Hypercontractility and impaired sildenafil relaxations in the BKCa channel deletion model of erectile dysfunction.
Hypercontractility and impaired sildenafil relaxations in the BKCa channel deletion model of erectile dysfunction.
复制标题
勃起功能障碍 BKCa 通道缺失模型中的过度收缩和西地那非松弛受损。
DOI：
10.1152/ajpregu.00173.2008
复制
发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Nelson,MarkT
中科院分区：
文献类型：
--
作者：
Werner,MatthiasE;Meredith,AndreaL;Aldrich,RichardW;Nelson,MarkT
勃起功能障碍（艾德）可由多种致病因素引起，特别是一氧化氮（NO）和下游效应物可溶性鸟苷酸环化酶（sGC）和cGMP依赖性蛋白激酶I（PKGI）的形成和反应性受损。平滑肌中PKGI的一个重要靶点是大电导、Ca 2+激活的钾（BKCa）通道。在我们以前的报告中，我们证明了在小鼠中删除BKCachanel诱导力振荡，并导致减少神经诱发的松弛和ED。在本研究中，我们使用这个艾德模型来探索BKCachanel在NO/sGC/PKGI通路中的作用。电场刺激（EFS）引起的阴茎海绵体平滑肌条的收缩在没有BKC通道功能的情况下显著增强。在用苯乙哌啶预收缩的条中，EFS诱导的舒张通过抑制sGC而转化为收缩，并且这通过BK通道功能的丧失而进一步增强。通过抑制sGC或BKC通道，西地那非诱导的舒张降低至相似程度。在浓度>1 μM时，西地那非引起的舒张与sGC或BKC通道的抑制无关。西地那非不影响BKCachanel功能丧失引起的增强力振荡。然而，这些振荡可以通过阻断L型电压依赖性钙通道（VDCCs）完全消除。这些结果表明，治疗相关浓度的西地那非通过cGMP和BKCa通道起作用，BKCa通道功能丧失导致收缩过度，这依赖于VDCC，不能被cGMP途径修饰。
Erectile dysfunction (ED) can be elicited by a variety of pathogenic factors, particularly impaired formation of and responsiveness to nitric oxide (NO) and the downstream effectors soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase I (PKGI). One important target of PKGI in smooth muscle is the large-conductance, Ca2+-activated potassium (BKCa) channel. In our previous report , we demonstrated that deletion of the BKCachannel in mice induced force oscillations and led to reduced nerve-evoked relaxations and ED. In the current study, we used this ED model to explore the role of the BKCachannel in the NO/sGC/PKGI pathway. Electrical field stimulation (EFS)-induced contractions of corpus cavernosum smooth muscle strips were significantly enhanced in the absence of BKCachannel function. In strips precontracted with phenylephrine, EFS-induced relaxations were converted to contractions by inhibition of sGC, and this was further enhanced by loss of BK channel function. Sildenafil-induced relaxations were decreased to a similar extent by inhibition of sGC or BKCachannels. At concentrations >1 μM, sildenafil caused relaxations independent of inhibition of sGC or BKCachannels. Sildenafil did not affect the enhanced force oscillations that were induced by the loss of BKCachannel function. Yet, these oscillations could be completely eliminated by blocking L-type voltage-dependent Ca2+channels (VDCCs). These results suggest that therapeutically relevant concentrations of sildenafil act through cGMP and BKCachannels, and loss of BKCachannel function leads to hypercontractility, which depends on VDCCs and cannot be modified by the cGMP pathway.
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DOI：
10.1152/ajpcell.1993.265.1.c299
发表时间：
1993-07
期刊：
The American journal of physiology
影响因子：
--
作者：
B. E. Robertson;R. Schubert;Jorgen Hescheler;M. Nelson
通讯作者：
B. E. Robertson;R. Schubert;Jorgen Hescheler;M. Nelson
影响因子：
56.9
作者：
BURNETT, AL;LOWENSTEIN, CJ;SNYDER, SH
通讯作者：
SNYDER, SH
影响因子：
3.4
作者：
Ückert, S;Hedlund, P;Stief, CG
通讯作者：
Stief, CG
猪冠状动脉内皮介导的舒张对氧和代谢的依赖性。
DOI：
10.1152/ajpheart.1993.265.1.h299
发表时间：
1993
期刊：
The American journal of physiology
影响因子：
--
作者：
Hashimoto,M;Close,LA;Ishida,Y;Paul,RJ
通讯作者：
Paul,RJ
影响因子：
4
作者：
L. Toro;J. Marijić;K. Nishimaru;Yoshio Tanaka;Min-Cheol Song;E. Stefani
通讯作者：
L. Toro;J. Marijić;K. Nishimaru;Yoshio Tanaka;Min-Cheol Song;E. Stefani