Abstract
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 BaCl(2) 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.