Effect of the Novel BKCa Channel Opener LDD175 on the Modulation of Corporal Smooth Muscle Tone

Abstract

Introduction The BKCa channel has been reported to play an important role in erectile function. Recently, novel BKCa channel activator, LDD175, was introduced. Aim 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. Main Outcome Measures 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.

Down-regulation of KCa2.3 channels causes erectile dysfunction in mice

“…Although the precise mechanism of action needs to be clarified, other drugs, such as calcium dobesilate, can enhance EDH type relaxation in human erectile tissue and restore erectile function in a diabetic rat model by activation of K Ca 2.3 and K Ca 3.1 channels 40, 41 . Knockout mice of K Ca 1.1 channels have reduced erectile function 42 , and openers of K Ca 1.1 channels can enhance rat erectile function 43, 44 , but so far this is the first study reporting that down-regulation of K Ca 2.3 channels causes erectile dysfunction in mice.…”

Castration impairs erectile organ structure and function by inhibiting autophagy and promoting apoptosis of corpus cavernosum smooth muscle cells in rats

“…Fifteen rats in each group were used for the corpus cavernosum strip bath test, as described previously [20][21][22][23][24]. Two corporal strips of approximately equal size (1 × 1 × 5 mm) were obtained from each penis.…”

Intracellular calcium-dependent regulation of the sperm-specific calcium-activated potassium channel, hSlo3, by the BKCaactivator LDD175

“…Since Gormemis et al first reported the potent activity of the BK Ca channel expressed in Xenopus oocytes [16], LDD175 has demonstrated relaxation-inducing actions on the urinary bladder, antispasmodic actions on intestinal motility, and erectile responses in corporal smooth muscle [171819]. Although the underlying mechanism of action of LDD175 on BK Ca is not fully elucidated, it is known that LDD175 shifts the conductance-voltage relationship of the channel leftward without changing its voltage dependence [20].…”