Disease relevance of Zatebradine

• Because EMD 60263 decreased heart rate from 106 +/- 4 to 76 +/- 3 beats per minute (P < .05) in the animals with stunned myocardium, we performed five experiments with the specific negative chronotropic compound zatebradine (UL-FS 49, 0.1 to 0.5 mg/kg) to rule out bradycardia as a factor contributing to the effects of EMD 60263 [1].
• Thus, the sinus node inhibitor zatebradine belongs to a new class of "I(f) blockers" with possible advantages over currently available drugs for the treatment of ischemic heart disease [2].
• We examined the antianginal and anti-ischemic effects of oral zatebradine, a direct sinus node inhibitor that has no blood pressure-lowering or negative inotropic effects in patients with chronic stable angina pectoris taking extended-release nifedipine [3].
• Zatebradine had no effect on coronary blood flow and there was a 100% increase in flow with reactive hyperemia [4].
• The bradycardic agent zatebradine enhances baroreflex sensitivity and heart rate variability in rats early after myocardial infarction [5].

Psychiatry related information on Zatebradine

• 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 [6].

High impact information on Zatebradine

• BACKGROUND: Zatebradine is a bradycardic agent that inhibits the hyperpolarization-activated current (I(f)) in the rabbit sinoatrial node [7].
• CONCLUSIONS: These results indicate that (1) zatebradine is an open-channel blocker of hKv 1.5, (2) binding occurs in the internal mouth of the ion pore, (3) unbinding is required before the channel can close, and (4) zatebradine-induced block is use dependent because of slower recovery kinetics in the presence of the drug [7].
• These zatebradine doses lowered heart rate from 116 +/- 5 to 55 +/- 1 beats per minute (P < .05) but had no effect on SLS of stunned and not-stunned myocardium [1].
• Zatebradine and exercise tolerance [8].
• In a single-blind placebo run-in, randomized double-blind, placebo-controlled, multicenter study, patients already receiving extended-release nifedipine (30 to 90 mg once a day) were randomized to receive zatebradine (5 mg twice a day [n = 64]) or placebo (n = 60) [3].

Chemical compound and disease context of Zatebradine

• 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 [6].
• These results demonstrate that in contrast to CV nerve activation or verapamil, zatebradine and SAP stimulation cause bradycardia but preserve the myocardial contractile force and AVCT in response to sympathetic nerve activation or sympathomimetic drugs in the heart in situ [9].
• Control of dobutamine-induced tachycardia by zatebradine decreases myocardial oxygen consumption but does not alter the positive inotropic and lusitropic effects of dobutamine [10].
• Ischemia-induced biphasic arrhythmias were suppressed in both zatebradine and propranolol groups [11].
• To determine whether a hyperpolarization-activated current (If) participates in ventricular tachyarrhythmias, we investigated the effects of zatebradine, an I(f) inhibitor, on the ventricular tachyarrhythmias induced by ouabain, two-stage coronary ligation and epinephrine infusion in the dog heart [12].

Biological context of Zatebradine

• This use-dependent block of the If channel can account for most of the pharmacological characteristics of zatebradine and is probably the mechanism of heart rate reduction caused by this agent [2].
• In the group that received zatebradine, mean (+/- SE) heart rate decreased from 143 +/- 8 to 99 +/- 4 beats/min (p < 0.01) and there was no significant change in either peak left ventricular systolic pressure, dP/dt or tau [4].
• Isolated isovolumetric pig hearts were prepared and left ventricular pressure, its first derivative (dP/dt), tau and heart rate were measured both before and after administration of either 0.975 mg of zatebradine (Group I, n = 8) or 125 micrograms of verapamil (Group II, n = 8) [4].
• Action potential recordings in the SHHF rats demonstrated abnormal automaticity, which was abolished by the addition of an I(f) blocker (10 muM zatebradine) [13].
• Zatebradine improved stroke volume index in all treated rats but increased left ventricular volume in rats with small MI (2.43 +/- 0.10 vs. 1.81 +/- 0.10 ml/kg, P < 0.05) but not in rats with large MI (2.34 +/- 0.09 vs. 2.35 +/- 0.11 ml/kg, not significant) [14].

Anatomical context of Zatebradine

• We also assessed the effects of zatebradine and verapamil on coronary vascular tone by measuring flow in the left anterior descending coronary artery in intact anesthetized open chest pigs both before and after the intracoronary administration of these drugs (n = 8 for each) [4].
• Zatebradine also attenuated the increased rate by 53% and shifted the EAR from the anterior to the posterior-superior right atrium [15].
• Since the cation conductance activated by hyperpolarization seems to represent an ubiquitous class of membrane channel in mammals, the present study was undertaken to evaluate the influence of specific bradycardic agents [UL-FS 49 (zatebradine) and its derivative DK-AH 268] on excitable cells of the central nervous system [16].
• The different actions of two I(h) channel blockers, zatebradine (UL-FS 49) and ZD7288, on rod photoresponses were analysed by computer simulation using a newly revised ionic current model of the rod photoreceptor, based on Hodgkin-Huxley equations [17].
• Alinidine lengthened the effective refractory period (ERP) in the AV node (p < 0.01), whereas zatebradine did not induce a statistically significant prolongation [18].

Associations of Zatebradine with other chemical compounds

• Zatebradine administered in the presence of dobutamine caused a decrease in heart rate, an increase in subendocardial/subepicardial blood flow ratio (0.48 +/- 0.05 to 0.78 +/- 0.09) and allowed an increase in ischemic zone segment shortening [19].
• We tested the potential subtype-specificity of the sinus node inhibitors cilobradine, ivabradine, and zatebradine using cloned HCN channels [6].
• Haemodynamic actions of a novel sino-atrial node function modulator, ZENECA ZD7288, in the anaesthetized dog: a comparison with zatebradine, atenolol and nitrendipine [20].
• The cardiovascular and left ventricular (LV) functional effects of levosimendan were examined (LSM; 0.5, 1.0, 2.0 and 4.0 micrograms.kg-1.min-1) in conscious, chronically instrumented dogs (n = 8) in the presence and absence of heart rate control with zatebradine (ZAT) or ZAT alone (0.25, 0.5 and 1.0 mg.kg-1) [21].
• Of the 31 dogs subjected to reperfusion, mortality rates in the zatebradine, propranolol, and control groups were 56%, 75%, and 86%, respectively, and there were no significant differences [11].

Gene context of Zatebradine

• Zatebradine reduced rest heart rate both at 4 weeks ([mean +/- SEM] 12.9 +/- 1.23 vs. 2.3 +/- 1.6 [placebo] beats/min, p < 0.0001) and at the end of comparable stages of Bruce exercise (16.7 +/- 1.2 vs. 3.4 +/- 1.2 [placebo] beats/min, p < 0.0001) [3].
• Zatebradine (0.5 mg/kg i.v.) reduced heart rate in MI-rats from 400 +/- 15 to 350 +/- 19 and in SH-rats from 390 +/- 19 to 324 +/- 6 beats/min without changing mean arterial pressure [5].
• Inhibition of the hHCN1-mediated current by ZD 7288 was apparently independent of prior channel activation (i.e. non-use-dependent), whereas that induced by zatebradine was use-dependent [22].

Analytical, diagnostic and therapeutic context of Zatebradine

• We used the whole-cell patch-clamp technique to study the effects of zatebradine on ionic currents underlying diastolic depolarization of isolated rabbit SA node cells [2].
• Thirty minutes after left coronary artery ligation or sham operation, the rats were randomized to receive either placebo or zatebradine (100 mg x kg(-1) x day(-1) per gavage) continued for 8 wk [14].
• Zatebradine: pharmacokinetics of a novel heart-rate-lowering agent after intravenous infusion and oral administration to healthy subjects [23].
• In the heart beating 10 beats/min faster than the predrug heart rate by atrial pacing, both zatebradine and propranolol attenuated ischemia-induced arrhythmias but did not affect reperfusion arrhythmias [11].
• UL-FS 49 (Zatebradine) and its quaternary derivative, UL-AH 99, were injected by iontophoresis in shortened sheep cardiac Purkinje fibres [24].

References