title: Evidence that ranolazine behaves as a weak beta1- and beta2-adrenoceptor antagonist in the rat [correction of cat] 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.
authors.affiliation: Division of Cardiovascular Diseases II, Centre de Recherche Pierre Fabre, Castres, France.
authors.forename: R
authors.initials: R
authors.lastname: Létienne
authors.forename: B
authors.initials: B
authors.lastname: Vié
authors.forename: A
authors.initials: A
authors.lastname: Puech
authors.forename: S
authors.initials: S
authors.lastname: Vieu
authors.forename: B
authors.initials: B
authors.lastname: Le Grand
authors.forename: G W
authors.initials: GW
authors.lastname: John
mesh_terms: D000083:Acetanilides; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D007545:Isoproterenol / Q000037:antagonists & inhibitors; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D000069458:Ranolazine; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
chemical_list: D000083:Acetanilides; D000319:Adrenergic beta-Antagonists; D004791:Enzyme Inhibitors; D010879:Piperazines; D011943:Receptors, Adrenergic, beta; D000069458:Ranolazine; D007545:Isoproterenol