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

초록

Alprenolol is a nonselective beta-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-HT1A and 5-HT1B 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 mu M but decreased them at 300-1,000 mu M 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 mu M, 50 mu M, and 100 mu M and 12 min of treatment with 10 mu M and 50 mu M. Furthermore, alprenolol affected the time constants of intrinsic inactivation and ultrarapid activation. However, no significant changes in V1/2 and k value were found for steady-state activation and inactivation curves, except for the k value between 50 mu M and 1,000 mu M of the inactivation curve. At 1,000 mu M, 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.

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