Effect of the novel BKCa channel opener LDD175 on the modulation of corporal smooth muscle tone.
BACKGROUND
The BKCa channel has been reported to play an important role in erectile function. Recently, novel BKCa channel activator, LDD175, was introduced.


OBJECTIVE
This study aims to investigate whether LDD175 relaxes corporal smooth muscle (CSM) via BKCa channel activation.


METHODS
After isolation of CSM strip from a male rabbit model, contraction studies using organ bath was performed. Isolating human tissue and cell cultures, electrophysiological studies were done via whole-cell patch-clamp recording.


METHODS
Vasodilatory effects of LDD175 were evaluated by cumulative addition ranging from 10(-7) to 10(-4) M in corpus cavernosal strips after precontraction with 10(-5) M phenylephrine via organ bath system. Using cultured human CSM cells, patch-clamp recording was performed. Erectile function was measured by in vivo rat cavernous nerve stimulation.


RESULTS
LDD175 caused an endothelium-independent relaxation of corporal tissues, and this effect was abolished by pretreatment with iberiotoxin. The relaxation effect of 10(-4) M LDD175 was greater than that of 10(-6) M udenafil (54.0 ± 3.1% vs. 34.5 ± 3.9%, P < 0.05); 10(-5) M LDD175 with 10(-6) M udenafil caused a greater relaxation effect on strips than 10(-5) M LDD175 or 10(-6) M udenafil alone (50.7%, 34.1%, vs. 20.7%, respectively, P < 0.001). In patch-clamp recordings, LDD175 increased K(+) currents in a dose-dependent manner, and washout of LDD175 or the addition of iberiotoxin fully reversed the increase. Intravenous LDD175 improved erectile function measured by area under the curve (AUC) of the intracavernosal pressure (ICP)/arterial blood pressure (ABP) ratio (1,612.1 ± 135.6 vs. 1,093.7 ± 123.1, P < 0.05). There was no difference between 10 mg/kg LDD175 and 1 mg/kg udenafil regarding maximal ICP, maximal ICP/ABP ratio, and the AUC of the ICP/ABP ratio (P > 0.05).


CONCLUSIONS
LDD175 leads to an endothelium-independent relaxation of erectile tissue, primarily through the opening of BKCa channels. The results suggest that LDD175 might be a new candidate treatment for erectile dysfunction.
The Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea.
Hyun Hwan
HH
Sung
Seol Ho
SH
Choo
Deok Hyun
DH
Han
Mee Ree
MR
Chae
Su Jeong
SJ
Kang
Chul-Seung
CS
Park
Insuk
I
So
Jong Kwan
JK
Park
Sung Won
SW
Lee
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009129:Muscle Tonus / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000473:pathology*; D018408:Patch-Clamp Techniques; D010410:Penile Erection / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D011817:Rabbits
C540673:4-chloro-7-trifluoromethyl-10H-benzo(4,5)furo(3,2-b)indole-1-carboxylic acid; D001572:Benzofurans; D007211:Indoles; D010656:Phenylephrine
BKCa Channel; Corpus Cavernosum; Erectile Dysfunction; LDD175; PDE5