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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Does Cyclic AMP Mediate Rat Urinary Bladder Relaxation by Isoproterenol?

Department of Pharmacology and Pharmacotherapy, University of Amsterdam, Academisch Medisch Centrum, Amsterdam, The Netherlands

Cyclic AMP is the prototypical second messenger of -adrenergic receptors, but recent findings have questioned its role in mediating smooth muscle relaxation upon -adrenergic receptor stimulation. We have investigated the signaling mechanisms underlying -adrenergic receptor-mediated relaxation of rat urinary bladder. Concentration-response curves for isoproterenol-induced bladder relaxation were generated in the presence or absence of inhibitors, with concomitant experiments using passive tension and KCl-induced precontraction. The adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22,536; 1 µM), the protein kinase A inhibitors 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7; 10 µM), N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89; 1 µM), and Rp-adenosine 3',5'-cyclic monophosphorothioate (Rp-cAMPS; 30 µM), and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ; 3 µM) produced only minor if any inhibition of relaxation against passive tension or KCl-induced precontraction. Among various potassium channel inhibitors, BaCl₂ (10 µM), tetraethylammonium (3 µM), apamin (300 nM), and glibenclamide (10 µM) did not inhibit isoproterenol-induced relaxation. Some inhibition of the isoproterenol effects against KCl-induced tone but not against passive tension was seen with inhibitors of calcium-dependent potassium channels such as charybdotoxin and iberiotoxin (30 nM each). A combination of SQ 22,536 and ODQ significantly inhibited relaxation against passive tension by about half, but not that against KCl-induced tone. Moreover, the combination failed to enhance inhibition by charybdotoxin against KCl-induced tone. We conclude that cAMP and cGMP each play a minor role in -adrenergic receptor-mediated relaxation against passive tension, and calcium-dependent potassium channels play a minor role against active tension.

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

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