González-Corrochano R, La Fuente Jm, Cuevas P, Fernández A, Chen Mx, Sáenz de Tejada I, Angulo J
Servicio de Histología-Investigación, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, Spain.
Br J Pharmacol. 2013 May;169(2):449-61. doi: 10.1111/bph.12143.
We have evaluated the influence of calcium-activated potassium channels (KCa ) activation on cGMP-mediated relaxation in human penile tissues from non-diabetic and diabetic patients, and on the effects of PDE5 inhibitors on erectile responses in control and diabetic rats.
Cavernosal tissues were collected from organ donors and from patients with erectile dysfunction (ED). Relaxations of corpus cavernosum strips (HCC) and penile resistance arteries (HPRA) obtained from these specimens were evaluated. Intracavernosal pressure (ICP) increases to cavernosal nerve electrical stimulation were determined in anaesthetized diabetic and non-diabetic rats.
Concentration-dependent vasodilation to the PDE5 inhibitor, sildenafil, in HPRA was sensitive to endothelium removal, NO/cGMP pathway inhibition and KCa blockade. Accordingly, activation of KCa with NS-8 (10 μM) significantly potentiated sildenafil-induced relaxations in HPRA (EC50 0.49 ± 0.22 vs. 5.21 ± 0.63 μM). In HCC, sildenafil-induced relaxation was unaffected by KCa blockade or activation. Potentiating effects in HPRA were reproduced with an alternative PDE5 inhibitor (tadalafil) and KCa activator (NS1619) and prevented by removing the endothelium. Large-conductance KCa (BK) and intermediate-conductance KCa (IK) contribute to NS-8-induced effects and were immunodetected in human and rat penile arteries. NS-8 potentiated sildenafil-induced enhancement of erectile responses in rats. Activation of KCa recovered the impaired relaxation to sildenafil in diabetic HPRA while sildenafil completely reversed diabetes-induced ED in rats only when combined with KCa activation.
Activation of KCa improves vasodilatory capacity of PDE5 inhibitors in diabetic and non-diabetic HPRA, resulting in the recovery of erectile function in diabetic rats. These results suggest a therapeutic potential for KCa activation in diabetic ED.
我们评估了钙激活钾通道（KCa）激活对非糖尿病和糖尿病患者的人阴茎组织中cGMP介导的舒张作用的影响，以及磷酸二酯酶5（PDE5）抑制剂对对照大鼠和糖尿病大鼠勃起反应的影响。
从器官捐献者和勃起功能障碍（ED）患者中收集海绵体组织。评估从这些标本中获得的海绵体条带（HCC）和阴茎阻力动脉（HPRA）的舒张情况。在麻醉的糖尿病大鼠和非糖尿病大鼠中测定海绵体内压（ICP）对海绵体神经电刺激的升高情况。
在HPRA中，PDE5抑制剂西地那非浓度依赖性血管舒张对内皮去除、NO/cGMP途径抑制和KCa阻断敏感。因此，用NS-8（10 μM）激活KCa可显著增强西地那非诱导的HPRA舒张（半数有效浓度[EC50] 0.49±0.22对5.21±0.63 μM）。在HCC中，西地那非诱导的舒张不受KCa阻断或激活的影响。用另一种PDE5抑制剂（他达拉非）和KCa激活剂（NS1619）可重现HPRA中的增强作用，且通过去除内皮可阻止该作用。大电导KCa（BK）和中电导KCa（IK）参与NS-8诱导的作用，并在人和大鼠阴茎动脉中通过免疫检测到。NS-8增强了西地那非诱导的大鼠勃起反应。KCa激活可恢复糖尿病HPRA中对西地那非受损的舒张，而西地那非仅在与KCa激活联合使用时才能完全逆转糖尿病诱导的大鼠ED。
KCa激活可改善糖尿病和非糖尿病HPRA中PDE5抑制剂的血管舒张能力，从而恢复糖尿病大鼠的勃起功能。这些结果提示KCa激活在糖尿病ED中有治疗潜力。
