Selective inhibition of phosphodiesterase 1 relaxes urinary bladder smooth muscle: role for ryanodine receptor-mediated BK channel activation.
Selective inhibition of phosphodiesterase 1 relaxes urinary bladder smooth muscle: role for ryanodine receptor-mediated BK channel activation.
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选择性抑制磷酸二酯酶 1 可放松膀胱平滑肌：兰尼碱受体介导的 BK 通道激活的作用。
DOI：
10.1152/ajpcell.00162.2012
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Petkov,GeorgiV
中科院分区：
文献类型：
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作者：
Xin,Wenkuan;Soder,RupalP;Cheng,Qiuping;Rovner,EricS;Petkov,GeorgiV
大电导电压和 Ca2+ 激活的 K+(BK) 通道是逼尿肌平滑肌 (DSM) 兴奋性和收缩性的主要调节因子。最近，我们发现非选择性磷酸二酯酶 (PDE) 抑制通过增加 BK 通道活性来降低豚鼠 DSM 兴奋性和收缩性。在这里，我们研究了选择性抑制 1 型 PDE (PDE1) 时 DSM 兴奋性和收缩性如何变化，以及涉及兰尼碱受体 (RyRs) 和 BK 通道的潜在细胞机制。使用 8-甲氧基甲基-3-异丁基-1-甲基黄嘌呤（8MM-IBMX；10 μM）抑制 PDE1 会增加豚鼠 DSM 细胞中的 cAMP 水平。对新鲜分离的 DSM 细胞进行膜片钳实验表明，8MM-IBMX 使瞬时 BK 电流和自发瞬时超极化 (STH) 频率分别增加约 2.5 倍和约 1.8 倍。 8MM-IBMX 使豚鼠和人 DSM 细胞膜电位超极化，并显着降低豚鼠 DSM 细胞的细胞内 Ca2+ 水平。用 1 μM paxilline 阻断 BK 通道或用 30 μM ryanodine 抑制 RyRs 消除了 STH 和 8MM-IBMX 对 DSM 细胞膜电位的抑制作用。等长 DSM 张力记录显示，8MM-IBMX 显着降低了 DSM 隔离条的自发相性收缩幅度、肌力积分、持续时间、频率和音调。电场刺激引起的 DSM 收缩幅度、肌力积分和持续时间也被 10 μM 8MM-IBMX 减弱。用 paxilline 阻断 BK 通道消除了 8MM-IBMX 对 DSM 收缩的影响。我们的数据提供证据表明，PDE1 抑制通过提高细胞 cAMP 水平来放松 DSM，并随后刺激 RyR，从而导致 BK 通道激活、膜电位超极化和细胞内 Ca2+ 水平降低。
The large conductance voltage- and Ca2+-activated K+(BK) channel is a major regulator of detrusor smooth muscle (DSM) excitability and contractility. Recently, we showed that nonselective phosphodiesterase (PDE) inhibition reduces guinea pig DSM excitability and contractility by increasing BK channel activity. Here, we investigated how DSM excitability and contractility changes upon selective inhibition of PDE type 1 (PDE1) and the underlying cellular mechanism involving ryanodine receptors (RyRs) and BK channels. PDE1 inhibition with 8-methoxymethyl-3-isobutyl-1-methylxanthine (8MM-IBMX; 10 μM) increased the cAMP levels in guinea pig DSM cells. Patch-clamp experiments on freshly isolated DSM cells showed that 8MM-IBMX increased transient BK currents and the spontaneous transient hyperpolarization (STH) frequency by ∼2.5- and ∼1.8-fold, respectively. 8MM-IBMX hyperpolarized guinea pig and human DSM cell membrane potential and significantly decreased the intracellular Ca2+levels in guinea pig DSM cells. Blocking BK channels with 1 μM paxilline or inhibiting RyRs with 30 μM ryanodine abolished the STHs and the 8MM-IBMX inhibitory effects on the DSM cell membrane potential. Isometric DSM tension recordings showed that 8MM-IBMX significantly reduced the spontaneous phasic contraction amplitude, muscle force integral, duration, frequency, and tone of DSM isolated strips. The electrical field stimulation-induced DSM contraction amplitude, muscle force integral, and duration were also attenuated by 10 μM 8MM-IBMX. Blocking BK channels with paxilline abolished the 8MM-IBMX effects on DSM contractions. Our data provide evidence that PDE1 inhibition relaxes DSM by raising cellular cAMP levels and subsequently stimulates RyRs, which leads to BK channel activation, membrane potential hyperpolarization, and decrease in intracellular Ca2+levels.