Bisoprolol, Known to Be a Selective β1-Receptor Antagonist, Differentially but Directly Suppresses IK(M) and IK(erg) in Pituitary Cells and Hippocampal Neurons

Abstract

Bisoprolol (BIS) is a selective antagonist of β₁ adrenergic receptors. We examined the effects of BIS on M-type K⁺ currents (I_K(M)) or <i>erg</i>-mediated K⁺ currents (I_K(erg)) in pituitary GH_3, R1220 cells, and hippocampal mHippoE-14 cells. As GH₃ cells were exposed to BIS, amplitude of I_K(M) was suppressed with an IC₅₀ value of 1.21 μM. The BIS-induced suppression of I_K(M) amplitude was not affected by addition of isoproterenol or ractopamine, but attenuated by flupirtine or ivabradine. In cell-attached current, BIS decreased the open probability of M-type K⁺ (K_M) channels, along with decreased mean opening time of the channel. BIS decreased I_K(erg) amplitude with an IC₅₀ value of 6.42 μM. Further addition of PD-118057 attenuated BIS-mediated inhibition of I_K(erg). Under current-clamp conditions, BIS depolarization increased the firing of spontaneous action potentials in GH₃ cells; addition of flupirtine, but not ractopamine, reversed BIS-induced firing rate. In R1220 cells, BIS suppressed I_K(M); subsequent application of ML-213(Kv7.2 channel activator) reversed BIS-induced suppression of the current. In hippocampal mHippoE-14 neurons, BIS inhibited I_K(M) to a greater extent compared to its depressant effect on I_K(erg). This demonstrated that in pituitary cells and hippocampal neurons the presence of BIS is capable of directly and differentially suppressing I_K(M) and I_K(erg), despite its antagonism of β₁-adrenergic receptors.