PT - JOURNAL ARTICLE AU - Koji Nobe AU - Taigi Yamazaki AU - Toshio Kumai AU - Masako Okazaki AU - Shinichi Iwai AU - Terumasa Hashimoto AU - Shinichi Kobayashi AU - Katsuji Oguchi AU - Kazuo Honda TI - Alterations of Glucose-Dependent and -Independent Bladder Smooth Muscle Contraction in Spontaneously Hypertensive and Hyperlipidemic Rat AID - 10.1124/jpet.107.131334 DP - 2008 Feb 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 631--642 VI - 324 IP - 2 4099 - http://jpet.aspetjournals.org/content/324/2/631.short 4100 - http://jpet.aspetjournals.org/content/324/2/631.full SO - J Pharmacol Exp Ther2008 Feb 01; 324 AB - Alteration of bladder contractility was examined in the spontaneously hypertensive and hyperlipidemic rat (SHHR; age, 9 months; systolic blood pressure, >150 mm Hg; plasma cholesterol, >150 mg/dl). Carbachol (CCh) induced time- and dose-dependent contractions in Sprague-Dawley (age-matched control) rats and SHHR; however, maximal levels differed significantly (13.3 ± 2.2 and 5.4 ± 1.9 μN/mm2 following 10 μM CCh treatment, respectively; n = 5). This difference, which was maintained in calcium-replaced physiological salt solution (PSS), was suppressed by pretreatment with rho kinase inhibitor, 1 μM Y27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide]; moreover, total activity of rho kinase was also reduced in SHHR bladder. Pretreatment of bladders under high-glucose (HG) conditions (22.2 mM glucose-contained PSS for 30 min) led to enhancement of CCh-induced contraction solely in control animals. Under HG conditions, both protein kinase C (PKC) activity and production of diacylglycerol (DG) derived from incorporated glucose declined in SHHR bladder; however, sustained elevation of plasma glucose level was not detected in SHHR. These results suggested that bladder contractility dysfunction in SHHR is attributable to alteration of rho kinase activity and the DG-PKC pathway. This dysfunction may occur prior to chronic hyperglycemia onset in progressive hypertension and hyperlipidemia. The American Society for Pharmacology and Experimental Therapeutics