Benign prostatic hyperplasia/obstruction ameliorated using a soluble guanylate cyclase activator.

Area of Science:

• Urology
• Pharmacology
• Gerontology

Background:

• Benign prostatic hyperplasia (BPH) affects aging males, often causing bladder outlet obstruction (BOO) and lower urinary tract symptoms (LUTS).
• Current BPH therapies, including PDE5 inhibitors, are not universally effective, and refractoriness can develop.
• Nitric oxide (NO), soluble guanylate cyclase (sGC), and cGMP pathways are implicated in BPH, but oxidative stress can impair these pathways.

Purpose of the Study:

• To evaluate the effects of the sGC activator cinaciguat on the prostate and lower urinary tract (LUT) function in aged mice.
• To determine if cinaciguat can ameliorate BPH/BOO phenotypes and address potential limitations of PDE5 inhibitors.

Main Methods:

• Aged mice (≥24 months) were assessed for BPH/BOO phenotypes using telemetric cystometry and histological analysis.
• Aged mice were treated daily with cinaciguat (BAY 58-2667) for two weeks.
• Effects were compared to adult mice and CYB5R3 smooth muscle knockout mice to assess efficacy and mechanism.

Main Results:

• Aged mice exhibited a functional BPH/BOO phenotype, characterized by delayed voiding and elevated intravesical pressures.
• Cinaciguat treatment attenuated urethral constriction, reduced prostate weight, decreased collagen deposition, and improved cellular hyperplasia in aged mice.
• Cinaciguat demonstrated a positive safety profile with transient cardiovascular effects and reversed an overactive cystometric profile in a model of oxidative dysfunction.

Conclusions:

• The aged male mouse serves as a suitable model for studying BPH-induced BOO.
• Cinaciguat effectively reduces prostate-induced obstruction and improves bladder function in aged mice.
• Cinaciguat represents a promising therapeutic agent for BPH/BOO, particularly in cases where PDE5 inhibitors may be ineffective.