© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
β3-Adrenergic regulation of an ion channel in the heart—inhibition of the slow delayed rectifier potassium current IKs in guinea pig ventricular myocytes
aDepartment of Cardiology, University of Tuebingen, Otfried-Mueller-Strasse 10, D-72076 Tuebingen, Germany
bDepartment of Pharmacology, University of Tuebingen, Tuebingen, Germany
cDepartment of Cardiology, University of Heidelberg, Heidelberg, Germany
* Corresponding author. Tel.: +49-7071-298-2712; fax: +49-7071-295-285
Objectives: IKs, the slow component of the delayed rectifier potassium current, underlies a strong β-adrenergic regulation in the heart. Catecholamines, like isoproterenol, induce a strong increase in IKs. Recent work has pointed to an opposing biological effect of β1- and β3-adrenoceptors in the heart. However the role of these subtypes in the regulation of cardiac ion channel function is unknown. Methods: We investigated the effects of β1- and β3-adrenoceptor modulation on IKs in guinea-pig ventricular myocytes, using patch-clamp techniques. Results: Superfusion with 100 nmol/l isoproterenol increased the step current amplitude by 81.3±8.0%. In contrast, after block of β1- (1 µmol/l atenolol) and β2-receptors (1 µmol/l ICI118,551), isoproterenol induced a reduction of the step current amplitude by 34.3±3.5%. The β3-selective agonist BRL37344 significantly reduced the IKs step current at +70 mV in a concentration-dependent manner (IC50: 5.01 nmol/l). In the presence of bupranolol (β1-, β2- and β3-adrenoceptor antagonist), the effect of BRL37344 was markedly attenuated, from 27.3±5.6% (100 nmol/l BRL37344 alone) to 4.0±1.3% (100 nmol/l BRL37344+1 µmol/l bupranolol). BRL37344 (100 µmol/) did not alter current amplitudes of KvLQT1/minK expressed in CHO cells or in Xenopus oocytes, excluding a direct effect of BRL37344 on the channel. 1 µmol/l BRL37344 mildly prolonged action potentials in guinea pig ventricle (APD90:+7.8%) Conclusions: We have demonstrated a functional coupling between the β3-adrenoceptor and ion channel function in the mammalian heart. Our findings point to a potential role for β3-adrenoceptors in cardiac electrophysiology and pathophysiology.
KEYWORDS Adrenergic (ant)agonists; Ion channels; K-channel; Membrane currents; Myocytes; Receptors
1 Both authors contributed equally.
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