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      A Single Intravenous Dose of Ivabradine, a Novel I f Inhibitor, Lowers Heart Rate but Does Not Depress Left Ventricular Function in Patients with Left Ventricular Dysfunction

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          Abstract

          This randomized, single-blind, placebo-controlled study investigated the effect of ivabradine, a novel heart rate-lowering agent, on echocardiographic indices of left ventricular (LV) systolic function in patients with regional (coronary artery disease) or global (cardiomyopathy) LV dysfunction. Patients were randomized on an unequal basis to receive ivabradine 0.25 mg/kg (n = 31) or placebo (n = 13) by intravenous infusion. Resting heart rate was reduced by a mean of 17.6 ± 4.7% with ivabradine and 1.5 ± 5.8% with placebo. The mean maximum decrease in LV ejection fraction was 0.2% with ivabradine and 1.7% with placebo. Fractional shortening and stroke volume were also fully preserved after ivabradine administration. Thus, a single intravenous dose of ivabradine produced a substantial reduction in resting heart rate without affecting LV function in patients with regional or global LV dysfunction.

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          Most cited references 6

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          Antianginal and Antiischemic Effects of Ivabradine, an I f Inhibitor, in Stable Angina: A Randomized, Double-Blind, Multicentered, Placebo-Controlled Trial

          Heart rate reduction should benefit patients with chronic stable angina by improving myocardial perfusion and reducing myocardial oxygen demand. This study evaluated the antianginal and antiischemic effects of ivabradine, a new heart rate-lowering agent that acts specifically on the sinoatrial node. In a double-blind, placebo-controlled trial, 360 patients with a > or =3-month history of chronic stable angina were randomly assigned to receive ivabradine (2.5, 5, or 10 mg BID) or placebo for 2 weeks, followed by an open-label 2- or 3-month extension on ivabradine (10 mg BID) and a 1-week randomized withdrawal to ivabradine (10 mg BID) or placebo. Primary efficacy criteria were changes in time to 1-mm ST-segment depression and time to limiting angina during bicycle exercise (exercise tolerance tests), performed at trough of drug activity. In the per-protocol population (n=257), time to 1-mm ST-segment depression increased in the 5 and 10 mg BID groups (P<0.005); time to limiting angina increased in the 10 mg BID group (P<0.05). Deterioration in all exercise tolerance test parameters occurred in patients who received placebo during randomized withdrawal (all P<0.02) but not in those still receiving ivabradine. No rebound phenomena were observed on treatment cessation. Ivabradine produces dose-dependent improvements in exercise tolerance and time to development of ischemia during exercise. These results suggest that ivabradine, representing a novel class of antianginal drugs, is effective and safe during 3 months of use; longer-term safety requires additional assessment.
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            Properties and functional roles of hyperpolarization-gated currents in guinea-pig retinal rods.

            1. The inward rectification induced by membrane hyperpolarization was studied in adult guinea-pig rods by the perforated-patch-clamp technique. 2. CsCl blocked the rectification observed in both voltage- and current-clamp recordings at voltages negative to -60 mV, while BaCl2 blocked the inward relaxation observed at voltages positive to -60 mV. The current activated at -90 mV had a low selectivity between sodium and potassium and reversed at -31.0 mV. 3. These observations suggest that two inward rectifiers are present in guinea-pig rods: a hyperpolarization-activated (Ih) and a hyperpolarization-deactivated (Ikx) current. The functional roles of Ih and Ikx were evaluated by stimulating rods with currents sinusoidally modulated in time. 4. Rods behave like bandpass amplifiers, with a peak amplification of 1.5 at about 2 Hz. For hyperpolarizations that mainly gate Ikx, amplification and phase shifts are fully accounted for by a rod membrane analogue model that includes an inductance. For hyperpolarizations that also gate Ih, a harmonic distortion became apparent. 5. Bandpass filtering and amplification of rod signals, associated with Ih and Ikx gating by membrane hyperpolarization, are strategically located to extend, beyond the limits imposed by the slow phototransductive cascade, the temporal resolution of signals spreading to the rod synapse.
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              Kinetic and ionic properties of the human HCN2 pacemaker channel.

              Human cDNA coding for the hyperpolarization-activated "pacemaker" channel HCN2 was expressed in Phoenix cells and yielded an inward current (IhHCN2) activated on hyperpolarization. The average IhHCN2 was half-activated at -83.1 mV and its kinetics could be described by second-order Hodgkin-Huxley gating. The time constant curve was bell-shaped and peaked at -82.2 mV. With 115 mM external Na+ and 30 mM external K+, IhHCN2 reversed at -17.1 mV, and had a mean conductance of 5.6 nS. Reducing the external K+ or Na+ concentration led to a concentration-dependent reduction of the IhHCN2 conductance and to a hyperpolarizing shift of reversal potential. External Cs+ ions (5 mM) blocked IhHCN2 in a voltage-dependent way according to a Woodhull-type block model, at an electrical distance of 0.66 from the external membrane surface, and with a dissociation constant of 15 mM at 0 mV. Increasing cytoplasmic cAMP using forskolin increased IhHCN2 by shifting the current activation curve to more positive voltages (11.7 mV). Exposure of the intracellular side of inside-out macro-patches to cAMP led to a depolarizing shift of the channel open probability curve (15.2 mV with 10 microM cAMP). These results indicate that although hHCN2 channels share several properties with native cardiac f-channels, differences also exist in permeability and block properties, suggesting that native channels may not be composed simply of homomeric constructs.
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2003
                November 2003
                21 November 2003
                : 100
                : 3
                : 149-155
                Affiliations
                aDepartment of Cardiology, Marienhof Hospital, Koblenz, bDepartments of Medicine and Cardiology, University of Bonn, Bonn, Germany
                Article
                73933 Cardiology 2003;100:149–155
                10.1159/000073933
                14631136
                © 2003 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Tables: 3, References: 27, Pages: 7
                Categories
                Clinical Pharmacology

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