The Effectiveness in Activating M-Type K(+) Current Produced by Solifenacin ([(3R)-1-azabicyclo[2.2.2]octan-3-yl] (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate): Independent of Its Antimuscarinic Action

Solifenacin (Vesicare(®), SOL), known to be a member of isoquinolines, is a muscarinic antagonist that has anticholinergic effect, and it has been beneficial in treating urinary incontinence and neurogenic detrusor overactivity. However, the information regarding the effects of SOL on membrane ionic currents is largely uncertain, despite its clinically wide use in patients with those disorders. In this study, the whole-cell current recordings revealed that upon membrane depolarization in pituitary GH(3) cells, the exposure to SOL concentration-dependently increased the amplitude of M-type K(+) current (I(K(M))) with effective EC(50) value of 0.34 μM. The activation time constant of I(K(M)) was concurrently shortened in the SOL presence, hence yielding the K(D) value of 0.55 μM based on minimal reaction scheme. As cells were exposed to SOL, the steady-state activation curve of I(K(M)) was shifted along the voltage axis to the left with no change in the gating charge of the current. Upon an isosceles-triangular ramp pulse, the hysteretic area of I(K(M)) was increased by adding SOL. As cells were continually exposed to SOL, further application of acetylcholine (1 μM) failed to modify SOL-stimulated I(K(M)); however, subsequent addition of thyrotropin releasing hormone (TRH, 1 μM) was able to counteract SOL-induced increase in I(K(M)) amplitude. In cell-attached single-channel current recordings, bath addition of SOL led to an increase in the activity of M-type K(+) (K(M)) channels with no change in the single channel conductance; the mean open time of the channel became lengthened. In whole-cell current-clamp recordings, the SOL application reduced the firing of action potentials (APs) in GH(3) cells; however, either subsequent addition of TRH or linopirdine was able to reverse SOL-mediated decrease in AP firing. In hippocampal mHippoE-14 neurons, the I(K(M)) was also stimulated by adding SOL. Altogether, findings from this study disclosed for the first time the effectiveness of SOL in interacting with K(M) channels and hence in stimulating I(K(M)) in electrically excitable cells, and this noticeable action appears to be independent of its antagonistic activity on the canonical binding to muscarinic receptors expressed in GH(3) or mHippoE-14 cells.