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 microM 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.
Nobe
Koji
K
Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. kojinobe@pharm.showa-u.ac.jp
Yamazaki
Taigi
T
Tsumita
Naoki
N
Hashimoto
Terumasa
T
Honda
Kazuo
K
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology*; D010743:Phospholipids / Q000097:blood; D011493:Protein Kinase C / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D001743:Urinary Bladder / Q000187:drug effects / Q000503:physiopathology*; D054460:rho-Associated Kinases / Q000378:metabolism*
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D010743:Phospholipids; D014280:Triglycerides; D002217:Carbachol; D002784:Cholesterol; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D005947:Glucose