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Research ArticleArticle

ATP-Sensitive Potassium Channel Blocker HMR 1883 Reduces Mortality and Ischemia-Associated Electrocardiographic Changes in Pigs with Coronary Occlusion

Klaus J. Wirth, Björn Rosenstein, Jörg Uhde, Heinrich C. Englert, Andreas E. Busch and Bernward A. Schölkens
Journal of Pharmacology and Experimental Therapeutics November 1999, 291 (2) 474-481;
Klaus J. Wirth
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Björn Rosenstein
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Jörg Uhde
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Heinrich C. Englert
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Andreas E. Busch
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Bernward A. Schölkens
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Abstract

ATP-sensitive potassium (KATP) channels are activated during myocardial ischemia. The ensuing potassium efflux leads to a shortening of the action potential duration and depolarization of the membrane by accumulation of extracellular potassium favoring the development of reentrant arrhythmias, including ventricular fibrillation. The sulfonylthiourea HMR 1883 was designed as a cardioselective blocker of myocardial KATP channels for the prevention of arrhythmic sudden death in patients with ischemic heart disease. We investigated the effect of HMR 1883 on sudden cardiac arrhythmic death and electrocardiography (ECG) changes induced by 20 min of left anterior descending coronary artery occlusion in pentobarbital-anesthetized pigs. HMR 1883 (3 mg/kg i.v.) protected pigs from arrhythmic death (91% survival rate versus 33% in control animals; n = 12; p < .05). Ischemic areas were of a similar size. The compound had no effect on hemodynamics and ECG, including Q-T interval, under baseline conditions and no effect on hemodynamics during occlusion. In control animals, left anterior descending coronary artery occlusion lead to a prompt and significant depression of the S-T segment (−0.35 mV) and a prolongation of the Q-J time (+46 ms), the former reflecting heterogeneity in the plateau phase of the action potentials and the latter reflecting irregular impulse propagation and delayed ventricular activation. Both ischemic ECG changes were significantly attenuated by HMR 1883 (S-T segment, −0.14 mV; Q-J time, +15 ms), indicating the importance of KATP channels in the genesis of these changes. In conclusion, the KATP channel blocker HMR 1883, which had no effect on hemodynamics and ECG under baseline conditions, reduced the extent of ischemic ECG changes and sudden death due to ventricular fibrillation during coronary occlusion.

Footnotes

  • Send reprint requests to: Dr. Klaus J. Wirth, Hoechst AG, H 813, HMR DG Cardiovascular Diseases, 65926 Frankfurt am Main, Germany. E-mail: klaus.wirth{at}hmrag.com

  • Abbreviations:
    KATP
    ATP-sensitive potassium
    BP
    blood pressure
    BPs
    systolic blood pressure
    ECG
    electrocardiographic (electrocardiography, electrocardiogram)
    dp/dt
    left ventricular contractility
    HR
    heart rate
    LVEDP
    left ventricular end-diastolic pressure
    CO
    cardiac output
    SV
    stroke volume
    TPR
    total peripheral resistance
    LVSW
    left ventricular stroke work
    LVP
    left ventricular systolic pressure
    LAD
    left anterior descending coronary artery
    VF
    ventricular fibrillation
    • Received February 17, 1999.
    • Accepted July 6, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 2
1 Nov 1999
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Research ArticleArticle

ATP-Sensitive Potassium Channel Blocker HMR 1883 Reduces Mortality and Ischemia-Associated Electrocardiographic Changes in Pigs with Coronary Occlusion

Klaus J. Wirth, Björn Rosenstein, Jörg Uhde, Heinrich C. Englert, Andreas E. Busch and Bernward A. Schölkens
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 474-481;

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Research ArticleArticle

ATP-Sensitive Potassium Channel Blocker HMR 1883 Reduces Mortality and Ischemia-Associated Electrocardiographic Changes in Pigs with Coronary Occlusion

Klaus J. Wirth, Björn Rosenstein, Jörg Uhde, Heinrich C. Englert, Andreas E. Busch and Bernward A. Schölkens
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 474-481;
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