Effects of β‐adrenoceptor stimulation on delayed rectifier K + currents in canine ventricular cardiomyocytes

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.