Abstract
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 GH3 cells, the exposure to SOL concentration-dependently increased the amplitude of M-type K+ current (IK(M)) with effective EC50 value of 0.34 μM. The activation time constant of IK(M) was concurrently shortened in the SOL presence, hence yielding the KD value of 0.55 μM based on minimal reaction scheme. As cells were exposed to SOL, the steady-state activation curve of IK(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 IK(M) was increased by adding SOL. As cells were continually exposed to SOL, further application of acetylcholine (1 μM) failed to modify SOL-stimulated IK(M); however, subsequent addition of thyrotropin releasing hormone (TRH, 1 μM) was able to counteract SOL-induced increase in IK(M) amplitude. In cell-attached single-channel current recordings, bath addition of SOL led to an increase in the activity of M-type K+ (KM) 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 GH3 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 IK(M) was also stimulated by adding SOL. Altogether, findings from this study disclosed for the first time the effectiveness of SOL in interacting with KM channels and hence in stimulating IK(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 GH3 or mHippoE-14 cells.
Highlights
Solifenacin (Vesicare®, SOL), a member of isoquinolines (Figure 1), has been viewed as an oral anticholinergic and antispasmodic agent used to treat the symptoms of overactive bladder, neurogenic detrusor overactivity, or urinary incontinence [1,2,3,4,5,6,7,8]
In attempts to measure the magnitude of IK(M), we kept cells bathed in high-K+, Ca2+-free solution which contained 1 magnitude of IK(M), we kept cells bathed in high-K+, Ca2+ -free solution+ which contained μM tetrodotoxin (TTX), and the recording pipette was backfilled with a K -containing
Population of K currents with a slowly activating and deactivating property was robustly a specific population of K+ currents with a slowly activating and deactivating property evoked and it has been viewed as an IK(M) [48,49,51,56]. This type of IK(M) found in was robustly evoked and it has been viewed as an IK(M) [48,49,51,56]. This type of pituitary lactotrophs including GH3 cells has been demonstrated to be sensitive to be IK(M) found in pituitary lactotrophs including GH3 cells has been demonstrated to be blocked by thyrotropin releasing hormone (TRH) [48,57]
Summary
Solifenacin (Vesicare® , SOL), a member of isoquinolines (Figure 1), has been viewed as an oral anticholinergic (i.e., a competitive muscarinic [M1 and M3 ] receptor antagonist) and antispasmodic agent used to treat the symptoms of overactive bladder, neurogenic detrusor overactivity, or urinary incontinence [1,2,3,4,5,6,7,8]. It has been reported to be a muscarinic (M2 and M3 ) receptor antagonist that has anticholinergic effects such as relaxation of the detrusor muscle in urinary bladder [9]. It has been reported to be a mu rinic (M2 and M3) receptor antagonist that has anticholinergic effects such as relaxatio the detrusor muscle in urinary bladder [9]. Earlier clinicalwith investigations theincreased efficacyrisk and safety of the antimu that the treatment
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