Effects of bladder outlet obstruction on properties of Ca2+-activated K+ channels in rat bladder

In this study, we investigated the effects of bladder outlet obstruction (BOO) on the expression and function of large conductance (BK) and small conductance (SK) Ca2+-activated K+ channels in detrusor smooth muscle. The bladder from adult female Sprague-Dawley rats with 6-wk BOO were used. The mRNA expression of the BK channel α-subunit, β1-, β2-, and β4-subunits and SK1, SK2, and SK3 channels were investigated using real-time RT-PCR. All subunits except for the BK-β2, SK2, and SK3 channels were predominantly expressed in the detrusor smooth muscle rather than in the mucosa. The mRNA expression of the BK channel α-subunit was not significantly changed in obstructed bladders. However, the expression of the BK channel β1-subunit and the SK3 channel was remarkably increased in obstructed bladders. On the other hand, the expression of the BK channel β4-subunit was decreased as the severity of BOO-induced bladder overactivity progressed. In detrusor smooth muscle strips from obstructed bladders, blockade of BK channels by iberiotoxin (IbTx) or charybdotoxin (CTx) and blockade of SK channels by apamin increased the amplitude of spontaneous contractions. These blockers also increased the contractility and affinity of these strips for carbachol during cumulative applications. The facilitatory effects elicited by these K+ channel blockers were larger in the strips from obstructed bladders compared with control bladders. These results suggest that long-term exposure to BOO for 6 wk enhances the function of both BK and SK types of Ca2+-activated K+ channels in the detrusor smooth muscle to induce an inhibition of bladder contractility, which might be a compensatory mechanism to reduce BOO-induced bladder overactivity

Efficacy and safety of cabazitaxel therapy in elderly (≥75 years) patients with castration-resistant prostate cancer: A multiinstitutional study

Background: There is little data on the outcome of cabazitaxel (CBZ) treatment of elderly patients with castration-resistant prostate cancer (CRPC). This study assessed the efficacy and safety of CBZ chemotherapy in patients with CRPC aged 75 years or older in a multiinstitutional study. Methods: We retrospectively reviewed the 74 patients with CRPC treated with CBZ enrolled in 10 institutions. Clinicopathological backgrounds, prognosis including prostate-specific antigen decline, time to treatment failure, progression-free survival, overall survival, and safety profiles were compared between younger (<75 years) and elder (≥75 years) patients. Results: In total, 74 patients were enrolled; 50 patients were younger than 75 years and 24 were ≥75 years. Clinicopathological characteristics were comparable between younger and elder patients, with the exception of serum albumin values at the time of CBZ treatment. The median prostate-specific antigen decline in younger and elder men was −8.8% and −32.3% from baseline, respectively. The median time to treatment failure, progression-free survival, and overall survival for younger and elder men were 0.24 and 0.33 years, 0.23 and 0.43 years, and 0.69 and 1.17 years, respectively. In addition, safety profiles were comparable between younger and elder patients. Conclusions: This multiinstitutional study suggests that patients with CRPC aged 75 years or older eligible for CBZ treatment can be treated safely and with noninferior efficacy compared with those younger than 75 years

Etiology of Overactive Bladder and Its Therapeutic Perspective : Focusing on a Myogenic Basis for the Overative Bladder

膀胱平滑筋は，他の平滑筋と異なり袋臓器としての蓄尿と排尿という特徴的な役割を担っている．蓄尿時には，下部尿路では，膀胱は弛緩し，内および外尿道括約筋が収縮し，排尿時には膀胱収縮，尿道弛緩という巧妙な協調運動によって機能を発揮する．ゆえにその機能が障害された時の治療は，特に薬物治療となると，ターゲットとなる神経や平滑筋に対して，興奮と同時に抑制というまったく逆の作用を同時に発揮させなければならないので非常に困難である．本総説では蓄尿・排尿の障害である過活動膀胱の発症機序の解明にあたり最新の知見，特に再び注目を集めることとなりつつある筋原性説に焦点をあて，その治療法の実際と将来の展望について紹介する

The involvement of L-type Ca(2+) channels in the relaxant effects of the ATP-sensitive K(+) channel opener ZD6169 on pig urethral smooth muscle

1. The effects of ZD6169, a novel ATP-sensitive K(+) channel (K(ATP) channel) opener, were investigated on membrane currents in isolated myocytes using patch-clamp techniques. Tension measurement was also performed to study the effects of ZD6169 on the resting tone of pig urethral smooth muscle. 2. Levcromakalim was more potent than ZD6169 in lowering the resting urethral tone. Relaxation induced by low concentrations of ZD6169 (⩽3 μM) was completely suppressed by additional application of glibenclamide (1 μM). In contrast, glibenclamide (1 – 10 μM) only partially inhibited the relaxation induced by higher concentrations of ZD6169 (⩾10 μM). 3. Bay K8644 (1 μM) reduced the maximum relaxation produced by ZD6169 (⩾10 μM). 4. In whole-cell configuration, ZD6169 suppressed the peak amplitude of voltage-dependent Ba(2+) currents in a concentration- and voltage-dependent manner, and at 100 μM, shifted the steady-state inactivation curve of the voltage-dependent Ba(2+) currents to the left at a holding potential of −90 mV. 5. In cell-attached configuration, open probability of unitary voltage-dependent Ba(2+) channels (27 pS, 90 mM Ba(2+)) was inhibited by 100 μM ZD6169 and by 10 μM nifedipine. 6. Reverse transcriptase-polymerase chain reaction (RT – PCR) analysis revealed the presence of the transcript of the α(1C) subunit of L-type Ca(2+) channels in pig urethra. 7. These results demonstrate that ZD6169 causes urethral relaxation through two distinct mechanisms, activation of K(ATP) channels at lower concentrations and inhibition of voltage-dependent Ca(2+) channels at higher concentrations (about 10 μM)

Dual action of ZD6169, a novel K(+) channel opener, on ATP-sensitive K(+) channels in pig urethral myocytes

1. The effects of ZD6169, a novel K(+) channel opener, on both membrane and unitary currents in pig urethra were investigated using patch-clamp techniques. Its effect was also examined on currents in inside-out patches of COS7 cells expressing carboxy terminus truncated inwardly rectifying K(+) channel (Kir6.2) subunits (Kir6.2ΔC36) which form ATP-sensitive K(+) channels (K(ATP) channels). 2. In current-clamp mode, ZD6169 (⩽10 μM) induced a concentration-dependent membrane hyperpolarization. Higher concentrations (⩾30 μM) caused a transient membrane hyperpolarization, followed by a gradual membrane depolarization. On removal of ZD6169, an after hyperpolarization was observed. 3. In conventional voltage-clamp configuration, at −50 mV in symmetrical 140 mM K(+) conditions, ZD6169 (100 μM) caused a transient inward current which gradually decayed. Removal of ZD6169 evoked a much larger amplitude K(+) current with a similar time course. 4. ZD6169 produced an inward glibenclamide-sensitive K(+) current, demonstrating a bell-shaped concentration-response relationship. 5. In cell-attached configuration in symmetrical 140 mM K(+) conditions, ZD6169 (⩽30 μM) activated an K(ATP) channel which was reversibly suppressed by application of glibenclamide. In contrast, ZD6169 (100 μM) inhibited the activity of the levcromakalim-induced K(ATP) channels. 6. ZD6169 (100 μM) had no significant effect on the channel activity of Kir6.2ΔC36 in inside-out configuration, although cibenzoline greatly suppressed the channel activity. 7. These results demonstrate that ZD6169 possesses a dual effect on the activity of the K(ATP) channel; activating at low concentration and inhibiting at higher concentration