title: Beta-adrenoceptor activation plays a role in the reverse rate-dependency of effective refractory period lengthening by dofetilide in the guinea-pig atrium, in vitro.
abstract: 1. Blockers of the rapid component of the delayed rectifier potassium current (I(Kr)) prolong cardiac action potential duration (APD) and effective refractory period (ERP) in a reverse rate-dependent manner. Since activation of beta-adrenoceptors attenuates prolongation of APD evoked by I(Kr) blockers, rate-dependent neuronal noradrenaline liberation in the myocardium may contribute to the reverse rate-dependent nature of the effects of I(Kr) blockers. In order to test this hypothesis, we studied the effects of dofetilide, a pure I(Kr) blocker, on ERP after activation or blockade of beta-adrenoceptors and after catecholamine depletion in guinea-pig left atrial myocardium paced at 3, 2 and 1 Hz, in vitro. 2. Dofetilide (100 nM) lengthened ERP in a reverse rate-dependent manner in the left atrial myocardium of guinea-pigs. Strong activation of beta-adrenoceptors using 10 nM isoproterenol abolished the dofetilide-induced lengthening of ERP at all pacing rates. 3. Blockade of the beta-adrenoceptors with metoprolol (1 micro M), atenolol (3 micro M) or propranolol (300 nM) increased the dofetilide-evoked prolongation of ERP at 3 and 2 Hz, but not at 1 Hz. As a consequence, metoprolol attenuated while propranolol and atenolol fully eliminated the reverse rate-dependent nature of the dofetilide-induced ERP lengthening. In catecholamine-depleted atrial preparations of the guinea-pig (24 h pretreatment with 5 mg kg(-1) reserpine i.p.), the effect of dofetilide on ERP was not frequency dependent, and propranolol did not alter the effects of dofetilide. 4. In contrast to results obtained in guinea-pig atrial preparations, propranolol failed to change the reverse rate-dependent effect of dofetilide on ERP in the right ventricular papillary muscles of rabbits and guinea-pigs. 5. As an indication of the functional consequences of rate-dependent noradrenaline liberation, propranolol decreased twitch tension at 3 and 2 Hz but not at 1 Hz in the atrial myocardium of control guinea-pigs, whereas no such effect was detected in catecholamine-depleted atrial preparations. Propranolol failed to change contractility of ventricular myocardium in guinea-pigs and rabbits. 6. It is concluded that rate-dependent noradrenaline release and the ensuing beta-adrenoceptor activation contributed to the reverse rate-dependent nature of ERP prolongation caused by I(Kr) blockers in isolated guinea-pig atrial myocardium.
authors.affiliation: Pharmacology Laboratory I, EGIS Pharmaceuticals Ltd., Keresztúri út 34, Budapest 10, PO Box 100, Budapest H-1475, Hungary.
authors.forename: Anikó
authors.initials: A
authors.lastname: Kovács
authors.forename: János
authors.initials: J
authors.lastname: Magyar
authors.forename: Tamás
authors.initials: T
authors.lastname: Bányász
authors.forename: Péter P
authors.initials: PP
authors.lastname: Nánási
authors.forename: Gábor
authors.initials: G
authors.lastname: Szénási
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002304:Cardiac Pacing, Artificial; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism; D010627:Phenethylamines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000319:Adrenergic beta-Antagonists; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D011943:Receptors, Adrenergic, beta; D013449:Sulfonamides; C063533:dofetilide