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β ‐adrenoceptor activation plays a role in the reverse rate‐dependency of effective refractory period lengthening by dofetilide in the guinea‐pig atrium, in vitro
Author(s) -
Kovács Anikó,
Magyar János,
Bányász Tamás,
Nánási Péter P,
Szénási Gábor
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705395
Subject(s) - dofetilide , refractory period , guinea pig , effective refractory period , atrium (architecture) , in vitro , medicine , period (music) , refractory (planetary science) , cardiology , pharmacology , chemistry , biology , atrial fibrillation , biochemistry , physics , astrobiology , acoustics
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 β ‐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 β ‐adrenoceptors and after catecholamine depletion in guinea‐pig left atrial myocardium paced at 3, 2 and 1 Hz, in vitro . Dofetilide (100 n M ) lengthened ERP in a reverse rate‐dependent manner in the left atrial myocardium of guinea‐pigs. Strong activation of β ‐adrenoceptors using 10 n M isoproterenol abolished the dofetilide‐induced lengthening of ERP at all pacing rates. Blockade of the β ‐adrenoceptors with metoprolol (1 μ M ), atenolol (3 μ M ) or propranolol (300 n M ) 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. 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. 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. It is concluded that rate‐dependent noradrenaline release and the ensuing β ‐adrenoceptor activation contributed to the reverse rate‐dependent nature of ERP prolongation caused by I Kr blockers in isolated guinea‐pig atrial myocardium.British Journal of Pharmacology (2003) 139 , 1555–1563. doi: 10.1038/sj.bjp.0705395