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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Signal Transduction Underlying Carbachol-Induced Contraction of Rat Urinary Bladder. I. Phospholipases and Ca²⁺ Sources

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

We have reexamined the muscarinic receptor subtype mediating carbachol-induced contraction of rat urinary bladder and investigated the role of phospholipase (PL)C, D, and A₂ and of intra- and extracellular Ca²⁺ sources in this effect. Based on the nonsubtype-selective tolterodine, the highly M₂ receptor-selective (R)-4-{2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl}-piperidine-1-carboxylic acid amide (Ro-320-6206), and the highly M₃ receptor-selective darifenacin and 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(4-methoxyphenylethyl)pyrrolidine (APP), contraction occurs via M₃ receptors. Carbachol stimulated inositol phosphate formation in rat bladder slices, and this was abolished by 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; 10 µM). Nevertheless, U 73,122 (1–10 µM) did not significantly affect carbachol-stimulated bladder contraction. Carbachol had only little effect on PLD activity in bladder slices, but the PLD inhibitor butan-1-ol, relative to its negative control butan-2-ol (0.3% each), caused detectable inhibition of carbachol-induced bladder contraction. The cytosolic PLA₂ inhibitor arachidonyltrifluoromethyl ketone weakly inhibited carbachol-induced contraction at a concentration of 300 µM, but the cyclooxygenase inhibitor indomethacin (1–10 µM) remained without effect. The Ca²⁺ entry blocker nifedipine (10–100 nM) almost completely inhibited carbachol-induced bladder contraction. In contrast, 1-[-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl (SKF 96,365; 10 µM), an inhibitor of store-operated Ca²⁺ channels, caused little inhibition. We conclude that carbachol-induced contraction of rat bladder largely depends on Ca²⁺ entry through nifedipine-sensitive channels and, perhaps, PLD, PLA₂, and store-operated Ca²⁺ channels, whereas cyclooxygenase and, surprisingly, also PLC are not involved to a relevant extent.

Address correspondence to: Professor 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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