NS11021, a novel opener of large‐conductance Ca²⁺‐activated K⁺ channels, enhances erectile responses in rats

Abstract

Background and purpose: Large‐conductance Ca2+‐activated K+ channels (BKCa), located on the arterial and corporal smooth muscle, are potential targets for treatment of erectile dysfunction (ED). This study investigated whether NS11021 (1‐(3,5‐Bis‐trifluoromethyl‐phenyl)‐3‐[4‐bromo‐2‐(1H‐tetrazol‐5‐yl)‐phenyl]‐thiourea), a novel opener of BKCa channels, relaxes erectile tissue in vitro and enhances erectile responses in intact rats. The effects were compared with sildenafil, an inhibitor of phosphodiesterase type 5. Experimental approach: Patch clamp was used to record whole cell current in rat isolated corpus cavernosum smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs). Isometric tension was measured in intracavernous arterial rings and corpus cavernosum strips isolated from rats and men, and simultaneous measurements of intracellular Ca2+ concentration ([Ca2+]i) and tension were performed in intracavernous arteries. Erectile response was measured in anaesthetized rats. Key results: In patch clamp recordings, NS11021 increased currents sensitive to the selective BKCa channel blocker, iberiotoxin (IbTX) in SMCs, but did not modulate K+ current in HUVECs. NS11021 reduced [Ca2+]i and tension in penile arteries. IbTX inhibited the vasorelaxation induced by NS11021 and sildenafil in human erectile tissue. NS11021 and sildenafil but not vehicle increased erectile responses in anaesthetized rats, an effect which was abolished after pretreatment with tetraethylammonium. Conclusions and implications: NS11021 leads to relaxation of both intracavernous arteries and corpus cavernosum strips primarily through opening of BKCa channels. It is also effective in facilitating erectile responses in anaesthetized rats. These results suggest a potential for use of BKCa openers in the treatment of ED.

Opening of Small and Intermediate Calcium-Activated Potassium Channels Induces Relaxation Mainly Mediated by Nitric-Oxide Release in Large Arteries and Endothelium-Derived Hyperpolarizing Factor in Small Arteries from Rat

“…In the present study, we found that in primary HUVECs both SK Ca 3 and IK Ca channels were expressed, whereas BK Ca channel expression was undetectable. These findings agree with previous work in early passage HUVECs (Kestler et al, 1998) and our previous observations that an opener of BK Ca channels, 1-(3,5-bis-trifluoromethyl-phenyl)-3-[4-bromo-2-(1H-tetrazol-5-yl)-phenyl]-thiourea) (NS11021), does not change the currentvoltage relationship in early passage HUVECs (Kun et al, 2009). Furthermore, our patch-clamp studies in HUVECs indicated that the increased potassium conductance induced by NS309 was dependent on the presence of [Ca 2ϩ ] i and that it was inhibited partially by apamin and abolished by ChTX and TRAM-34, whereas it remained unaltered in the presence of IbTX.…”

Ca2+‐activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

“…Relaxation of HCC induced by exposure to KCa activators has been demonstrated for NS1619 and another novel activator, NS11021 (Kun et al, 2009). In agreement with these findings, the KCa activators, NS-8 and NS1619, caused relaxation of HCC.…”

“…These reports are consistent with the present findings of the contribution of KCa to PDE5 inhibitor-induced vasodilatation of HPRA. The lack of influence of KCa blockade on relaxations driven by PDE5 inhibition in HCC is, however, in contradiction to the previously reported sensitivity of sildenafil-induced relaxation to IbTx in HCC (Kun et al, 2009), and the suggested participation of KCa in PDE5 inhibitor-induced relaxation in rabbit clitoris (Gragasin et al, 2004) and mouse corpus cavernosum (Werner et al, 2008). Our results nevertheless were strengthened by the absence of significant effects of NS-8 or NS1619 on sildenafil-induced relaxation of HCC.…”

“…Importantly, this potentiating effect was achieved at a dose of KCa activator that did not significantly impact arterial pressure, a characteristic that represents an advantage over the KATP activation. Although NS-8 did not significantly augment erectile responses by itself at the dose used in the present study, a positive modulation of erectile responses in rats by BK stimulation with the novel activator, NS11021 has been reported (Kun et al, 2009).…”

Mechanisms of Penile Erection and Basis for Pharmacological Treatment of Erectile Dysfunction

“…Opening of BK Ca channels would be an alternative way of restoring an insufficient erectile function (e.g., Boy et al, 2004). Kun et al (2009) found that NS11021 (1-(3,5-Bis trifluoromethylphenyl)-3-[4-bromo-2-(1H-tetrazol-5-yl)-phenyl]-thiourea), a novel opener of BK Ca channels caused relaxation of both intracavernosal arteries and CC strips primarily through opening of BK Ca channels. It was also effective in facilitating erectile responses in anesthetized rats.…”