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首页> 外文期刊>The journal of sexual medicine >Erectile Dysfunction in Heme-Deficient Nitric Oxide-Unresponsive Soluble Guanylate Cyclase Knock-In Mice
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Erectile Dysfunction in Heme-Deficient Nitric Oxide-Unresponsive Soluble Guanylate Cyclase Knock-In Mice

机译：血液缺乏一氧化氮的勃起功能障碍 - 无响应可溶性胍基酸环酶敲根小鼠

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ABSTRACT Introduction: The nitric oxide (NO), soluble guanylate cyclase (sGC), and cyclic guanosine monophosphate (cGMP) pathway is the leading pathway in penile erection. Aim: To assess erectile function in a mouse model in which sGC is deficient in heme (apo-sGC) and unresponsive to NO. Methods: Mutant mice (sGCbeta_1~(ki/ki)) that express an sGC enzyme that retains basal activity but fails to respond to NO because of heme deficiency (apo-sGC) were used. Isolated corpora cavernosa from sGCbeta_1~(ki/ki) and wild-type mice were mounted in vitro for isometric tension recordings in response to sGC-dependent and -independent vasorelaxant agents. In addition, the erectile effects of some of these agents were tested in vivo at intracavernosal injection. Main Outcome Measures: In vitro and in vivo recordings of erectile responses in sGCbeta_1~(ki/ki) and wild-type mice after stimulation with sGC-dependent and -independent vasorelaxant agents. Results: NO-induced responses were abolished in sGCbeta_1~(ki/ki) mice in vitro and in vivo. The ability of the heme-dependent, NO-independent sGC stimulator BAY 41-2272 to relax the corpora cavernosa was markedly attenuated in sGCbeta_1~(ki/ki) mice. In contrast, the relaxation response to the heme- and NO-independent sGC activator BAY 58-2667 was significantly enhanced in sGCbeta_1~(ki/ki) mice. The relaxing effect of sGC-independent vasorelaxant agents was similar in wild-type and sGCbeta_1~(ki/ki) mice, illustrating that the observed alterations in vasorelaxation are limited to NO-sGC-cGMP-mediated processes. Conclusion: Our results suggest that sGC is the sole target of NO in erectile physiology. Furthermore, this study provides indirect evidence that, in addition to sGCalpha_1beta_1, sGCalpha_2beta_1 is important for erectile function. In addition, the significant relaxation observed in sGCbeta_1~(ki/ki) mice with the cumulative addition of the sGC activator BAY 58-2667 indicates that sGC activators might offer value in treating erectile dysfunction.
机译：摘要介绍：一氧化氮（NO），可溶性胍基环化酶（SGC）和循环鸟苷（CGMP）途径是阴茎勃起的领先途径。目的：评估鼠标模型中的勃起功能，其中SGC缺乏血红素（APO-SGC）并没有反应NO。方法：突变小鼠（SGCBeta_1〜（Ki / ki）），其表达保留基底活性但由于血红素缺乏（apo-sgc）而不能响应NO响应的SGC酶而表达SGC酶。来自SGCBETA_1〜（ki / ki）和野生型小鼠的孤立的Corpora Cavernosa在体外安装了等距张力记录，以应对SGC依赖性和依赖性的血管链X剂。此外，将一些这些试剂的勃起效果在体内进行体内注射。主要结果措施：在SGCBETA_1〜（ki / ki）和野生型小鼠刺激后，体外和体内录制勃起与SGC依赖性和依赖性血管链囊剂刺激后的野生型小鼠。结果：在体外和体内在SGCBeta_1〜（Ki / Ki）小鼠中没有诱导的反应。血红素依赖性无独立的SGC刺激湾41-2272放松的能力在SGCBeta_1〜（ki / ki）小鼠中显着减弱。相反，在SGCBETA_1〜（KI / KI）小鼠中显着增强了对血红素和无独立的SGC活化剂托架58-2667的弛豫响应。野生型和SGCBeta_1〜（Ki / Ki）小鼠的SGC-血管烷增殖剂的松弛效果类似，说明血管内的观察到的改变限于No-SGC-CGMP介导的方法。结论：我们的研究结果表明，SGC是勃起生理学中唯一的唯一目标。此外，本研究提供了间接证据，即除了Sgcalpha_1beta_1，Sgcalpha_2beta_1对于勃起功能很重要。此外，在SGCBeta_1〜（Ki / ki）小鼠中观察到的具有累积添加的SGC活化剂托架58-2667的显着弛豫表明SGC激活剂可以提供治疗勃起功能障碍的价值。

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