NS11021, a novel opener of large-conductance Ca(2+)-activated K(+) channels, enhances erectile responses in rats.
OBJECTIVE
Large-conductance Ca(2+)-activated K(+) channels (BK(Ca)), 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 BK(Ca) 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.


METHODS
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 Ca(2+) concentration ([Ca(2+)](i)) and tension were performed in intracavernous arteries. Erectile response was measured in anaesthetized rats.


RESULTS
In patch clamp recordings, NS11021 increased currents sensitive to the selective BK(Ca) channel blocker, iberiotoxin (IbTX) in SMCs, but did not modulate K(+) current in HUVECs. NS11021 reduced [Ca(2+)](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
NS11021 leads to relaxation of both intracavernous arteries and corpus cavernosum strips primarily through opening of BK(Ca) channels. It is also effective in facilitating erectile responses in anaesthetized rats. These results suggest a potential for use of BK(Ca) openers in the treatment of ED.
Kun
A
A
Department of Pharmacology, University of Aarhus, Denmark.
Matchkov
V V
VV
Stankevicius
E
E
Nardi
A
A
Hughes
A D
AD
Kirkeby
H J
HJ
Demnitz
J
J
Simonsen
U
U
D000368:Aged; D000818:Animals; D002118:Calcium / Q000378:metabolism; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018408:Patch-Clamp Techniques; D010413:Penis / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
C524410:1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-bromo-2-(1H-tetrazol-5-yl)phenyl)thiourea; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D013777:Tetrazoles; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D013890:Thiourea; D002118:Calcium