Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal, Madrid, Spain; Servicio de Histología-Investigación, Unidad de Investigación Traslacional en Cardiología (IRYCIS-UFV), Hospital Universitario Ramón y Cajal, Madrid, Spain.
Fundación para la Investigación Biomédica del Hospital Universitario de Getafe, Getafe, Spain; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.
J Sex Med. 2022 Dec;19(12):1733-1749. doi: 10.1016/j.jsxm.2022.08.200. Epub 2022 Oct 1.
Stromal interaction molecule (STIM)/Orai calcium entry system appears to have a role in erectile dysfunction (ED) pathophysiology but its specific contribution to diabetic ED was not elucidated.
To evaluate STIM/Orai inhibition on functional alterations associated with diabetic ED in rat and human penile tissues and on in vivo erectile responses in diabetic rats.
Rat corpus cavernosum (RCC) strips from nondiabetic (No DM) and streptozotocin-induced diabetic (DM) rats and human penile resistance arteries (HPRA) and corpus cavernosum (HCC) from ED patients undergoing penile prosthesis insertion were functionally evaluated in organ chambers and wire myographs. Erectile function in vivo in rats was assessed by intracavernosal pressure (ICP) responses to cavernous nerve electrical stimulation (CNES). Expression of STIM/Orai elements in HCC was determined by immunofluorescence and immunoblot.
Functional responses in RCC, HCC and HPRA and STIM/Orai protein expression in HCC. In vivo erectile responses to CNES.
Inhibition of Orai channels with YM-58483 (20 µM) significantly reduced adrenergic contractions in RCC but more effectively in DM. Thromboxane-induced and neurogenic contractions were reduced by STIM/Orai inhibition while defective endothelial, neurogenic and PDE5 inhibitor-induced relaxations were enhanced by YM-58483 (10 µM) in RCC from DM rats. In vivo, YM-58483 caused erections and attenuated diabetes-related impairment of erectile responses. YM-58483 potentiated the effects of PDE5 inhibition. In human tissues, STIM/Orai inhibition depressed adrenergic and thromboxane-induced contractions in ED patients more effectively in those with type 2 diabetes. Diabetes was associated with increased expression of Orai1 and Orai3 in ED patients.
Targeting STIM/Orai to alleviate diabetes-related functional alterations of penile vascular tissue could improve erectile function and potentiate therapeutic effects of PDE5 inhibitors in diabetic ED.
Improving effects of STIM/Orai inhibition on diabetes-related functional impairment was evidenced in vitro and in vivo in an animal model and validated in human tissues from ED patients. Functional findings were complemented with expression results. Main limitation was low numbers of human experiments due to limited human tissue availability.
STIM/Orai inhibition alleviated alterations of functional responses in vitro and improved erectile responses in vivo in diabetic rats, potentiating the effects of PDE5 inhibition. STIM/Orai inhibition was validated as a target to modulate functional alterations of human penile vascular tissue in diabetic ED where Orai1 and Orai3 channels were upregulated. STIM/Orai inhibition could be a potential therapeutic strategy to overcome poor response to conventional ED therapy in diabetic patients. Sevilleja-Ortiz A, El Assar M, García-Gómez B, et al. STIM/Orai Inhibition as a Strategy for Alleviating Diabetic Erectile Dysfunction Through Modulation of Rat and Human Penile Tissue Contractility and in vivo Potentiation of Erectile Responses. J Sex Med 2022;19:1733-1749.
基质相互作用分子（STIM）/Orai 钙内流系统似乎在勃起功能障碍（ED）发病机制中发挥作用，但它在糖尿病 ED 中的具体作用尚未阐明。
评估 STIM/Orai 抑制对大鼠和人阴茎组织中与糖尿病 ED 相关的功能改变以及糖尿病大鼠体内勃起反应的影响。
在器官室和钢丝肌描记器中评估来自非糖尿病（No DM）和链脲佐菌素诱导的糖尿病（DM）大鼠的大鼠海绵体（RCC）条以及来自接受阴茎假体植入的 ED 患者的人阴茎阻力动脉（HPRA）和海绵体（HCC）的功能。通过海绵体内压（ICP）对海绵体神经电刺激（CNES）的反应评估大鼠体内的勃起功能。通过免疫荧光和免疫印迹测定 HCC 中 STIM/Orai 元素的表达。
RCC、HCC 和 HPRA 的功能反应以及 HCC 中 STIM/Orai 蛋白表达。CNES 对体内勃起反应的影响。
Orai 通道抑制剂 YM-58483（20 μM）显著降低了 RCC 中的肾上腺素能收缩，但在 DM 中更有效。STIM/Orai 抑制可减少血栓素诱导和神经源性收缩，而 YM-58483（10 μM）可增强 DM 大鼠 RCC 中的内皮、神经源性和 PDE5 抑制剂诱导的舒张作用。体内，YM-58483 引起勃起并减轻糖尿病相关的勃起反应障碍。YM-58483 增强了 PDE5 抑制剂的作用。在人类组织中，STIM/Orai 抑制在 ED 患者中更有效地抑制了肾上腺素能和血栓素诱导的收缩，尤其是 2 型糖尿病患者。糖尿病与 ED 患者 Orai1 和 Orai3 表达增加有关。
靶向 STIM/Orai 以减轻阴茎血管组织与糖尿病相关的功能改变可能改善勃起功能，并增强糖尿病 ED 中 PDE5 抑制剂的治疗效果。
在动物模型中，体外和体内研究均证实了 STIM/Orai 抑制对糖尿病相关功能障碍的改善作用，并在 ED 患者的人组织中得到了验证。功能研究结果得到了表达结果的补充。主要限制是由于人类组织可用性有限，人类实验数量较少。
STIM/Orai 抑制可减轻糖尿病大鼠体内和体外功能反应的改变，并增强体内勃起反应，增强 PDE5 抑制作用。在糖尿病 ED 中，STIM/Orai 抑制被验证为调节人阴茎血管组织功能改变的靶点，在此情况下，Orai1 和 Orai3 通道上调。STIM/Orai 抑制可能是克服糖尿病患者对常规 ED 治疗反应不佳的一种潜在治疗策略。Sevilleja-Ortiz A, El Assar M, García-Gómez B, et al. STIM/Orai Inhibition as a Strategy for Alleviating Diabetic Erectile Dysfunction Through Modulation of Rat and Human Penile Tissue Contractility and in vivo Potentiation of Erectile Responses. J Sex Med 2022;19:1733-1749.
