Effects of β-adrenoceptor antagonist and 5-HT1A and 5-HT1B receptor antagonist alprenolol on human Kv1.3 currents.

Abstract

Alprenolol is a nonselective β-adrenoceptor antagonist used in treating cardiovascular diseases by stabilizing elevated heart rates and myocardial contractility through the inhibition of sympathetic nerve transmissions alongside its role as an antagonist of 5-HT_1A and 5-HT_1B receptors. This study aimed to examine whether alprenolol can affect human Kv1.3 channel (hKv1.3) currents, which contribute to the proliferation and activation of T lymphocytes by regulating the driving force of Ca²⁺ influx. We investigated the acute effects of alprenolol on hKv1.3 channel currents using two-microelectrode voltage clamp recordings in Xenopus oocytes. Alprenolol exhibited concentration-dependent biphasic effects on hKv1.3 currents: it increased the current amplitudes at 1-100 μM but decreased them at 300-1,000 μM during a +50 mV depolarization step. A significant difference was found in alprenolol's effects on the peak and steady-state currents after 6 min of treatment with 10 μM, 50 μM, and 100 μM and 12 min of treatment with 10 μM and 50 μM. Furthermore, alprenolol affected the time constants of intrinsic inactivation and ultrarapid activation. However, no significant changes in V_1/2 and k value were found for steady-state activation and inactivation curves, except for the k value between 50 μM and 1,000 μM of the inactivation curve. At 1,000 μM, alprenolol suppressed hKv1.3 currents more rapidly during 5 sec inter-stimulus intervals compared to 15 sec intervals, indicating use-dependent blockade. Therefore, the effects of alprenolol on the biphasic and various biophysical properties of hKv1.3 channels could cause drug concentration-dependent changes in immune function.