Bisoprolol, Known to Be a Selective β ₁-Receptor Antagonist, Differentially but Directly Suppresses I _K(M) and I _K(erg) in Pituitary Cells and Hippocampal Neurons

Abstract

Bisoprolol (BIS) is a selective antagonist of β ₁ adrenergic receptors. We examined the effects of BIS on M-type K ⁺ currents (I _K(M)) or erg-mediated K ⁺ currents (I _K(erg)) in pituitary GH _3, R1220 cells, and hippocampal mHippoE-14 cells. As GH ₃ cells were exposed to BIS, amplitude of I _K(M) was suppressed with an IC ₅₀ 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 IC ₅₀ 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 GH ₃ 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 β ₁-adrenergic receptors.