreceptors which contributes to photoreceptor degeneration ( Schon et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Screening effects of HCN channel blockers on sleep/wake behavior in zebrafish

Doldur-Balli,

Smieszek,

Keenan

et al. 2024

Front. Neurosci.

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels generate electrical rhythmicity in various tissues although primarily heart, retina and brain. The HCN channel blocker compound, Ivabradine (Corlanor), is approved by the US Food and Drug Administration (FDA) as a medication to lower heart rate by blocking hyperpolarization activated inward current in the sinoatrial node. In addition, a growing body of evidence suggests a role for HCN channels in regulation of sleep/wake behavior. Zebrafish larvae are ideal model organisms for high throughput drug screening, drug repurposing and behavioral phenotyping studies. We leveraged this model system to investigate effects of three HCN channel blockers (Ivabradine, Zatebradine Hydrochloride and ZD7288) at multiple doses on sleep/wake behavior in wild type zebrafish. Results of interest included shorter latency to daytime sleep at 0.1 μM dose of Ivabradine (ANOVA, p: 0.02), moderate reduction in average activity at 30 μM dose of Zatebradine Hydrochloride (ANOVA, p: 0.024) in daytime, and increased nighttime sleep at 4.5 μM dose of ZD7288 (ANOVA, p: 0.036). Taken together, shorter latency to daytime sleep, decrease in daytime activity and increased nighttime sleep indicate that different HCN channel antagonists affected different parameters of sleep and activity.

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Section: Discussionmentioning

confidence: 99%

Screening effects of HCN channel blockers on sleep/wake behavior in zebrafish

Doldur-Balli,

Smieszek,

Keenan

et al. 2024

Front. Neurosci.

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“…Furthermore, the potential mechanisms contributing to PR prolongation induced by ivabradine include not only the expression of the If channel on the atrioventricular node but also the activation of vagal tone [26]. It is anticipated that these combined factors will exert an influence on the PR interval during the chronic phase following ivabradine administration, thereby contributing to favorable outcomes.…”

Section: Clinical Perspectivementioning

confidence: 99%

PR Interval as a Novel Therapeutic Target of Ivabradine Therapy—Prognostic Impact of Ivabradine-Induced PR Prolongation in Heart Failure Patients

Yamamoto,

Kataoka,

Imamura

et al. 2024

JCM

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Background: Ivabradine reduces heart rate by inhibiting the “funny current” expressed on the sinoatrial node and improves mortality and morbidity in patients with systolic heart failure and sinus tachycardia. The funny current is known to be expressed also on the atrioventricular node according to experimental studies. However, the impact of ivabradine on PR interval remained unknown. Methods: Patients with a left ventricular ejection fraction of less than 50% who received 1 month of ivabradine were screened. Electrocardiographic and echocardiographic data, particularly concerning heart rate, the PR interval, and trans-mitral flow pattern, were collected at baseline and 1-month follow-up. The primary endpoint was defined as the composite of cardiovascular death and hospital readmission for worsening heart failure following ivabradine administration. Results: In the cohort of 29 enrolled patients (median age: 66 years, 62% male), the median baseline heart rate was 86 beats per minute and the median PR interval was 168 milliseconds. Following ivabradine administration, a significant decrease of 20 beats per minute in the heart rate and a significant increase of 24 milliseconds in the PR interval were observed. The truncated interval of the A-wave, detected in the trans-mitral flow, consistently demonstrated a negative correlation with the PR interval both before and after the administration of ivabradine. During a median of 1.8 years of follow-up, six patients reached the primary endpoint. A combination of heart rate reduction and PR prolongation following ivabradine administration, both of which were independent factors associated with the primary endpoint (p < 0.05 for both), was associated with greater freedom from the primary endpoint compared with either/neither of them (p = 0.002). Conclusions: Ivabradine seems to prolong PR interval, which is a novel surrogate marker of favorable clinical outcomes in patients with systolic heart failure. This effect may be associated with the dynamics of the trans-mitral flow pattern, in conjunction with heart rate and the PR interval. Clinical implications of PR interval-guided ivabradine therapy remains the future concern.

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“…Despite the existing concern, studies including BEAUTIFUL, SIGNIFY, and SHIFT did not show an arrhythmogenic effect [ 93 ]. In addition, some studies suggest that Ivabradine might modulate the vagal effect with the result of preventing atrial arrhythmias [ 94 , 95 ]. Its antiarrhythmic or arrhythmogenic effects await further studies.…”

Section: Future Directionsmentioning

confidence: 99%

Sympathetic Modulation in Cardiac Arrhythmias: Where We Stand and Where We Go

Chung

Lin

et al. 2023

JPM

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The nuance of autonomic cardiac control has been studied for more than 400 years, yet little is understood. This review aimed to provide a comprehensive overview of the current understanding, clinical implications, and ongoing studies of cardiac sympathetic modulation and its anti-ventricular arrhythmias’ therapeutic potential. Molecular-level studies and clinical studies were reviewed to elucidate the gaps in knowledge and the possible future directions for these strategies to be translated into the clinical setting. Imbalanced sympathoexcitation and parasympathetic withdrawal destabilize cardiac electrophysiology and confer the development of ventricular arrhythmias. Therefore, the current strategy for rebalancing the autonomic system includes attenuating sympathoexcitation and increasing vagal tone. Multilevel targets of the cardiac neuraxis exist, and some have emerged as promising antiarrhythmic strategies. These interventions include pharmacological blockade, permanent cardiac sympathetic denervation, temporal cardiac sympathetic denervation, etc. The gold standard approach, however, has not been known. Although neuromodulatory strategies have been shown to be highly effective in several acute animal studies with very promising results, the individual and interspecies variation between human autonomic systems limits the progress in this young field. There is, however, still much room to refine the current neuromodulation therapy to meet the unmet need for life-threatening ventricular arrhythmias.

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Long-Term Effects of Ivabradine on Cardiac Vagal Parasympathetic Function in Normal Rats

Cited by 8 publications

References 48 publications

Screening effects of HCN channel blockers on sleep/wake behavior in zebrafish

Screening effects of HCN channel blockers on sleep/wake behavior in zebrafish

PR Interval as a Novel Therapeutic Target of Ivabradine Therapy—Prognostic Impact of Ivabradine-Induced PR Prolongation in Heart Failure Patients

Sympathetic Modulation in Cardiac Arrhythmias: Where We Stand and Where We Go

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