piperidines and cilobradine

Heart rate (HR) is often elevated in cats with cardiomyopathies (CMPs). Pharmacologic modulation of HR may reduce cardiac morbidity and mortality.. To investigate the effects of cilobradine vs. placebo, regarding time to cardiac mortality or morbidity in cats with first episode of congestive heart failure (CHF) due to primary CMP.. Three hundred and sixty-seven client-owned cats with primary CMP that had presented with a first episode of CHF at 50 centers in Europe. Per-protocol population comprised 193 cats (n = 89 cilobradine, n = 104 placebo). An interim analysis for futility was planned.. Prospective, randomized, placebo-controlled, double-blinded, multicenter clinical trial. Primary outcome variable was the time to a composite of cardiac mortality or cardiac morbidity.. Median time to primary outcome was 84 days (95% confidence interval [CI]: 63-219 days) in the cilobradine group (CG) and 203 days in the placebo group (95% CI: 145-377 days) with observed hazard ratio of 1.44, indicating a higher hazard for the CG (P = 0.057). Mean HR was 28 beats per minute (bpm) lower at Day 7 (P < 0.0001) and remained 29 bpm lower at Day 360 (P = 0.026) in the CG than that in the placebo group. Although the number of adverse events did not differ, there were more serious adverse events in the CG.. Heart rate reduction by cilobradine in cats with a first episode of CHF due to primary CMP did not reduce cardiac mortality and morbidity.

Topics: Animals; Benzazepines; Cardiomyopathies; Cat Diseases; Cats; Heart Failure; Piperidines; Prospective Studies

Cilobradine (CIL, DK-AH269), an inhibitor of hyperpolarization-activated cation current (

Topics: Animals; Benzazepines; Cations; Cell Line, Tumor; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ion Transport; Ivabradine; Kinetics; Patch-Clamp Techniques; Piperidines; Pituitary Neoplasms; Potassium; Shab Potassium Channels; Sodium

Hyperpolarization-activated currents (I(h)) affect multiple neuronal functions including membrane potential, intrinsic firing properties, synaptic integration and frequency-dependent resonance behavior. Consistently, I(h) plays a key role for oscillations at the cellular and network level, including theta and gamma oscillations in rodent hippocampal circuits. Little is known, however, about the contribution of I(h) to a prominent memory-related pattern of network activity called sharp-wave-ripple complexes (SPW-R). Here we report that pharmacological suppression of I(h) induces specific changes in SPW-R in mouse hippocampal slices depending on the specific drug used and the region analyzed. Spontaneous generation of the events was reduced by blocking I(h) whereas the amplitude was unaffected or increased. Interestingly, the superimposed ripple oscillations at ∼200 Hz persisted with unchanged frequency, indicating that I(h) is not critical for generating this rhythmic pattern. Likewise, coupling between field oscillations and units was unchanged, showing unaltered recruitment of neurons into oscillating assemblies. Control experiments exclude a contribution of T-type calcium channels to the observed effects. Together, we report a specific contribution of hyperpolarization-activated cation currents to the generation of sharp waves in the hippocampus.

Topics: Action Potentials; Animals; Benzazepines; Brain Waves; Cyclic Nucleotide-Gated Cation Channels; Hippocampus; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Male; Mice; Mice, Inbred C57BL; Organ Culture Techniques; Piperidines; Potassium Channels

To develop a semi-mechanistic population pharmacokinetic/pharmacodynamic (PKPD) model for the selective bradycardic agent cilobradine describing simultaneously the heart rate (HR) measured at rest and just after the end of exercise sharing the same set of PKPD parameters.. Healthy subjects received cilobradine orally once daily over 2 weeks at 0.25-5 mg doses or placebo. Plasma drug concentrations and HR were measured at rest and following 3 min of exercise over the entire study period. PK and HR data were analyzed using the population approach with NONMEM VII.. Plasma disposition of cilobradine was described with a three compartment model. Cilobradine showed dose proportional and time independent pharmacokinetics. HR response was drug concentration dependent and appeared with a significant delay with respect to PK profiles, a phenomenon modeled using two transit compartments. Perturbation in HR at rest as a consequence of exercise was described assuming that physiological processes controlling cardiac frequency were constantly increased over the period of exercise only.. The selected model provides a useful modeling tool for cases where the PD response measured is the result of a temporal experimental induced perturbation.

Topics: Adult; Benzazepines; Exercise; Female; Heart; Heart Rate; Humans; Male; Middle Aged; Models, Biological; Piperidines; Rest; Young Adult

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate the rhythmic beating of mammalian hearts. We identified an HCN homolog in the colonial ascidian Botryllus schlosseri, a nonvertebrate chordate which possesses a tubular heart that beats bidirectionally. Contractions initiate at one end of the heart and travel across the length of the organ, and these periodically reverse, suggesting the presence of two pacemakers, one on each side. We find that HCN expression is highly enriched in cells scattered throughout the myocardium. We functionally analyzed the role of HCN channels in heartbeat using the antagonists Cilobradine and Zatebradine, which decreased the heartbeat in a reversible manner. We also assessed the role of β-adrenoreceptors in regulating HCN function using the antagonist Metoprolol, which lowered heartbeat rate (HR), as well as the agonist Isoproterenol, which did not alter HR, but caused simultaneous beating, analogous to a fibrillation. Measurements of direction and velocity of blood flow by making use of a novel system to study heart function in model systems amenable to live imaging revealed a significant correlation between heartbeat arrhythmia and drug treatment, similar to that observed with the same drugs in vertebrates. These results suggest that the heart pacemaker in tunicates may be homologous to that in their vertebrate counterparts in both development and function.

Topics: Adrenergic beta-Antagonists; Animals; Benzazepines; Biological Clocks; Blood Flow Velocity; Cyclic Nucleotide-Gated Cation Channels; Gene Expression Regulation, Developmental; Heart; Humans; Metoprolol; Piperidines; Receptors, Adrenergic, beta; RNA; Sequence Homology, Amino Acid; Urochordata

HCN1-4 subunits form Na+/K+-permeable ion channels that are activated by hyperpolarization and carry the current known as I(h). I(h) has been characterized in vestibular hair cells of the inner ear, but its molecular correlates and functional contributions have not been elucidated. We examined Hcn mRNA expression and immunolocalization of HCN protein in the mouse utricle, a mechanosensitive organ that contributes to the sense of balance. We found that HCN1 is the most highly expressed subunit, localized to the basolateral membranes of type I and type II hair cells. We characterized I(h) using the whole-cell, voltage-clamp technique and found the current expressed in 84% of the cells with a mean maximum conductance of 4.4 nS. I(h) was inhibited by ZD7288, cilobradine, and by adenoviral expression of a dominant-negative form of HCN2. To determine which HCN subunits carried I(h), we examined hair cells from mice deficient in Hcn1, 2, or both. I(h) was completely abolished in hair cells of Hcn1⁻/⁻ mice and Hcn1/2⁻/⁻ mice but was similar to wild-type in Hcn2⁻/⁻ mice. To examine the functional contributions of I(h), we recorded hair cell membrane responses to small hyperpolarizing current steps and found that activation of I(h) evoked a 5-10 mV sag depolarization and a subsequent 15-20 mV rebound upon termination. The sag and rebound were nearly abolished in Hcn1-deficient hair cells. We also found that Hcn1-deficient mice had deficits in vestibular-evoked potentials and balance assays. We conclude that HCN1 contributes to vestibular hair cell function and the sense of balance.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Age Factors; Animals; Animals, Newborn; Benzazepines; Cyclic Nucleotide-Gated Cation Channels; Ear, Inner; Electric Stimulation; Female; Forkhead Transcription Factors; Gene Expression Regulation, Developmental; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Male; Membrane Potentials; Mice; Mice, Knockout; Motion; Nerve Tissue Proteins; Neurofilament Proteins; Patch-Clamp Techniques; Piperidines; Postural Balance; Potassium Channels; Pyrimidines; RNA, Messenger; Rotarod Performance Test; Saccule and Utricle; Vestibular Evoked Myogenic Potentials

Ivabradine represents a novel heart-rate-lowering agent that acts on the sino-atrial node supposedly by selectively inhibiting the 'funny' current (I(f) current). In clinical studies, it was reported that ivabradine effectively reduced resting heart rate and was well tolerated. The aim of this study was to evaluate potential effects of ivabradine on cardiac contractility. Contractile effects of ivabradine were studied in isolated electrically driven atrial preparations from patients undergoing cardiac bypass surgery and for comparison in isolated spontaneously beating right atria and electrically driven left atria from mice. In human trabeculae, a concentration-dependent negative inotropic effect was noted in 7 from 10 patients. However, in 3 patients from 10, a pronounced positive inotropic effect of ivabradine was noted. As expected, in spontaneously beating mouse right atria ivabradine exerted a concentration-dependent negative chronotropic effect. Unexpectedly, contractile effects in mouse and man seem to disagree. In mouse left atria, ivabradine and cilobradine, another hyperpolarization-activated cyclic-nucleotide-gated blocker, always exerted a pronounced positive inotropic effect. These positive inotropic effects were converted to negative inotropic effects in the additional presence of the L-type Ca²+ channel blocker verapamil. The present study demonstrates that ivabradine at high concentrations can affect the force of contraction in atrial preparations from the human heart.

Topics: Adult; Aged; Aged, 80 and over; Animals; Benzazepines; Dose-Response Relationship, Drug; Electric Stimulation; Female; Heart Atria; Humans; Ivabradine; Male; Mice; Middle Aged; Myocardial Contraction; Piperidines; Species Specificity; Verapamil

To evaluate the population pharmacokinetic characteristics of cilobradine including a covariate analysis based on six phase I trials and to assess the predictive performance of the model developed.. Single or multiple doses of cilobradine were administered as solution, capsule or infusion. Two thousand, seven hundred and thirty-three plasma samples (development data set) were used for model development in NONMEM. Model evaluation was performed using also an external data set.. Data were best described by a linear three-compartment model. Typical V ss was large ( approximately 100 l) and CL was 21.5 l/h. Covariate analysis revealed a statistically significant but clinically irrelevant relation between KA and dose. Inter-individual variability was moderate (15-46%); imprecision of estimates was generally low. The final model was successfully applied to the external data set revealing its robustness and general applicability. Its final estimates resembled those of the development data set except for the covariate relation not being supported. When excluding the covariate relation, all observations were well predicted.. A robust population PK model has been developed for cilobradine predicting plasma concentrations from a different study design well. Therefore, the model can serve as a tool to simulate and evaluate different dosing regimens for further clinical trials.

Topics: Benzazepines; Biological Availability; Clinical Trials, Phase I as Topic; Cross-Over Studies; Cyclic Nucleotide-Gated Cation Channels; Data Interpretation, Statistical; Double-Blind Method; Humans; Models, Biological; Piperidines; Randomized Controlled Trials as Topic

Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels mediate the pacemaker current (Ih or If) observed in electrically rhythmic cardiac and neuronal cells. Here we describe a hyperpolarization-activated time-dependent cationic current, beta-Ih, in pancreatic beta-cells. Transcripts for HCN1-4 were detected by RT-PCR and quantitative PCR in rat islets and MIN6 mouse insulinoma cells. beta-Ih in rat beta-cells and MIN6 cells displayed biophysical and pharmacological properties similar to those of HCN currents in cardiac and neuronal cells. Stimulation of cAMP production with forskolin/3-isobutyl-1-methylxanthine (50 microM) or dibutyryl-cAMP (1 mM) caused a significant rightward shift in the midpoint activation potential of beta-Ih, whereas expression of either specific small interfering (si)RNA against HCN2 (siHCN2b) or a dominant-negative HCN channel (HCN1-AAA) caused a near-complete inhibition of time-dependent beta-Ih. However, expression of siHCN2b in MIN6 cells had no affect on glucose-stimulated insulin secretion under normal or cAMP-stimulated conditions. Blocking beta-Ih in intact rat islets also did not affect membrane potential behavior at basal glucose concentrations. Taken together, our experiments provide the first evidence for functional expression of HCN channels in the pancreatic beta-cell.

Topics: Animals; Benzazepines; Cells, Cultured; Cyclic AMP; Cyclic Nucleotide-Gated Cation Channels; Electrophysiology; Exocytosis; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Insulin; Insulin Secretion; Insulin-Secreting Cells; Insulinoma; Membrane Potentials; Mice; Piperidines; Potassium Channel Blockers; Potassium Channels; Pyrimidines; Rats; RNA, Small Interfering

Both beta-adrenergic blockade and bradycardia may contribute to the therapeutic effect of beta-blockers in chronic heart failure (CHF). This study tested the relative importance of bradycardia by comparing cilobradine (Cilo), a sinus node inhibitor, with a beta-blocker, metoprolol (Meto), in an established canine model of CHF. Dogs were chronically instrumented for hemodynamic and left ventricular (LV) volume measurements. CHF was created by daily coronary embolization via a chronically implanted coronary (left anterior descending coronary artery) catheter. After establishment of CHF, control (n=6), Meto (30 mg/day, n=5), Cilo (low) (1 mg/kg/day, n=5), or Cilo (high) (3 mg/kg/day, n=5) was given orally for 12 weeks. Systemic hemodynamics, echocardiography, and pressure volume analysis were measured at baseline, at CHF, and 3 months after treatment in an awake state. Protein levels of cardiac sarcoplasmic reticulum calcium-ATPase (SERCA2a), ryanodine receptor (RyR2), and Na+-Ca2+ exchanger (NCX1) were measured by Western blot. RyR2 protein kinase A (PKA) phosphorylation was determined by back-phosphorylation. After 12 weeks, Meto and Cilo (high and low) produced similar bradycardic effects, accompanied by a significantly improved LV dP/dt versus control [Meto, 2602+/-70; Cilo (low), 2517+/-45; Cilo (high), 2579+/-78; control, 1922+/-115 mm Hg/s; p<0.05]. Both Meto and Cilo (high) normalized protein levels of SERCA2a and NCX1 and reversed PKA hyperphosphorylation of RyR2, in contrast to controls. High-dose cilobradine effectively produced bradycardia and improved cardiac function after CHF, comparable with metoprolol. Restored protein levels of SERCA2a and improved function of RyR2 may be important mechanisms associated with cilobradine therapy.

Topics: Adrenergic beta-Antagonists; Animals; Benzazepines; Calcium; Coronary Stenosis; Dogs; Echocardiography; Female; Heart Failure; Heart Rate; Male; Metoprolol; Piperidines; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sodium-Calcium Exchanger; Ventricular Function, Left; Ventricular Remodeling

Sinus node inhibitors reduce the heart rate presumably by blocking the pacemaker current If in the cardiac conduction system. This pacemaker current is carried by four hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels. We tested the potential subtype-specificity of the sinus node inhibitors cilobradine, ivabradine, and zatebradine using cloned HCN channels. All three substances blocked the slow inward current through human HCN1, HCN2, HCN3, and HCN4 channels. There was no subtype-specificity for the steady-state block, with mean IC50 values of 0.99, 2.25, and 1.96 microM for cilobradine, ivabradine, and zatebradine, respectively. Native If, recorded from mouse sinoatrial node cells, was slightly more efficiently blocked by cilobradine (IC50 value of 0.62 microM) than were the HCN currents. The block of I(f) in sinoatrial node cells resulted in slower and dysrhythmic spontaneous action potentials. The in vivo action of these blockers was analyzed using telemetric ECG recordings in mice. Each compound reduced the heart rate dose-dependently from 600 to 200 bpm with ED50 values of 1.2, 4.7, and 1.8 mg/kg for cilobradine, ivabradine, and zatebradine, respectively. beta-Adrenergic stimulation or forced physical activity only partly reversed this bradycardia. In addition to bradycardia, all three drugs induced increasing arrhythmia at concentrations greater than 5 mg/kg for cilobradine, greater than 10 mg/kg for zatebradine, or greater than 15 mg/kg for ivabradine. This dysrhythmic heart rate is characterized by periodic fluctuations of the duration between the T and P wave, resembling a form of sick sinus syndrome in humans. Hence, all available sinus node inhibitors possess an as-yet-unrecognized proarrhythmic potential.

Topics: Animals; Arrhythmias, Cardiac; Benzazepines; Bradycardia; Cardiotonic Agents; Cloning, Molecular; Electrocardiography; Humans; Ivabradine; Mice; Mice, Inbred C57BL; Piperidines; Sinoatrial Node; Up-Regulation

We have compared the effect of two distinct Ih inhibitors on the temporal properties of the ERG response that, as previously shown, correlates well with the HCN activation in rods. The present results confirm the notion that cilobradine is more effective than zatebradine in inducing bradycardia. Importantly, the doses of cilobradine that reduce the heart rate to values comparable to, or lower than, those obtained with higher doses of zatebradine have little effect on the frequency response of the ERG. While more potent than zatebradine in its bradycardic action, cilobradine appears comparatively less effective on the visual response. A possible explanation is that the affinity of cilobradine for the HCN channels in the heart is higher than that for the HCN channels of retinal neurons.

Topics: Animals; Benzazepines; Bradycardia; Cardiotonic Agents; Dose-Response Relationship, Drug; Electroretinography; Heart; Heart Rate; Ion Channels; Membrane Potentials; Piperidines; Rats; Rats, Long-Evans; Retina; Retinal Ganglion Cells; Retinal Rod Photoreceptor Cells; Tachycardia

Decreasing heart rate might be beneficial for improvement of myocardial energetics and could reduce the severity of myocardial ischemia. We examined the contribution of heart rate reduction by cilobradine (DK-AH 269), a direct sinus node inhibitor, on left ventricular function and peripheral vasomotion in anesthetized rabbits with experimental myocardial infarction. The rabbits were randomized to receive either placebo (n=10) or cilobradine (n=7). Cilobradine decreased significantly heart rate from 163 +/- 33 to 131 +/- 13 bpm, p< 0.05, without any inotopic or vascular effects. After 60 min coronary occlusion and 30 min reperfusion, both systolic and diastolic ventricular function were more reduced in the cilobradine group; i.e. maximal left ventricular pressure significantly decreased to 62 +/- 11 mmHg, p < 0.05 (placebo: 77 +/- 9 mmHg); dP/dt(min) significantly decreased to -904 +/- 247 mmHg, p < 0.05 (placebo: -1106 +/- 242 mmHg). However, infarct size in the cilobradine group was significantly smaller compared with the placebo group. In conclusion, cilobradine reduced heart rate without any negative inotropic effect and reduced infarct size. On that account, this bradycardic agent might open a promising therapeutical avenue to treat postischemic dysfunction.

Topics: Animals; Benzazepines; Bradycardia; Heart Rate; Myocardial Ischemia; Piperidines; Rabbits