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.
This article has supplemental material available at jpet.aspetjournals.org.
- Received October 2, 2012.
- Accepted October 9, 2012.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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