Evidence that ranolazine behaves as a weak beta(1)- and beta(2)-adrenoceptor antagonist in the rat cardiovascular system

The clinical anti-anginal effectiveness of ranolazine is currently being ev aluated. However, the mechanism of its anti-ischaemic action is still uncle ar. The aim of this work was to establish whether ranolazine exerts functio nal beta -adrenoceptor antagonist activity in the rat cardiovascular system . Radioligand binding studies were performed in rat hearts and guinea-pig lun gs for beta (1)- and beta (2)-adrenoceptor affinity, respectively. Ranolazi ne had micromolar affinity for both beta (1)- and beta (2)-adrenoceptors (p K(i)5.8 and 6.3, respectively). Developed tension was measured in isolated rat left atria (electrically driven at 4 Hz) and cumulative concentration/r esponse curves to (+/- )isoprenaline (0.01-1000 nM) constructed. Ranolazine (0.32-10 muM) surmountably but weakly antagonised isoprenaline-induced pos itive inotropic responses, with an apparent pA(2) of 5.85 (5.69-6.00) and a slope of -0.74 (-0.70 to -0.77). In bivagotomised, atropinised pithed rats , ranolazine per se evoked marked bradycardia at doses above 10 mg/kg i.v. (maximum variation at 80 mg/kg -125 +/- 15 bpm, n=6, P<0.001) by a mechanis m apparently unrelated to blockade of <beta>(1)- or beta (2)-adrenoceptors. Cumulative incremental doses of (+/- )isoprenaline (0.63 ng/kg to 0.16 mg/ kg i.v.) administered to pithed rats induced concomitant depressor and chro notropic responses. Animals received either vehicle (saline 0.9% i.v., n=12 ), atenolol (0.04-2.5 mg/kg i.v., n=6 per dose), ICI 118551 (0.01-0.63 mg/k g i.v., n=6 or 7 per dose), (+/- )propranolol (0.01-0.63 mg/kg i.v., n=6 pe r dose) or ranolazine (2.5-80 mg/kg i.v., n=6 or 7 per dose) 10 min prior t o isoprenaline. Ranolazine dose-dependently and competitively antagonised i soprenaline-induced decreases in diastolic arterial pressure (DAP, dose rat io 12.2 with 80 mg/kg ranolazine) and increases in heart rate (HR, dose rat io 20.3 with 80 mg/kg ranolazine). Collectively, these results demonstrate that ranolazine behaves as a weak beta (1)- and beta (2)-adrenoceptor antag onist in the rat cardiovascular system.