Effect of diabetes on cooling-induced detrusor muscle contraction: mediation via Rho-kinase activation.

Objectives: To investigate the possible involvement of Rho-kinase in cooling-induced contraction of the detrusor muscle. The etiology of diabetic cystopathy is not clear. It may be due to various changes in bladder innervation and/or detrusor muscle dysfunction. Because cooling of urinary bladder smooth muscle normally is a potent stimulus to micturition due to increase in muscle tone, we studied the effects of cooling on normal and diabetic bladder specimens.

Methods: Urinary detrusor muscle strips isolated from rats were suspended in organ baths containing Krebs solution for isometric tension recording. Tissue responses to stepwise cooling were examined from normal and 12-week streptozocin-induced diabetic rats. We examined the effects of calcium-free, ethylene glycol bis (beta-aminoethylether)-N,N,N,N,-tetraacetic acid (1 mm)-containing Krebs solution, and the Rho-kinase inhibitor Y-27632 on the cooling responses.

Results: Stepwise cooling from 37 degrees C to 5 degrees C induced a rapid and reproducible increase in basal tone, proportional to cooling temperature. This response was more pronounced in diabetic specimens. Cooling-induced contractions were significantly inhibited in calcium-free solutions in both control and diabetic bladders. Our investigation showed that the influx of extracellular calcium is important in inducing the cooling response. The Rho-kinase inhibitor Y-27632 (1 microm) inhibited cooling (20 degrees C)-induced contraction. It reduced the response by 52.1% +/- 10.0% in control and by 70.0% +/- 12.0% in diabetic rats.

Conclusions: Cooling-induced contractions in control and diabetic detrusor muscle preparations are highly calcium dependant. It also involves activation of Rho-kinase, which might be upregulated in the diabetic detrusor muscle. These results may help in the management of diabetes-induced incontinence due to involuntary detrusor muscle activity.