INO-8875, a highly selective A1 adenosine receptor agonist: evaluation of chronotropic, dromotropic, and hemodynamic effects in rats.
Selective pharmacological activation of the adenosine 1 receptor (A(1)R) 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 A(1)R 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 A(1)R agonist. INO-8875 exhibits an increased dromotropic effect and greater duration of action compared with CVT-510.
Cardiac Arrhythmia Research Laboratory & Division of Internal Medicine, Soroka University Medical Center, P.O. Box 151, Beer-Sheva 84101, Israel.
Michal
M
Mor
Aryeh
A
Shalev
Shani
S
Dror
Oleg
O
Pikovsky
Ofer
O
Beharier
Arie
A
Moran
Amos
A
Katz
Yoram
Y
Etzion
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents; D001283:Atrioventricular Node / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009566:Nitrates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013617:Tachycardia, Supraventricular / Q000188:drug therapy
D058907:Adenosine A1 Receptor Agonists; D000889:Anti-Arrhythmia Agents; D005663:Furans; C578457:INO-8875; D009566:Nitrates; C118601:tecadenoson; D000241:Adenosine