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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

M₂ and M₃ Muscarinic Receptor Activation of Urinary Bladder Contractile Signal Transduction. I. Normal Rat Bladder

Departments of Urology (A.S.B., A.S.T., M.R.R.) and Pharmacology (M.R.R.), Temple University School of Medicine, Philadelphia, Pennsylvania

The muscarinic receptor subtype-activated signal transduction mechanisms mediating rat urinary bladder contraction are incompletely understood. M₃ mediates normal rat bladder contractions; however, the M₂ receptor subtype has a more dominant role in contractions of the hypertrophied bladder. Normal bladder muscle strips were exposed to inhibitors of enzymes thought to be involved in signal transduction in vitro followed by a single cumulative concentration-response curve to the muscarinic receptor agonist carbachol. The outcome measures were the maximal contraction, the potency of carbachol, and the affinity of the M₃ -selective antimuscarinic agent darifenacin for inhibition of contraction. Inhibition of phosphoinositide-specific phospholipase C (PI-PLC) with 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphorylcholine (ET-18-OCH₃) reduces carbachol potency and reduces darifenacin affinity, whereas inhibition of phosphatidyl choline-specific phospholipase C (PC-PLC) with O-tricyclo[5.2.1.02,6]dec-9-yl dithiocarbonate potassium salt (D609) attenuates the carbachol maximal contraction. Inhibition of rho kinase with (R)-(+)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride (Y-27632) reduces carbachol potency and increases darifenacin affinity. Inhibition of rho kinase, protein kinase A (PKA), and protein kinase G (PKG) with 1-(5-isoquinolinesulfonyl)-homopiperazine·HCl (HA-1077) reduces the carbachol maximal contraction, carbachol potency, and darifenacin affinity. Inhibition of protein kinase C (PKC) with chelerythrine increases darifenacin affinity, whereas inhibition of rho kinase, PKA, PKG, and PKC with 1-(5-isoquinolinesulfonyl)-2-methylpiperazine·2HCl (H7) reduces the carbachol maximum and carbachol potency while increasing darifenacin affinity. Inhibition of rho kinase, PKA, and PKG with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide·2HCl (H89) reduces carbachol maximum and carbachol potency. Both the M₂ and the M₃ receptor subtype are involved in normal rat bladder contractions. The M₃subtype seems to mediate contraction by activation of PI-PLC, PC-PLC, and PKA, whereas the M₂ signal transduction cascade may include activation of rho kinase, PKC, and an additional contractile signal transduction mechanism independent of rho kinase or PKC.

Address correspondence to: Dr. Michael R. Ruggieri, Sr., 715 OMS, 3400 N. Broad St., Philadelphia, PA 19140. E-mail: rugg1{at}msn.com

This article has been cited by other articles:

				E. P. Frazier, A. S. Braverman, S. L. M. Peters, M. C. Michel, and M. R. Ruggieri Sr. Does Phospholipase C Mediate Muscarinic Receptor-Induced Rat Urinary Bladder Contraction? J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 998 - 1002. [Abstract] [Full Text] [PDF]

				A. S. Braverman, L. R. Doumanian, and M. R. Ruggieri Sr M2 and M3 Muscarinic Receptor Activation of Urinary Bladder Contractile Signal Transduction. II. Denervated Rat Bladder J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 875 - 880. [Abstract] [Full Text] [PDF]