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Research ArticleCardiovascular

INO-8875, a Highly Selective A1 Adenosine Receptor Agonist: Evaluation of Chronotropic, Dromotropic, and Hemodynamic Effects in Rats

Michal Mor, Aryeh Shalev, Shani Dror, Oleg Pikovsky, Ofer Beharier, Arie Moran, Amos Katz and Yoram Etzion
Journal of Pharmacology and Experimental Therapeutics January 2013, 344 (1) 59-67; DOI: https://doi.org/10.1124/jpet.112.200873
Michal Mor
Cardiac Arrhythmia Research Laboratory and Division of Internal Medicine, Soroka University Medical Center, Beer-Sheva, Israel (M.M., A.S., S.D., O.P., O.B., A.K., Y.E.); Department of Physiology, Faculty of Health Sciences (M.M., S.D., O.B., A.M.) and Department of Cardiology, Barzilai Medical Center, Ashkelon Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel (A.K.)
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Aryeh Shalev
Cardiac Arrhythmia Research Laboratory and Division of Internal Medicine, Soroka University Medical Center, Beer-Sheva, Israel (M.M., A.S., S.D., O.P., O.B., A.K., Y.E.); Department of Physiology, Faculty of Health Sciences (M.M., S.D., O.B., A.M.) and Department of Cardiology, Barzilai Medical Center, Ashkelon Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel (A.K.)
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Shani Dror
Cardiac Arrhythmia Research Laboratory and Division of Internal Medicine, Soroka University Medical Center, Beer-Sheva, Israel (M.M., A.S., S.D., O.P., O.B., A.K., Y.E.); Department of Physiology, Faculty of Health Sciences (M.M., S.D., O.B., A.M.) and Department of Cardiology, Barzilai Medical Center, Ashkelon Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel (A.K.)
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Oleg Pikovsky
Cardiac Arrhythmia Research Laboratory and Division of Internal Medicine, Soroka University Medical Center, Beer-Sheva, Israel (M.M., A.S., S.D., O.P., O.B., A.K., Y.E.); Department of Physiology, Faculty of Health Sciences (M.M., S.D., O.B., A.M.) and Department of Cardiology, Barzilai Medical Center, Ashkelon Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel (A.K.)
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Ofer Beharier
Cardiac Arrhythmia Research Laboratory and Division of Internal Medicine, Soroka University Medical Center, Beer-Sheva, Israel (M.M., A.S., S.D., O.P., O.B., A.K., Y.E.); Department of Physiology, Faculty of Health Sciences (M.M., S.D., O.B., A.M.) and Department of Cardiology, Barzilai Medical Center, Ashkelon Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel (A.K.)
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Arie Moran
Cardiac Arrhythmia Research Laboratory and Division of Internal Medicine, Soroka University Medical Center, Beer-Sheva, Israel (M.M., A.S., S.D., O.P., O.B., A.K., Y.E.); Department of Physiology, Faculty of Health Sciences (M.M., S.D., O.B., A.M.) and Department of Cardiology, Barzilai Medical Center, Ashkelon Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel (A.K.)
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Amos Katz
Cardiac Arrhythmia Research Laboratory and Division of Internal Medicine, Soroka University Medical Center, Beer-Sheva, Israel (M.M., A.S., S.D., O.P., O.B., A.K., Y.E.); Department of Physiology, Faculty of Health Sciences (M.M., S.D., O.B., A.M.) and Department of Cardiology, Barzilai Medical Center, Ashkelon Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel (A.K.)
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Yoram Etzion
Cardiac Arrhythmia Research Laboratory and Division of Internal Medicine, Soroka University Medical Center, Beer-Sheva, Israel (M.M., A.S., S.D., O.P., O.B., A.K., Y.E.); Department of Physiology, Faculty of Health Sciences (M.M., S.D., O.B., A.M.) and Department of Cardiology, Barzilai Medical Center, Ashkelon Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel (A.K.)
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Abstract

Selective pharmacological activation of the adenosine 1 receptor (A1R) is a promising new approach to achieve a potent block of atrioventricular (A-V)–nodal conduction without significant cardiovascular side effects. The purpose of the present study was to evaluate the cardiovascular profile of INO-8875, a highly selective A1R agonist, and to compare its properties with N-[3(R)-tetrahydrofuranyl]-6-aminopurine riboside (CVT-510), which has already been shown to induce negative dromotropic effects with minimal cardiovascular side effects in animals and in clinical studies. Dose-response experiments in the isolated hearts of rats were used to evaluate the functional selectivity of INO-8875 for the slowing of A-V–nodal conduction. Ventilated adult rats were used to study the effects of INO-8875, in vivo, on arterial blood pressure as well as on supraventricular electrophysiology. Ex vivo, INO-8875 (100 nM to 3 μM) progressively prolonged A-V–nodal conduction without reducing left ventricular function or coronary resistance. In vivo, INO-8875 up to a dose of 50 μg/kg did not reduce the carotid arterial blood pressure (n = 4). INO-8875 (1–50 μg/kg) and CVT-510 (20 and 50 μg/kg) both induced a dose-dependent decrease in heart rate and atrial refractoriness, as well as slowing of A-V–nodal conduction. However, compared with CVT-510, the activity of INO-8875 was more pronounced in A-V–nodal function. INO-8875 exhibited a greater duration of action, lasting up to 2.5 hours post dosing, whereas the effects of CVT-510 dissipated over 1 hour. INO-8875 demonstrates functional properties of a highly selective A1R agonist. INO-8875 exhibits an increased dromotropic effect and greater duration of action compared with CVT-510.

Footnotes

  • This study was supported by Inotek Pharmaceuticals Corporation (Lexington, MA).

  • ↵Parts of this work were previously presented at the following meeting: Etzion Y, Shaley A, Mor M, Dror S, Pikovsky O, Beharier O, Moran A, Katz A (2008) INO-8875, a highly selective A1 adenosine receptor agonist: evaluation of chronotropic, dromotropic, and hemodynamic effects in rats. The 57th Annual Meeting of the American College of Cardiology; 2008 Mar 29–Apr 1; Chicago, IL.

  • M.M. and A.S. contributed equally to this study.

  • Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • dx.doi.org/10.1124/jpet.112.200873.

  • Received October 2, 2012.
  • Accepted October 9, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 1
1 Jan 2013
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Research ArticleCardiovascular

Cardiovascular Effects of INO-8875 in Rats

Michal Mor, Aryeh Shalev, Shani Dror, Oleg Pikovsky, Ofer Beharier, Arie Moran, Amos Katz and Yoram Etzion
Journal of Pharmacology and Experimental Therapeutics January 1, 2013, 344 (1) 59-67; DOI: https://doi.org/10.1124/jpet.112.200873

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Research ArticleCardiovascular

Cardiovascular Effects of INO-8875 in Rats

Michal Mor, Aryeh Shalev, Shani Dror, Oleg Pikovsky, Ofer Beharier, Arie Moran, Amos Katz and Yoram Etzion
Journal of Pharmacology and Experimental Therapeutics January 1, 2013, 344 (1) 59-67; DOI: https://doi.org/10.1124/jpet.112.200873
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