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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Signal Transduction Underlying Carbachol-Induced Contraction of Human Urinary Bladder

Departments of Medicine (T.S., C.F., M.C.M.) and Urology (T.S., S.K.), University of Essen, Essen, Germany; and Department of Pharmacology and Pharmacotherapy (M.C.M.), University of Amsterdam, Amsterdam, The Netherlands

The present study was designed to reexamine the muscarinic acetylcholine receptor subtype mediating carbachol-induced contraction of human urinary bladder and to investigate the underlying signal transduction. Based upon the nonselective tolterodine, the highly M₂-selective (R)-4-{2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl}piperidine-1-carboxylic acid amide (Ro-320-6206), and the highly M₃-selective darifenacin and 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(4-methoxyphenylethyl)pyrrolidine (APP), contraction occurs via M₃ receptors. The phospholipase C inhibitor 1-(6-[([17]-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl)-1H-pyrrole-2,5-dione (U 73,122) (1-10 µM) did not significantly affect carbachol-stimulated bladder contraction. The phospholipase D inhibitor butan-1-ol relative to its negative control butan-2-ol (0.3% each) caused small but detectable inhibition of carbachol-induced bladder contraction. The Ca²⁺ entry blocker nifedipine (10-100 nM) strongly inhibited carbachol-induced bladder contraction. In contrast, 1-[-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl (SK&F 96,365) (1-10 µM), an inhibitor of store-operated Ca²⁺ channels, caused little inhibition. The protein kinase C inhibitor bisindolylmaleimide I (1-10 µM) did not significantly affected carbachol-induced bladder contraction. In contrast, trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide (Y 27,632) (1-10 µM), an inhibitor of rho-associated kinases, concentration dependently and effectively attenuated the carbachol responses. We conclude that carbachol-induced contraction of human urinary bladder via M₃ receptors largely depends on Ca²⁺ entry through nifedipine-sensitive channels and activation of a rho kinase, whereas phospholipase D and store-operated Ca²⁺ channels contribute only in a minor way. Surprisingly, phospholipase C or protein kinase C do not seem to be involved to a relevant extent.

Address correspondence to: Prof. Martin C. Michel, Academisch Medisch Centrum, Afd. Farmacologie en Farmacotherapie, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. E-mail: m.c.michel{at}amc.uva.nl

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