Evidence that ranolazine behaves as a weak β₁- and β₂-adrenoceptor antagonist in the rat cardiovascular system

The clinical anti-anginal effectiveness of ranolazine is currently being evaluated. However, the mechanism of its anti-ischaemic action is still unclear. The aim of this work was to establish whether ranolazine exerts functional β-adrenoceptor antagonist activity in the rat cardiovascular system. Radioligand binding studies were performed in rat hearts and guinea-pig lungs for β₁- and β₂-adrenoceptor affinity, respectively. Ranolazine had micromolar affinity for both β₁- and β₂-adrenoceptors (pK_i5.8 and 6.3, respectively). Developed tension was measured in isolated rat left atria (electrically driven at 4 Hz) and cumulative concentration/response curves to (±)isoprenaline (0.01-1000 nM) constructed. Ranolazine (0.32-10 μM) surmountably but weakly antagonised isoprenaline-induced positive inotropic responses, with an apparent pA₂ 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 mechanism apparently unrelated to blockade of β₁- or β₂-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 chronotropic 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/kg i.v., n=6 or 7 per dose), (±)propranolol (0.01-0.63 mg/kg i.v., n=6 per dose) or ranolazine (2.5-80 mg/kg i.v., n=6 or 7 per dose) 10 min prior to isoprenaline. Ranolazine dose-dependently and competitively antagonised isoprenaline-induced decreases in diastolic arterial pressure (DAP, dose ratio 12.2 with 80 mg/kg ranolazine) and increases in heart rate (HR, dose ratio 20.3 with 80 mg/kg ranolazine). Collectively, these results demonstrate that ranolazine behaves as a weak β₁- and β₂-adrenoceptor antagonist in the rat cardiovascular system.