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

Abstract

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 beta-adrenoceptor antagonist activity in the rat cardiovascular system. Radioligand binding studies were performed in rat hearts and guinea-pig lungs for beta1- and beta2-adrenoceptor affinity, respectively. Ranolazine had micromolar affinity for both beta,- and beta2-adrenoceptors (pKi5.8 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 (0.01-1,000 nM) constructed. Ranolazine (0.32-10 microM) 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 beta1- or beta2-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 beta1- and beta2-adrenoceptor antagonist in the rat cardiovascular system.

The Late Na+ Current (INa) Inhibitor Ranolazine Attenuates Effects of Palmitoyl-L-Carnitine to Increase Late INa and Cause Ventricular Diastolic Dysfunction

“…2-7). Because ranolazine, in addition to its action to reduce late I Na , is also known to reduce hERG K ϩ current (Antzelevitch et al, 2004) and is an antagonist of ␤-adrenergic receptors (Létienne et al, 2001), the effects of the selective sodium channel antagonist TTX, the selective hERG inhibitor E-4031, and the ␤-adrenergic receptor blocker esmolol were tested in hearts treated with PC. Tetrodotoxin (2 M) significantly reversed the effects of PC to increase late I Na and coronary resistance.…”

Ranolazine for the Treatment of Chronic Angina and Potential Use in Other Cardiovascular Conditions

“…30 It has weak calcium channel antagonist activity. 31 Thus, its mechanism of action to alleviate angina is different from the currently available drug classes that affect heart rate, inotropic state, or hemodynamic state or increase coronary blood flow.…”

Inotropic Effects and Mechanisms of Matrine, a Main Alkaloid from Sophora flavescens AIT

“…19) In brief, the papillary muscles were isolated from guinea pigs and mounted vertically, while avoiding tissue stretch, in an organ bath filled with Krebs solution containing (in mM): 119 NaCl, 5.6 KCl, 1.17 MgSO 4 , 2.1 CaCl 2 , 1.0 NaH 2 PO 4 , 25.0 NaHCO 3 , 10.0 glucose, pH 7.4, gassed with a mixture of 95% O 2 ϩ5% CO 2 and maintained at 36°C. The papillary muscles were stimulated electrically with 1 Hz (impulse duration 1 ms, two-fold threshold current) via two electrodes (Campden, Stimulator 915, Phymep).…”