α₁-adrenergic Receptor Attenuates β₁-adrenergic Modulation of IKr by Protein Kinase C-dependent Suppression of Adenylyl Cyclase in Ventricular Myocytes

The rapid delayed rectifier K⁺ current (Ikr) is critical for repolarization of the cardiac action potential. Previous studies have shown activated α₁-adrenergic receptor (AR) attenuates β₁-adrenergic regulation of Ikr while the mechanisms involved are poorly understood. To evalutate how α₁-adrenergic receptor affect β₁-adrenergic modulation of Ikr, whole-cell patch-clamp recordings were peformed in isolated guinea-pig ventricular myocytes. Application of xamoterol, a selective β₁-AR agonist, induced a negative shift in the activation curve and Ikr current reduction by 40.50±6.66% at the test pulse of +40 mV. Forskolin and 8-Br-cAMP also resulted in Ikr reduction by 38.17±1.50% and 24.65±3.37%, respectively. Phenylephrine, a selective α₁-AR agonist, prevented the activation shift and Ikr current reduction induced by xamoterol and forskolin, but not by 8-Br-cAMP. The effect of xamoterol or forskolin on Ikr was also prevented by pretreatment with PDBu, a protein kinase C (PKC) activator, while the effect of cAMP on Ikr can not, which was similar to pretreatment with phenylephrine. When cells were pretreated with chelerythrine, a specific PKC inhibitor, phenylephrine failed to prevent Ikr reduction induced by xamoterol. Our data suggests that α₁-adrenergic stimulation attenuates β₁-adrenergic regulation of Ikr, through PKC-dependent downregulation of adenylyl cyclase/cyclic AMP pathway.