Acute Dual Therapeutic Effects of the BKCa Channel Opener LDD175 on Erectile Dysfunction and Lower Urinary Tract Symptoms in Chronic Pelvic Ischemia

The Common Pathophysiology of Erectile Dysfunction and LUTS

Erectile dysfunction and lower urinary tract symptoms often occur together in middle-aged and older men. This is not a coincidence. Both conditions share several risk factors: aging, hypertension, hyperlipidemia, diabetes, and cardiovascular disease. The underlying biological link appears to be endothelial dysfunction and atherosclerosis, which reduce blood flow to the pelvic region.

Chronic pelvic ischemia (CPI) has emerged as a potential “common denominator” connecting ED and LUTS. Reduced blood flow to the pelvis affects the bladder, prostate, and penis, leading to structural and functional impairments. Hypoxia triggers fibrosis, smooth muscle loss, and altered receptor expression. The result is both erectile dysfunction (due to cavernosal fibrosis and reduced nitric oxide signaling) and LUTS (due to bladder overactivity and increased prostatic smooth muscle tone).

Current treatments address one condition at a time. PDE5 inhibitors (sildenafil, tadalafil) are effective for ED and have some benefit for LUTS, but their effect on voiding symptoms is modest. Alpha-blockers (tamsulosin) are effective for LUTS but can cause ejaculatory disorders. There is no single drug that potently treats both conditions by targeting their shared pathophysiology.

A new approach involves activating large-conductance calcium-activated potassium channels (BKCa channels). These channels regulate vascular smooth muscle tone. Opening them causes hyperpolarization, relaxation of smooth muscle, and increased blood flow. LDD175 is a novel BKCa channel opener developed by AnyGen Co., Ltd. Previous studies by this research group showed that LDD175 relaxes cavernous smooth muscle and improves erectile function in diabetic rats. However, its potential to simultaneously treat both ED and LUTS in a model of chronic pelvic ischemia had not been tested.

The study by Yu and colleagues (2025) addresses this gap. Using a rat model of CPI that produces both ED and LUTS, the investigators evaluated the acute effects of LDD175 on erectile function (intracavernosal pressure) and voiding function (intraurethral pressure). The full text is available here:preclinical study by Yu and colleagues (2025) on LDD175 for ED and LUTS

Study Design: A Rat Model of Chronic Pelvic Ischemia

The investigators used male Sprague Dawley rats weighing 300-350 grams. CPI was induced using a well-established technique: balloon-induced endothelial injury of the common iliac arteries combined with a high-cholesterol diet.

Surgical procedure. A Fogarty arterial embolectomy catheter was inserted through the femoral artery into the common iliac artery. The balloon was inflated with 0.2 ml of air and withdrawn repeatedly (10 times per side) to damage the endothelium. The sham operation control group underwent the same procedure without balloon inflation.

Diet. After surgery, both the CPI group and the sham group were fed a 1.5% cholesterol diet for 12 weeks. The normal control group received a regular diet.

All drugs were administered intravenously via the tail vein. Measurements were taken 10 minutes after injection.

Outcome Measures

Erectile function. After exposing the pelvic ganglia, the cavernous nerve was stimulated electrically (2.5 V, 2 Hz, 5 ms pulse width, 60 seconds). Intracavernosal pressure (ICP) was measured with a catheter inserted into the corpus cavernosum. Systemic blood pressure was monitored via the carotid artery. The primary outcomes were peak ICP, the ratio of peak ICP to mean arterial pressure (ICP/MAP), and the area under the curve (AUC).

Voiding function. After exposing the bladder and prostate, a catheter was inserted into the urethra through the bladder. Saline was infused continuously (0.5 ml for 10 minutes). The hypogastric nerve was stimulated electrically (5 V, 10 Hz, 1 ms pulse width, 30 seconds). Intraurethral pressure (IUP) was measured. The primary outcomes were maximal IUP and AUC.

Histology and molecular biology. Common iliac arteries were stained with hematoxylin and eosin (H&E) to measure wall thickness. Penile tissue was stained with Masson’s trichrome to assess the ratio of smooth muscle to collagen (fibrosis). Western blotting measured protein expression in cavernous tissue (HIF-1α, TGF-β1, TGF-β2, eNOS, nNOS, iNOS) and prostate tissue (α1A, α1B, α1D adrenoceptors, TGF-β1, TGF-β2).

Results: Validation of the CPI Model

The CPI model successfully produced both erectile and voiding dysfunction, confirming that it mimics the human condition.

Histological changes. The CPI group showed significantly increased thickness of the common iliac artery wall (p=0.008) with neointimal formation, compared to normal and sham groups. This confirms that the balloon injury plus cholesterol diet induced arterial atherosclerosis.

Cavernous fibrosis. Masson’s trichrome staining revealed a significantly lower ratio of smooth muscle to collagen in the corpus cavernosum of the CPI group compared to both normal (p=0.014) and sham (p=0.036) groups. More collagen deposition means more fibrosis, which impairs erectile function.

Molecular Changes in Cavernous and Prostate Tissue

Results: Erectile Function

Before treatment, the CPI group had significantly lower peak ICP, ICP/MAP ratio, and AUC compared to the normal group (p<0.001 for all comparisons). The CPI model reduced erectile function by approximately 50%.

LDD175 dose-dependent improvement. After LDD175 administration, ICP improved in a dose-dependent manner. The 10 mg/kg dose produced a change in ΔICP/MAP of approximately 27. Previous studies using PDE5 inhibitors have established that a change of approximately 15 indicates a significant erectile response. Therefore, the LDD175 effect exceeded the threshold for clinical significance.

Comparison with sildenafil. The 10 mg/kg LDD175 group showed higher ICP values than the 1 mg/kg sildenafil group. The two treatments were comparable in their effect on erectile function in this acute model.

Results: Voiding Function

Before treatment, the CPI group had significantly higher maximal intraurethral pressure (MaxIUP) compared to the normal group (p=0.029). The AUC was also higher, though the difference did not reach statistical significance (p=0.063). The CPI model increased IUP by approximately 170%, reflecting increased urethral resistance and prostatic smooth muscle tone.

Effect of LDD175 on IUP. After LDD175 administration, IUP decreased in a dose-dependent manner. The 10 mg/kg dose produced a significant reduction in both MaxIUP and AUC, comparable to the effect of tamsulosin 10 µg/kg.

Comparison with tamsulosin. Tamsulosin, an alpha-blocker that is a standard treatment for LUTS, significantly reduced IUP. The effect of LDD175 10 mg/kg was similar in magnitude to that of tamsulosin.

Comparison with sildenafil shows an important distinction. Unlike LDD175, sildenafil (both 1 mg/kg and 5 mg/kg) did not produce a significant decrease in IUP. This is an important finding. While PDE5 inhibitors have some clinical benefit for LUTS, the effect is modest. In this acute CPI model, sildenafil did not improve voiding function, whereas LDD175 did.

Two Key Takeaways from the Yu Study

• LDD175, a BKCa channel opener, improves erectile function in a rat model of chronic pelvic ischemia to a degree comparable to sildenafil. The effect is dose-dependent, with the 10 mg/kg dose producing a ΔICP/MAP of approximately 27, exceeding the established threshold for a significant erectile response (ΔICP/MAP of 15). This suggests that BKCa channel activation is a viable alternative mechanism for treating ED, particularly in cases where PDE5 inhibitors may be less effective or contraindicated.
• LDD175 also improves voiding function (reduces intraurethral pressure) in the same CPI model, an effect not seen with sildenafil and comparable to tamsulosin. This dual effect is the most novel finding. While PDE5 inhibitors have some LUTS benefit in clinical studies, the effect is modest. In this acute model, sildenafil did not significantly reduce IUP, whereas LDD175 did. This suggests that BKCa channel activation may be more effective than PDE5 inhibition for the LUTS component of the ED-LUTS complex.

Biological Mechanism: Why BKCa Channel Activation Works on Both Conditions

The dual effect of LDD175 is biologically plausible based on the pathophysiology of chronic pelvic ischemia.

The CPI model reproduces human disease. The combination of endothelial injury and high-cholesterol diet produces arterial atherosclerosis, reduced pelvic blood flow, tissue hypoxia, and subsequent fibrosis. In this study, the CPI group showed elevated HIF-1α (hypoxia marker), elevated TGF-β1/β2 (fibrosis drivers), reduced eNOS (less nitric oxide), and increased α1A-adrenoceptor expression in the prostate (increased sympathetic tone). These molecular changes translated into functional impairment: reduced ICP (ED) and increased IUP (LUTS).

BKCa channels are expressed in both penile and prostate/urethral smooth muscle. Activation of these channels causes hyperpolarization of the smooth muscle cell membrane, closing voltage-gated calcium channels, reducing intracellular calcium, and causing relaxation. In the penis, this means relaxation of cavernosal smooth muscle, allowing increased blood flow and erection. In the prostate and urethra, this means relaxation of smooth muscle, reducing urethral resistance and improving urine flow.

BKCa channels are the direct target of LDD175. The study demonstrated that LDD175 improved both ICP (erection) and IUP (voiding) in the same animals. This is not simply an off-target effect or a result of improved systemic blood flow. The effect is mediated directly through BKCa channels on the smooth muscle cells of the corpus cavernosum and the prostate/urethra.

Why sildenafil did not improve IUP in this model. PDE5 inhibitors work by amplifying the nitric oxide-cGMP pathway. However, in CPI, eNOS expression is reduced (as shown in this study), so there is less nitric oxide to amplify. LDD175 works downstream of nitric oxide, directly on the potassium channel. It does not require intact NO signaling to be effective. This may explain why LDD175 improved voiding function while sildenafil did not in this acute model.

Limitations of the Study

The Yu study is a well-designed preclinical investigation, but its findings must be interpreted with caution before any clinical application.

Comparison with Existing Treatments

For ED. PDE5 inhibitors (sildenafil, tadalafil, vardenafil, avanafil) are first-line therapy. They work by inhibiting the degradation of cGMP, amplifying the NO signal. They are effective in 70-80% of men. However, they are contraindicated with nitrates and can cause headaches, flushing, and dyspepsia. Some men are non-responders. LDD175 offers a different mechanism (direct smooth muscle relaxation via potassium channel activation) and could potentially work in PDE5 non-responders. However, no human data exist.

For LUTS. Alpha-blockers (tamsulosin, alfuzosin, silodosin, doxazosin, terazosin) are first-line therapy. They reduce smooth muscle tone in the prostate and bladder neck. They are effective but can cause ejaculatory dysfunction (especially silodosin and tamsulosin), dizziness, and hypotension. 5-alpha reductase inhibitors (finasteride, dutasteride) reduce prostate size but take months to work and can cause ED and reduced libido. PDE5 inhibitors (tadalafil 5 mg daily) are approved for LUTS but have a modest effect size. LDD175 in this animal model showed an effect on IUP comparable to tamsulosin, but without the expected effect on ejaculation (though ejaculation was not measured in this study).

For the ED-LUTS combination, current treatment often involves combining multiple drugs rather than using a single mechanism-based therapy. Currently, some patients receive both a PDE5 inhibitor and an alpha-blocker. This combination can be effective but increases the risk of hypotension and drug interactions. A single drug that works on both conditions would be attractive. The Yu study suggests that LDD175 could fill this role, but again, only animal data exist.

Clinical Context and Future Directions

At Adult & Pediatric Urology (APUMN), we follow the development of novel therapeutic approaches that target the shared pathophysiology of ED and LUTS. The Yu study provides proof-of-concept for BKCa channel activation as such an approach. However, several steps are needed before this could become a clinical reality.

Phase I trials would need to establish the safety, tolerability, and pharmacokinetics of LDD175 in healthy human volunteers. Doses that are effective in rats (5-10 mg/kg) would need to be converted to human equivalent doses (likely much lower on a mg/kg basis due to metabolic differences). Cardiovascular safety would be a primary concern.

Phase II trials would need to demonstrate efficacy for both ED and LUTS in men with both conditions. The primary outcomes would be IIEF-5 (for ED) and IPSS (for LUTS), similar to the animal study’s ICP and IUP endpoints. The optimal dose and dosing schedule (once daily? as needed?) would need to be determined.

Phase III trials would need to compare LDD175 to existing treatments: PDE5 inhibitors for ED, alpha-blockers for LUTS, and potentially combination therapy for both. Long-term safety and durability of effect would be assessed.

The Yu study is an important first step. The demonstration of dual effects in a well-validated animal model of chronic pelvic ischemia is methodologically strong. The investigators used appropriate controls, measured both functional and molecular outcomes, and compared their novel compound to established standards (sildenafil for ED, tamsulosin for LUTS). The dose-response relationship for both outcomes adds confidence.

However, the gap between rat and human is large. Many drugs that showed promise in animal models of ED and LUTS have failed in clinical trials or been abandoned due to safety concerns. Patients should not seek out LDD175 or any BKCa channel opener for unapproved use. The drug is not available for human use, and its safety profile is unknown.

For clinicians, the take-home message is that BKCa channel activation represents a new and mechanistically distinct approach to treating the common pathophysiology of ED and LUTS. If subsequent clinical trials are successful, it could offer a single-pill solution for men suffering from both conditions. For now, standard treatments (PDE5 inhibitors for ED, alpha-blockers or PDE5 inhibitors for LUTS) remain the evidence-based standard of care.

Author

Jerome P. Keating, M.D