beta3-Adrenergic regulation of an ion channel in the heart-inhibition of the slow delayed rectifier potassium current I(Ks) in guinea pig ventricular myocytes.
OBJECTIVE
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 micromol/l atenolol) and beta(2)-receptors (1 micromol/l ICI118,551), 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 (IC(50): 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 micromol/l bupranolol). BRL37344 (100 micromol/) 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 micromol/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.
Bosch
Ralph F
RF
Department of Cardiology, University of Tuebingen, Otfried-Mueller-Strasse 10, Tuebingen, Germany.
Schneck
Alexander C
AC
Kiehn
Johann
J
Zhang
Wei
W
Hambrock
Annette
A
Eigenberger
Bernd W
BW
Rüb
Norman
N
Gogel
Jeannette
J
Mewis
Christian
C
Seipel
Ludger
L
Kühlkamp
Volker
V
D000200:Action Potentials / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D018929:Cell Culture Techniques; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology; D006168:Guinea Pigs; D007545:Isoproterenol / Q000494:pharmacology; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008297:Male; D032383:Myocytes, Cardiac / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology*; D014981:Xenopus
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D022702:Receptors, Adrenergic, beta-3; C057368:BRL 37344; D007545:Isoproterenol; D011188:Potassium; D009638:Norepinephrine