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Effects of β‐adrenoceptor stimulation on delayed rectifier K + currents in canine ventricular cardiomyocytes
Author(s) -
Harmati G,
Bányász T,
Bárándi L,
Szentandrássy N,
Horváth B,
Szabó G,
Szentmiklósi JA,
Szénási G,
Nánási PP,
Magyar J
Publication year - 2011
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 - 10.1111/j.1476-5381.2010.01092.x
Subject(s) - forskolin , isoprenaline , activator (genetics) , medicine , endocrinology , protein kinase a , stimulation , intracellular , chemistry , phosphorylation , biology , receptor , biochemistry
BACKGROUND AND PURPOSE While the slow delayed rectifier K + current ( I Ks ) is known to be enhanced by the stimulation of β‐adrenoceptors in several mammalian species, phosphorylation‐dependent regulation of the rapid delayed rectifier K + current ( I Kr ) is controversial. EXPERIMENTAL APPROACH In the present study, therefore, the effect of isoprenaline (ISO), activators and inhibitors of the protein kinase A (PKA) pathway on I Kr and I Ks was studied in canine ventricular myocytes using the whole cell patch clamp technique. KEY RESULTS IKr was significantly increased (by 30–50%) following superfusion with ISO, forskolin or intracellular application of PKA activator cAMP analogues (cAMP, 8‐Br‐cAMP, 6‐Bnz‐cAMP). Inhibition of PKA by Rp‐8‐Br‐cAMP had no effect on baseline I Kr . The stimulating effect of ISO on I Kr was completely inhibited by selective β 1 ‐adrenoceptor antagonists (metoprolol and CGP‐20712A), by the PKA inhibitor Rp‐8‐Br‐cAMP and by the PKA activator cAMP analogues, but not by the EPAC activator 8‐pCPT‐2'‐O‐Me‐cAMP. In comparison, I Ks was increased threefold by the activation of PKA (by ISO or 8‐Br‐cAMP), and strongly reduced by the PKA inhibitor Rp‐8‐Br‐cAMP. The ISO‐induced enhancement of I Ks was decreased by Rp‐8‐Br‐cAMP and completely inhibited by 8‐Br‐cAMP. CONCLUSIONS AND IMPLICATIONS The results indicate that the stimulation of β 1 ‐adrenoceptors increases I Kr , similar to I Ks, via the activation of PKA in canine ventricular cells.