Abstract
Modulation of endothelial calcium-activated potassium (KCa) channels has been proposed as an approach to restore endothelial function. The present study investigated whether novel openers of KCa channels with small (KCa2.x) and intermediate (KCa3.1) conductance, NS309 and NS4591, improve endothelium-dependent relaxation and erectile function. Rat corpus cavernosum (CC) strips were mounted for isometric tension recording and processed for immunoblotting. Mean arterial pressure (MAP), intracavernosal pressure (ICP), and electrocardiographic (ECG) measurements were conducted in anesthetized rats. Immunoblotting revealed the presence of KCa2.3 and large KCa conductance (KCa1.1) channels in the corpus cavernosum. NS309 and NS4591 increased current in CC endothelial cells in whole cell patch clamp experiments. Relaxation induced by NS309 (<1 μM) was inhibited by endothelial cell removal and high extracellular potassium. An inhibitor of nitric oxide (NO) synthase, and blockers of KCa2.x and KCa1.1 channels, apamin and iberiotoxin also inhibited NS309 relaxation. Incubation with NS309 (0.5 μM) markedly enhanced acetylcholine relaxation. Basal erectile function (ICP/MAP) increased during administration of NS309. Increases in ICP/MAP after cavernous nerve stimulation with NS309 were unchanged, whereas NS4591 significantly improved erectile function. Administration of NS309 and NS4591 caused small changes in the electrocardiogram, but neither arrhythmic events nor prolongation of the QTc interval were observed. The present study suggests that openers of KCa2.x and KCa3.1 channels improve endothelial and erectile function. The effects of NS309 and NS4591 on heart rate and ECG are small, but will require additional safety studies before evaluating whether activation of KCa2.3 channels has a potential for treatment of erectile dysfunction.
Highlights
Erectile dysfunction (ED) is defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance (NIH Consensus Conference, 1993)
Control experiments for KCa3.1 showed there was no expression in heart samples from KCa3.1 knockout mice, and in the presence of the anti-KCa1.1 peptide, no immunoreactive bands were detected for KCa1.1 in rat mesenteric arteries, corpus cavernosum (CC), and liver (Supplementary Figure S2C)
The main findings of the present study are the findings of KCa1.1 and KCa2.3 channels expression, and that apamin- and iberiotoxin-sensitive channels are involved in ACh-relaxation in rat CC
Summary
Erectile dysfunction (ED) is defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance (NIH Consensus Conference, 1993). Phosphodiesterase type 5 (PDE5) inhibitors are recommended as first line treatment of ED due to their efficacy and safety profile (Hatzimouratidis et al, 2016). 20% of the general population of patients with ED and 50% of patients with diabetes and ED exhibit suboptimal responses to oral PDE5 inhibitors (Kendirci et al, 2006). Besides PDE5 inhibitors appears to have marginal effects when combined with other oral treatments (Dhir et al, 2011). This suggests that there is an unmet need for developing novel treatments for erectile dysfunction
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