piperidines and zatebradine

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, 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

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

To investigate whether slow inward Ca2+ current (ICa), hyperpolarization-activated inward current (If), and a rapid type of delayed rectifier K+ current (IKr) similarly act on the pacemaker location, sinoatrial node region, and subsidiary superior and inferior pacemaker regions, we studied the effects of verapamil, zatebradine, and E-4031 on the atrial rate and the 3-ms earliest activation region (EAR) determined from the isochronal activation sequence map in the autonomically decentralized heart of the anesthetized dog. Three blockers decreased atrial rate similarly. Verapamil shifted the EAR from the SA node region to the inferior pacemaker region. The EAR induced by zatebradine was variable, but the EAR induced by E-4031 tended to shift to the inferior pacemaker region. Sympathetic nerve stimulation increased atrial rate and shifted the EAR to the superior pacemaker region. Verapamil attenuated the increased atrial rate by 28%, and it shifted the EAR to the lower pacemaker regions consistently. Zatebradine also attenuated the increased rate by 53% and shifted the EAR from the anterior to the posterior-superior right atrium. On the other hand, E-4031 affected neither the rate nor the EAR in response to sympathetic stimulation. These results suggest that ICa, If, and IKr inhibitors differentially influence the pacemaker activity among three pacemaker regions when sympathetic tone is absent or present and that the role of ICa, If, and IKr of the pacemaker cells distributed in the atrial pacemaker complex is different in the dog heart in situ.

Topics: Animals; Anti-Arrhythmia Agents; Benzazepines; Cardiotonic Agents; Delayed Rectifier Potassium Channels; Dogs; Dose-Response Relationship, Drug; Electric Stimulation; Heart; Heart Atria; Heart Conduction System; Heart Rate; Piperidines; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Pyridines; Sinoatrial Node; Sympathetic Nervous System; Verapamil

We investigated the effects of hypothermia (25 degrees C) on the chronotropic and inotropic effects of zatebradine (a blocker of hyperpolarization-activated inward current, I(f)), E-4031 (a blocker of the rapid type of the delayed rectifier K+ current, I(Kr)) and verapamil, and on the positive cardiac responses to isoproterenol after treatment with zatebradine and E-4031 in isolated, blood-perfused dog atria. Hypothermia shifted the dose-response curves to the right for the negative chronotropic and inotropic effects of verapamil and for the negative chronotropic and positive inotropic effects of zatebradine, but not for the negative chronotropic and positive inotropic effects of E-4031. Hypothermia attenuated the positive chronotropic response to isoproterenol or Bay k 8644 (an L type Ca2+ channel agonist) and was attenuated more than the inotropic one. Zatebradine selectively inhibited the positive chronotropic response to isoproterenol at a normal temperature, but in hypothermia, it inhibited neither the chronotropic nor inotropic responses. E-4031 did not affect the positive responses to isoproterenol. These results suggest that verapamil and zatebradine but not E-4031 influence the atrial rate and contractile force much less in hypothermia than in normothermia and that the I(f) and inward Ca2+ current are sensitive to hypothermia in the heart.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Benzazepines; Calcium Channel Agonists; Cardiovascular Agents; Cold Temperature; Dogs; Dose-Response Relationship, Drug; Heart Atria; Hypothermia, Induced; In Vitro Techniques; Isoproterenol; Myocardial Contraction; Perfusion; Piperidines; Pyridines; Verapamil

To investigate the effect of the delayed rectifier K+ current (IK) on the atrioventricular (AV) node of the heart in situ, we studied the direct effects of (1-[2-(6-methyl-2-pyridyl)ethyl]-4-(methylsulfonyl-aminobenzoyl)piperidi ne (E-4031), an IKr (a rapid type of IK) blocker, on the AV junctional rate, atrio-His interval (AH interval), and right ventricular pressure, and the cardiac responses to sympathetic nerve stimulation in the anesthetized dog heart. AV junctional rhythm was induced by clamping the sinoatrial (SA) pacemaker area. E-4031 (0.01-3 mumol/kg, i.v.) attenuated the AV junctional rate dose dependently. The junctional negative chronotropic effect was less than the decrease in sinus rate induced by E-4031 in the same doses. E-4031 did not affect the junctional rate increased by sympathetic stimulation. In the paced heart, E-4031 slightly increased the AH interval but did not change right ventricular pressure responses. E-4031 attenuated neither positive dromotropic nor positive ventricular pressure responses to sympathetic stimulation. After E-4031 treatment, zatebradine (a hyperpolarization-activated current blocker) additively decreased the junctional rate and the junctional positive chronotropic responses to sympathetic stimulation. These results suggest that IKr has much less effect on AV nodal pacemaker activity than on SA nodal pacemaker activity, and an IKr blocker, E-4031, unlike zatebradine, does not antagonize the junctional positive chronotropic responses to sympathetic activation in anesthetized dog heart.

Topics: Anesthesia; Animals; Anti-Arrhythmia Agents; Atrioventricular Node; Benzazepines; Cardiotonic Agents; Chronobiology Phenomena; Dogs; Electric Stimulation; Piperidines; Potassium Channels; Pyridines

Inhibition by zatebradine, a specific bradycardic agent, of the negative inotropic but not chronotropic responses to adenosine has been briefly reported in the isolated, perfused dog heart. We therefore investigated whether subtypes of adenosine receptors or postreceptor transduction mechanisms differentiated the negative chronotropic and inotropic responses to adenosine in the isolated, blood-perfused atrial and ventricular preparations of the dog. Adenosine (1-3000 nmol), adenosine A1 receptor agonists, 2-chloroadenosine (CAD, 0.1-300 nmol) and N6-cyclohexyladenosine (CHA, 1-300 nmol) and a nonselective adenosine receptor agonist, 5'-N-ethyl-carboxamidoadenosine (NECA, 0.1-100 nmol), induced the negative chronotropic and inotropic responses. The potency order was NECA > CAD > adenosine > or = CHA. An adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10-300 nmol), dose-dependently inhibited the negative chronotropic and inotropic responses to adenosine, CAD and NECA in the isolated, perfused right atrium. DPCPX also blocked the negative inotropic responses to adenosine, CAD and NECA in the isolated left ventricle. However, an adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX, 300 nmol), did not affect the negative cardiac responses to adenosine and NECA. Although the negative inotropic but not chronotropic responses to CAD and adenosine were dose-dependently inhibited by zatebradine, K+ channel inhibitors 4-aminopyridine and E-4031 did not modify the cardiac responses to adenosine and CAD. These results suggest that the negative cardiac responses to adenosine are mediated by adenosine A1 receptors and the negative chronotropic and inotropic responses to adenosine are differentiated at the postreceptor transduction level(s) in the dog heart.

Topics: 2-Chloroadenosine; 4-Aminopyridine; Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Benzazepines; Depression, Chemical; Dogs; Heart Rate; In Vitro Techniques; Myocardial Contraction; Piperidines; Pyridines; Receptors, Purinergic P1; Xanthines