Glucose-Dependent Enhancement of Diabetic Bladder Contraction Is Associated with a Rho Kinase-Regulated Protein Kinase C Pathway

Urinary bladder dysfunction, which is one of the most common diabetic complications, is associated with alteration of bladder smooth muscle contraction. However, details regarding the responses under high-glucose (HG) conditions in diabetes are poorly understood. The objective of this study was to identify a relationship between extracellular glucose level and bladder smooth muscle contraction in diabetes. Bladder smooth muscle tissues were isolated from spontaneously type II diabetic (ob/ob mouse; 16-20 weeks of age, male) and age-matched control (C57BL mouse) mice. Carbachol (CCh) induced time-and dose-dependent contractions in ob/ob and C57BL mice; however, maximal responses differed significantly (14.34 +/- 0.32 and 12.69 +/- 0.22 mN/mm(2) after 30 mu M CCh treatment, respectively; n = 5-8). Pretreatment of bladders under HG conditions (22.2 mM glucose; concentration is twice that of normal glucose for 30 min) led to enhancement of CCh-induced contraction solely in diabetic mice (15.9 +/- 0.26 mN/mm(2); n = 5). Basal extracellular glucose-dependent enhancement of bladder contraction in diabetes was documented initially in this study. The correlation between intracellular calcium concentration and contraction was enhanced only in the ob/ob mouse. This enhancement of contraction and total protein kinase C (PKC) activity were inhibited by pretreatment with not only a PKC inhibitor (rottlerin) but also with a rho kinase inhibitor, fasudil [1-(5-isoquinolinesulfonyl)homopiperazine HCl]. These reagents also suppressed the differences between ob/ob and C57BL mouse bladder contractions under HG conditions. The data indicated that glucose-dependent enhancement of contraction in diabetic bladder is involved in the activation of the rho kinase and calcium-independent PKC pathways. This dysfunction may contribute to bladder complications such as detrusor overactivity and reduced bladder capacity in diabetes.