Therapeutic effects of a soluble guanylate cyclase activator, BAY 60-2770, on lower urinary tract dysfunction in mice with spinal cord injury.

Abstract

We aimed to evaluate the effects of a soluble guanylate cyclase (sGC) activator, BAY 60-2770, on neurogenic lower urinary tract dysfunction in mice with spinal cord injury (SCI). Mice were divided into the following three groups: spinal cord intact (group A), SCI + vehicle (group B), and SCI + BAY 60-2770 (group C). SCI mice underwent Th8-Th9 spinal cord transection and treatment with BAY 60-2770 (10 mg/kg/day) once daily for 2-4 wk after SCI. We evaluated urodynamic parameters using awake cystometry and external urethral sphincter electromyograms (EMG); mRNA levels of mechanosensory channels, nitric oxide (NO)-, ischemia-, and inflammation-related markers in L6-S1 dorsal root ganglia, the urethra, and bladder tissues; and protein levels of cGMP in the urethra at 4 wk after SCI. With awake cystometry, nonvoiding contractions, postvoid residual, and bladder capacity were significantly larger in group B than in group C. Voiding efficiency (VE) was significantly higher in group C than in group B. In external urethral sphincter EMGs, the duration of notch-like reductions in intravesical pressure and reduced EMG activity time were significantly longer in group C than in group B. mRNA expression levels of transient receptor potential ankyrin 1, transient receptor potential vanilloid 1, acid-sensing ion channel (ASIC)1, ASIC2, ASIC3, and Piezo2 in the dorsal root ganglia, and hypoxia-inducible factor-1α, VEGF, and transforming growth factor-β1 in the bladder were significantly higher in group B than in groups A and C. mRNA levels of neuronal NO synthase, endothelial NO synthase, and sGCα1 and protein levels of cGMP in the urethra were significantly lower in group B than in groups A and C. sGC modulation might be useful for the treatment of SCI-related neurogenic lower urinary tract dysfunction.NEW & NOTEWORTHY This is the first report to evaluate the effects of a soluble guanylate cyclase activator, BAY 60-2770, on neurogenic lower urinary tract dysfunction in mice with spinal cord injury.

• Authors: Daisuke Gotoh, Tetsuichi Saito, Sergei Karnup, Yosuke Morizawa, Shunta Hori, Yasushi Nakai, Makito Miyake, Kazumasa Torimoto, Kiyohide Fujimoto, Naoki Yoshimura
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 323 Issue 4 Pg. F447-F454 (10 01 2022) ISSN: 1522-1466 [Electronic] United States
• PMID: 35952343 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid
• Benzoates
• Biphenyl Compounds
• Hydrocarbons, Fluorinated
• RNA, Messenger
• Nitric Oxide Synthase
• Soluble Guanylyl Cyclase

Topics

• Animals
• Benzoates
• Biphenyl Compounds
• Hydrocarbons, Fluorinated
• Mice
• Nitric Oxide Synthase (metabolism)
• RNA, Messenger (genetics, metabolism)
• Soluble Guanylyl Cyclase (metabolism)
• Spinal Cord Injuries (complications, drug therapy)
• Urinary Bladder (metabolism)