Channel Blocker Ivabradine Research Articles

A randomized, double-blinded, placebo-controlled, crossover study of the HCN channel blocker ivabradine in a capsaicin-induced pain model in healthy volunteers

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5–7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain (p = 0.7479), HPT (p = 0.7501), area of PMH (p = 0.1052) or flare size (p = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller (p < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.

Torsadogenic Potential of HCN Channel Blocker Ivabradine Assessed in the Rabbit Proarrhythmia Model.

Torsadogenic effects of ivabradine, an inhibitor of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, were assessed in an in vivo proarrhythmia model of acute atrioventricular block rabbit. Ivabradine at 0.01, 0.1, and 1 mg/kg was intravenously administered to isoflurane-anesthetized rabbits (n = 5) in the stable idioventricular rhythm. Ivabradine at 0.01 and 0.1 mg/kg hardly affected the atrial and ventricular automaticity, QT interval, or the monophasic action potential duration of the ventricle. Additionally administred ivabradine at 1 mg/kg decreased the atrial and ventricular rate significantly but increased the QT interval and duration of the monophasic action potential. Meanwhile, torsade de pointes arrhythmias were detected in 1 out of 5 animals and in 2 out of 5 animals after the administration of 0.1 and 1 mg/kg, respectively. Importantly, torsade de pointes arrhythmias could be observed only in 2 rabbits showing more potent suppressive effects on ventricular automaticity. These results suggest that the torsadogenic potential of ivabradine may become evident when its expected bradycardic action appears more excessively.

Caffeine and dobutamine challenge induces bidirectional ventricular tachycardia in normal rats.

BackgroundBidirectional ventricular tachycardia (BD-VT) is an intriguing arrhythmia, characterized by a beat-to-beat alternation of the QRS polarity on electrocardiogram. Currently there is no simple BD-VT animal model.ObjectiveWe report a simple animal model of BD-VT induced by caffeine and dobutamine (C+D) challenge in normal rats in which the arrhythmia can be attenuated by dantrolene (a ryanodine receptor stabilizer) treatment, but not by the pacemaker channel blocker ivabradine treatment.MethodsAdult (4–5 months old) Sprague-Dawley rats (both sexes) were randomized into C+D (n = 8, received caffeine 120 mg/kg intraperitoneally [IP] and dobutamine 60 μg/kg IP, sequentially) and control (n = 8) groups. In addition, a group of 7 rats were pretreated with dantrolene (10 mg/kg, IP) 30 minutes before the C+D challenge and another group of 8 rats were pretreated with ivabradine (5 mg/kg, IP) 30 minutes before the C+D challenge.ResultsC+D challenge induced spontaneous premature ventricular contractions (PVCs) in 7 of 8 rats and BD-VT (lasted 4.3 ± 2.9 minutes, terminated spontaneously) in 6 of 8 (75%) rats. No ventricular arrhythmia was induced in the control group (P < .05 vs C+D group). Dantrolene treatment significantly decreased BD-VT (1 of 7 rats in the Dantrolene+C+D group vs 6 of 8 rats in C+D group, P < .05). Ivabradine treatment did not affect C+D-induced BD-VT (7 of 8 rats in the Ivabradine+C+D group vs 6 of 8 in the C+D group, P > .05).ConclusionCaffeine and dobutamine challenge induces BD-VT in a majority of normal rats. Stabilizing cardiac ryanodine receptors with dantrolene treatment can significantly decrease the occurrence of BD-VT, but pacemaker channel blocker ivabradine treatment does not have effect in this animal model.

Cardiac effects of a specific I&lt;sub&gt;f&lt;/sub&gt; channel blocker ivabradine in anesthetized rabbits: simultaneous assessment of the atrial and ventricular automaticity

Cardiac effects of a specific I&lt;sub&gt;f&lt;/sub&gt; channel blocker ivabradine in anesthetized rabbits: simultaneous assessment of the atrial and ventricular automaticity

HiPSC-CMs from different sex and ethnic origin donors exhibit qualitatively different responses to several classes of pharmacological challenges

We investigated whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) created from diverse origins could have qualitatively (not just quantitatively) different responses to pharmacological reagents. Specifically, we challenged six hiPSC-CM syncytia made from a female Caucasian, a female black non-Hispanic, a female white non-Hispanic, a male Caucasian non-Hispanic, a male Asian Indian, and a male-Asian, respectively, with eight different classes of pharmacological reagents (hERG channel blocker cisapride and dofetilide, calcium channel opener FPL64176, β-adrenergic agonist Isoproterenol, HCN channel blocker Ivabradine, IKs current blocker L-000768673, sodium channel blocker tetrodotoxin, and calcium channel blocker verapamil). We focused our analysis and comparison on qualitative differences (e.g., yes or no), and, found the following: hiPSC-CMs from female donors were uniformly more sensitive to dofetilide or cisapride, whereas those from male donors of all races were less sensitive to the two typical hERG blockers; isoproterenol had no chronotropic effect at all in one line; and two lines reacted to tetrodotoxin at very low concentrations and were more sensitive to external stimulation. We conclude that not all hiPSC-CMs are suitable for drug testing in terms of cardiac safety assessment, and pre-set acceptance criteria need to be established before any hiPSC-CMs can be used in CiPA-style study to evaluate cardiac liabilities of drug candidates.

A randomised, double-blind, placebo-controlled crossover trial of the influence of the HCN channel blocker ivabradine in a healthy volunteer pain model: an enriched population trial.

Preclinical studies suggest that type 2 hyperpolarization-activated cyclic nucleotide gated ion channels (HCN2) are necessary for neuropathic pain. This trial assessed the influence of ivabradine, a nonselective HCN channel blocker, on capsaicin-induced hyperalgesia and pain in healthy human subjects. An enriched population comprising subjects who developed >20 cm of punctate hyperalgesia from topical capsaicin (0.5% cream applied onto 9 cm area) was identified. These subjects then received ivabradine (15 mg) or placebo 1 hour before capsaicin application in randomly allocated order in a crossover study. The forearm site for capsaicin alternated with each application of the cream. The interval of time from screening to the first and to the second treatment visits was at least 3 and 5 weeks, respectively, to minimize carryover effects. Fifty-five participants were screened, of which 25 completed at least 1 treatment visit. Intention-to-treat hierarchical analysis revealed no significant effects of the drug on primary trial outcome, defined as a difference in effects of placebo and ivabradine on the area of punctate hyperalgesia (ivabradine - placebo: mean = 3.22 cm, 95% confidence interval: = -4.04 to 10.48, P = 0.37). However, ivabradine caused a slowing of heart rate (difference of 10.10 beats per minute [95% confidence interval -6.48 to -13.73; P-value <0.0001]). We conclude that ivabradine lacks analgesic effects in the capsaicin pain model at a dose that caused appreciable slowing of heart rate and, hence, is unlikely to prove a useful analgesic in humans. More selective drugs are required to establish a role of HCN2 for pain in humans.

Role of Heart Rate Reduction in the Management of Myocarditis.

The morbidity of myocarditis demonstrates an upward tendency by years, is commonly defined as the inflammation of myocytes and is caused by multiple factors. With the development of the molecular biological technique, great breakthroughs in the diagnosis and understanding of pathophysiological mechanisms of myocarditis have recently been achieved. Several questions remain unresolved, however, including standard treatment approaches to myocarditis, which remain controversial and ambiguous. Heart rate, as an independent risk factor, has been shown to be related to cardiac disease. Recent studies also show that the autonomic nervous system is involved in immunomodulatory myocarditis processes. Heart rate reduction treatment is recommended in myocarditis based on a number of animal experiments and clinical trials. It is possible that heart rate-lowering treatments can help to attenuate the inflammatory response and myocyte injury and reverse ventricular remodeling. However, how to execute the protective effects of heart rate reduction on myocarditis is still not clear. In this review, we discuss the pathogenesis and pathophysiological process of viral myocarditis and propose heart rate lowering as a therapeutic target for myocarditis, especially in light of the third-generation β-blockade carvedilol and funny channel blocker ivabradine. We also highlight some additional beneficial effects of such heart rate reduction agents, including anti-inflammatory, antioxidation, anti-nitrosative stress, anti-fibrosis and antiapoptosis properties.

Increased HCN Channel Activity in the Gasserian Ganglion Contributes to Trigeminal Neuropathic Pain

Orofacial neuropathic pain caused by trigeminal nerve injury is a debilitating condition with limited therapeutic options. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability and are involved in the development and maintenance of chronic pain. However, the effect of HCN channel activity in the Gasserian ganglion on trigeminal neuropathic pain has not been examined. We evaluated nociceptive behaviors after microinjection of the HCN channel blockers ZD7288 or ivabradine into the Gasserian ganglion in rats with trigeminal nerve injury. Both blockers dose-dependently ameliorated evoked and spontaneous nociceptive behavior in rats with trigeminal neuropathic pain. Moreover, the clinically available HCN channel blocker ivabradine showed a prolonged antinociceptive effect. In the Gasserian ganglion, HCN1 and HCN2 are major HCN isoforms. After trigeminal nerve injury, the counts of HCN1 as well as HCN2 immuno-positive punctae were increased in the ipsilateral Gasserian ganglions. These results indicate that the increased HCN channel activity in the Gasserian ganglion directly contributes to neuropathic pain resulting from trigeminal nerve injury. PerspectiveTrigeminal nerve damage-induced orofacial pain is severe and more resistant to standard pharmacological treatment than other types of neuropathic pain. Our study suggests that targeting HCN channel activities in the Gasserian ganglion may provide an alternative treatment of trigeminal neuropathy including trigeminal neuralgia.

Defining the neural fulcrum for chronic vagus nerve stimulation: implications for integrated cardiac control.

The evoked cardiac response to bipolar cervical vagus nerve stimulation (VNS) reflects a dynamic interaction between afferent mediated decreases in central parasympathetic drive and suppressive effects evoked by direct stimulation of parasympathetic efferent axons to the heart. The neural fulcrum is defined as the operating point, based on frequency-amplitude-pulse width, where a null heart rate response is reproducibly evoked during the on-phase of VNS. Cardiac control, based on the principal of the neural fulcrum, can be elicited from either vagus. Beta-receptor blockade does not alter the tachycardia phase to low intensity VNS, but can increase the bradycardia to higher intensity VNS. While muscarinic cholinergic blockade prevented the VNS-induced bradycardia, clinically relevant doses of ACE inhibitors, beta-blockade and the funny channel blocker ivabradine did not alter the VNS chronotropic response. While there are qualitative differences in VNS heart control between awake and anaesthetized states, the physiological expression of the neural fulcrum is maintained. Vagus nerve stimulation (VNS) is an emerging therapy for treatment of chronic heart failure and remains a standard of therapy in patients with treatment-resistant epilepsy. The objective of this work was to characterize heart rate (HR) responses (HRRs) during the active phase of chronic VNS over a wide range of stimulation parameters in order to define optimal protocols for bidirectional bioelectronic control of the heart. In normal canines, bipolar electrodes were chronically implanted on the cervical vagosympathetic trunk bilaterally with anode cephalad to cathode (n=8, 'cardiac' configuration) or with electrode positions reversed (n=8, 'epilepsy' configuration). In awake state, HRRs were determined for each combination of pulse frequency (2-20Hz), intensity (0-3.5mA) and pulse widths (130-750μs) over 14months. At low intensities and higher frequency VNS, HR increased during the VNS active phase owing to afferent modulation of parasympathetic central drive. When functional effects of afferent and efferent fibre activation were balanced, a null HRR was evoked (defined as 'neural fulcrum') during which HRR≈0. As intensity increased further, HR was reduced during the active phase of VNS. While qualitatively similar, VNS delivered in the epilepsy configuration resulted in more pronounced HR acceleration and reduced HR deceleration during VNS. At termination, under anaesthesia, transection of the vagi rostral to the stimulation site eliminated the augmenting response to VNS and enhanced the parasympathetic efferent-mediated suppressing effect on electrical and mechanical function of the heart. In conclusion, VNS activates central then peripheral aspects of the cardiac nervous system. VNS control over cardiac function is maintained during chronic therapy.

Early ivabradine treatment in patients with acute peripartum cardiomyopathy: Subanalysis of the German PPCM registry

Peripartum Cardiomyopathy (PPCM) is a pregnancy associated form of heart failure and with a considerable rate of morbidity and mortality [1,2]. Although the pathophysiology of PPCM is not fully understood, emerging evidence point to vascular endothelial damage with subsequent impairment of the microcirculation as an essential pathomechanism of PPCM [3,4]. Current treatment recommendations for PPCM are based on standard heart failure therapy [1,5], although evidence-based data on any treatment option for PPCMare still missing. Among determinants of poor outcome very low baseline LVEF (b25%), LV dilatation and right ventricular function were identified in studies from different regions [6–9]. Importantly, elevated resting heart rate (HR) is common among PPCM patients and considered a negative predictor of outcome, in particular when coupled with low blood pressure (BP) [10]. In some patients with acute PPCM and severely reduced ejection fraction associated with particular poor outcome, the application of beta-blockers at higher doses is often limited due to low BP and, thus, with insufficient HR slowing effects in these patients [10]. Thus, additional HR reduction may be achieved by the “funny” (f)-channel blocker ivabradine, an established medication for patients with chronic heart failure [11]. While recommended in stable chronic heart failure at HR N70 bpm [12] data on application of ivabradine in

Improvement of left ventricular filling by ivabradine during chronic hypertension: involvement of contraction-relaxation coupling.

Chronic hypertension is associated with left ventricular (LV) hypertrophy and LV diastolic dysfunction with impaired isovolumic relaxation and abnormal LV filling. Increased heart rate (HR) worsens these alterations. We investigated whether the I f channel blocker ivabradine exerts beneficial effects on LV filling dynamic. In this setting, we also evaluated the relationship between LV filling and isovolumic contraction as a consequence of contraction-relaxation coupling. Therefore, hypertension was induced by a continuous infusion of angiotensin II during 28 days in 10 chronically instrumented pigs. LV function was investigated after stopping angiotensin II infusion to offset the changes in loading conditions. In the normal heart, LV relaxation filling, LV early filling, LV peak early filling rate were positively correlated to HR. In contrast, these parameters were significantly reduced at day 28 vs. day 0 (18, 42, and 26 %, respectively) despite the increase in HR (108 ± 6 beats/min vs. 73 ± 2 beats/min, respectively). These abnormalities were corrected by acute administration of ivabradine (1 mg/kg, iv). Ivabradine still exerted these effects when HR was controlled at 150 beats/min by atrial pacing. Interestingly, LV relaxation filling, LV early filling and LV peak early filling were strongly correlated with both isovolumic contraction and relaxation. In conclusion, ivabradine improves LV filling during chronic hypertension. The mechanism involves LV contraction-relaxation coupling through normalization of isovolumic contraction and relaxation as well as HR-independent mechanisms.

Cardiac Safety of the Sino Atrial Node f Channel Blocker Ivabradine in Chronic Heart Failure: An ECG-Holter Sub-study

Cardiac Safety of the Sino Atrial Node f Channel Blocker Ivabradine in Chronic Heart Failure: An ECG-Holter Sub-study

Diet-dependent modulation of gastro-oesphageal vagal afferent mechanosensitivity by endogenous nitric oxide.

Neuronal nitric oxide (NO) plays an important role in gastric motor activity and modulates the mechanosensitivity of gastro-oesophageal vagal afferents. Effects of NO on food intake are dependent on feeding status. We sought to determine the effect of NO on gastro-oesophageal vagal afferent activity in the normally fed and food-restricted states and the second messenger pathways mediating these effects. Eight week old female C56BL/6 mice were fed ad libitum or food restricted for 14h. An in vitro preparation was used to determine the functional effects of NO and the second messenger pathways involved. Expression of NO signal transduction molecules in vagal afferents was determined by reverse-transcription polymerase chain reaction (RT-PCR). Endogenous NO and the NO donor S-nitroso-N-acetylpenicillamine (SNAP) inhibited vagal mucosal afferent responses to tactile stimuli in mice fed ad libitum. After a 14h fast endogenous NO and SNAP potentiated tension and mucosal afferent responses to mechanical stimulation. The excitatory effect of NO was blocked by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin. After a 14h fast expression of NADPH oxidase 2 (NOX2) mRNA in whole nodose ganglia was significantly reduced and the excitatory effect of NO on gastro-oesophageal vagal afferents was lost. Under fasting conditions the inhibitory effect of NO was blocked with the hyperpolarisation-activated cyclic nucleotide-gated (HCN) channel blocker ivabradine and mRNA expression of HCN3 in the nodose ganglia was elevated. In conclusion, the role of NO in the peripheral modulation of gastro-oesophageal vagal afferents is dynamic and dependent on feeding status.

ROLE OF MEDICATIONS WITH NEGATIVE CHRONOTROPIC EFFECT IN THE TREATMENT OF PATIENTS WITH CORONARY HEART DISEASE AND HEART FAILURE

The study aim was to assess the importance of adequate administration of medications with negative chronotropic effect in the improvement of clinical course and prognosis among patients with coronary heart disease (CHD) and heart failure. The possibility and appropriateness of combination therapy with β-adrenoblockers (β-AB) and an If channel blocker ivabradine is justified. The authors analyse current real-world trends in the administration and dose titration of these medications among ambulatory Russian patients. Russian doctors need to be more active in the treatment of patients with CHD and heart failure and better understand the need for and benefits of dose titration of medications with negative chronotropic effect, as well as the importance of combination therapy for the improvement of clinical course, prognosis, and quality of life.

Novel approaches to heart rate modulation in chronic heart failure

Copyright © Polskie Towarzystwo Kardiologiczne INTRODUCTION The most recent version of the European Society of Cardiology (ESC) Guidelines for the management of heart failure (HF) has introduced two important innovations for the medical treatment of chronic HF with reduced ejection fraction (EF): mineralo-corticoid receptor antagonists (MCRA) and the If channel blocker ivabradine have now a recognised indication in patients remaining symptomatic despite diuretics, angiotensin converting enzyme inhibitors (or angiotensin receptor blockers in case of intolerance) and beta-blockers [1]. Mineralo-corticoid receptor antagonists are recommended following the EMPHASIS trial which demonstrated the benefit of eplerenone on cardiovascular mortality or HF hospitalisations as well as on all causes mortality in mild to moderate HF patients with reduced EF [2]. According to the ESC Guidelines, ivabradine should be considered when patients remain symptomatic despite the addition of a MCRA and when they have an increased heart rate (HR) ≥ 70 bpm in the context of sinus rhythm. This new recommendation derives from the results of the large outcome trial using this new agent, the SHIFT trial (Systolic Heart Failure Treatment with the If inhibitor Ivabradine trial) [3].

New onset migraine with aura after treatment initiation with ivabradine

BackgroundMigraine with aura is a complex neurological disorder modeled in animals by cortical spreading depression. It is less usual to find complete animal models for the disease so any opportunity to test a human effect back at the bench is welcome.FindingsWe report the case of a 24 year old woman who developed new onset episodic migraine with visual aura shortly after treatment initiation with the If ion channel blocker ivabradine for frequency control in hypertrophic cardiomyopathy. We studied whether ivabradine could alter cortical spreading depression in a suitable animal model. Sixteen rats received either ivabradine or saline, and the number of depolarization shifts and blood flow changes induced by cortical spreading depression were measured in both groups. No significant differences between the ivabradine and saline group were detected.ConclusionsIvabradine is an interesting substance since it is known to produce migraine-like phosphenes frequently and the patient we report developed de novo migraine with aura. However, we were unable to demonstrate that the drug influences the susceptibility of the brain to cortical spreading depression with acute administration. The combined data show the relationship of migraine aura to cortical spreading depression may have some nuances yet to be identified.

Immunohistochemical Distribution of Synaptophysin in the Rat Gastric Fundus and Distal Colon: Influence of Nociceptin/Orphanin FQ and Cold-Restraint Stress

G A A b st ra ct s mucosal receptors (p<0.01, n=9) to mechanical stimulation. This inhibitory effect of N-PLA was blocked by the non-selective HCN channel blocker ivabradine (3μM). Conclusion: NO has a substantial effect on the mechanosensitivity of gastroesophageal vagal afferents which can be dramatically altered by even short term changes in food intake. The mechanism for the switch in action of NO appears to be a change in expression and overall balance of NO signalling pathways. Supported by University of Adelaide and NHMRC Australia

If current inhibition with ivabradine: further perspectives

Beyond its antianginal properties, the specific If (pacemaker, or ‘funny’, current) channel blocker ivabradine has many possible clinical uses. The first potential application of ivabradine results from its ability to decrease myocardial ischaemia. Because myocardial ischaemia has a definite impact on outcome, its reduction is likely to improve prognosis in patients with coronary artery disease (CAD). In such patients, lowering the heart rate per se might also reduce risk for sudden cardiac death or acute coronary events, as a strong link exists between heart rate and plaque rupture, which is the triggering mechanism of most complications of CAD. Most importantly, If current inhibition might be useful in patients with congestive heart failure. In such patients, there is a parallel between heart rate reduction and the beneficial clinical effects achieved with beta-blockers. Observational studies, on the other hand, show that only a minority of patients with heart failure receive beta-blockers; If current inhibition might constitute an alternative in such patients. Diastolic heart failure remains a therapeutic challenge, and prolonging the diastolic time is likely to prove beneficial. Because ivabradine has no negative impact on left ventricular function, it might also be useful for controlling heart rate in patients with acute heart failure treated with agents such as dobutamine. Future studies will determine whether ivabradine fulfils part, or all, of this promise.