β3-Adrenergic regulation of an ion channel in the heart—inhibition of the slow delayed rectifier potassium current IKs in guinea pig ventricular myocytes

Objectives: I-Ks, the slow component of the delayed rectifier potassium current, underlies a strong beta-adrenergic regulation in the heart. Catecholamines, like isoproterenol, induce a strong increase in I-Ks. Recent work has pointed to an opposing biological effect of beta(1)- and beta(3)-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 beta(1)- and beta(3)-adrenoceptor modulation on I-Ks 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 beta(1) - (1 mumol/l atenolol) and beta(2)-receptors (1 mumol/l ICI1 18,551), isoproterenol induced a reduction of the step current amplitude by 34.3+/-3.5%. The beta(3)-selective agonist BRL37344 significantly reduced the I-Ks step current at +70 mV in a concentration-dependent manner (IC50: 5.01 nmol/l). In the presence of bupranolol (beta(1)-, beta(2)- and beta(3)-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 mumol/l bupranolol). BRL37344 (100 mumol/) 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 mumol/l BRL37344 mildly prolonged action potentials in guinea pig ventricle (APD(90):+ 7.8%) Conclusions: We have demonstrated a functional coupling between the beta(3)-adrenoceptor and ion channel function in the mammalian heart. Our findings point to a potential role for beta(3)-adrenoceptors in cardiac electrophysiology and pathophysiology. (C) 2002 Elsevier Science B.V. All rights reserved.