Beta-Adrenergic Activation of the Inward Rectifier K⁺ Current Is Mediated by the CaMKII Pathway in Canine Ventricular...

Several ion currents in the mammalian ventricular myocardium are substantially regulated by the sympathetic nervous system via β-adrenergic receptor activation, including the slow delayed rectifier K⁺ current and the L-type calcium current. This study investigated the downstream mechanisms of β-adrenergic receptor stimulation by isoproterenol (ISO) on the inward rectifier (I_K1) and the rapid delayed rectifier (I_Kr) K⁺ currents using action potential voltage clamp (APVC) and conventional voltage clamp techniques in isolated canine left ventricular cardiomyocytes. I_K1 and I_Kr were dissected by 50 µM BaCl₂ and 1 µM E-4031, respectively. Acute application of 10 nM ISO significantly increased I_K1 under the plateau phase of the action potential (0-+20 mV) using APVC, and similar results were obtained with conventional voltage clamp. However, β-adrenergic receptor stimulation did not affect the peak current density flowing during terminal repolarization or the overall I_K1 integral. The ISO-induced enhancement of I_K1 was blocked by the calcium/calmodulin kinase II (CaMKII) inhibitor KN-93 (1 µM) but not by the protein kinase A inhibitor H-89 (3 µM). Neither KN-93 nor H-89 affected the I_K1 density under baseline conditions (in the absence of ISO). In contrast, parameters of the I_Kr current were not affected by β-adrenergic receptor stimulation with ISO. These findings suggest that sympathetic activation enhances I_K1 in canine left ventricular cells through the CaMKII pathway, while I_Kr remains unaffected under the experimental conditions used.