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

Edmund So,Shun Ko,Sheng-Nan Wu,Ning-Ping Foo

doi:10.3390/ijms20030657

Abstract

Bisoprolol (BIS) is a selective antagonist of β1 adrenergic receptors. We examined the effects of BIS on M-type K+ currents (IK(M)) or erg-mediated K+ currents (IK(erg)) in pituitary GH3, R1220 cells, and hippocampal mHippoE-14 cells. As GH3 cells were exposed to BIS, amplitude of IK(M) was suppressed with an IC50 value of 1.21 μM. The BIS-induced suppression of IK(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+ (KM) channels, along with decreased mean opening time of the channel. BIS decreased IK(erg) amplitude with an IC50 value of 6.42 μM. Further addition of PD-118057 attenuated BIS-mediated inhibition of IK(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 IK(M); subsequent application of ML-213(Kv7.2 channel activator) reversed BIS-induced suppression of the current. In hippocampal mHippoE-14 neurons, BIS inhibited IK(M) to a greater extent compared to its depressant effect on IK(erg). This demonstrated that in pituitary cells and hippocampal neurons the presence of BIS is capable of directly and differentially suppressing IK(M) and IK(erg), despite its antagonism of β1-adrenergic receptors.

Highlights

Bisoprolol, a phenoxy-2-propanol derivative, is recognized as an oral synthetic selective blocker of β1-adrenoceptor with antioxidant activity which exerts a number of potentially beneficial pharmacological effects such as atrial fibrillation, heart failure and postural tachycardia syndrome [1,2,3,4]
In pituitary GH3 cells, as the M-type K+ current (IK(M)) was to be carried by the product of KCNQ2/KCNQ3 genes, we examined the mRNA levels of these genes
Of particular interest is how as GH3 cells were exposed to BIS, the IK(M) amplitude in response to such depolarizing step was progressively diminished in a concentration-dependent manner (Figure F2FiAgiguaurnerde12.1B.T)Th.heFeoerxepxexprearsemssipsoilnoen,lealvdeevdleistlisoofontfhotefh1eβ--μβaM-catciBntiI,nSK, sKCigNCnNCifC1ic1(aKn(VKtl3yV.31d.)1e,)cK,rKeCaCNsNeQdQ2c2u(Kr(KrVe7Vn7.t2.2)a)maanpndldiKtuKCdCNeNQfrQo33m(K(K1V9V767.3.±3)) i1si4osoltaloatet9ed7df±rfor1om1mpGAGHH(3n3c=ceel1ll2sls.,.pTTo

Summary

Introduction

Bisoprolol (zebeta®; BIS), a phenoxy-2-propanol derivative, is recognized as an oral synthetic selective blocker of β1-adrenoceptor with antioxidant activity which exerts a number of potentially beneficial pharmacological effects such as atrial fibrillation, heart failure and postural tachycardia syndrome [1,2,3,4]. Previous reports have demonstrated that BIS could bind to β1-adrenergic receptors inherently existing in brain areas including the pituitary gland and hippocampus [7,8,9,10,11]. Carvedilol or other blockers of β-adrenergic receptors were previously shown to suppress the amplitude of delayed-rectifier K+ currents (IK(DR)) and of HERG-mediated K+ currents [13,14]. Previous reports have shown that BIS was able to reverse the down-regulation in mRNA expression of Na+, hyperpolarization-activated cation (HCN) and small-conductance Ca2+-activated K+ (SK) channels in failing hearts [15,16]. Little information is available regarding the underlying mechanism of actions of BIS or other structurally similar compounds on ionic currents in endocrine cells, neuroendocrine cells, or neurons, despite their wide clinical usage [2]

Methods

Results

Conclusion