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 mu M) progressively prolonged A-V-nodal conduction without reducing left ventricular function or coronary resistance. In vivo, INO-8875 up to a dose of 50 mu g/kg did not reduce the carotid arterial blood pressure (n = 4). INO-8875 (1-50 mu g/kg) and CVT-510 (20 and 50 mu g/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.