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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

M₂ and M₃ Muscarinic Receptor Activation of Urinary Bladder Contractile Signal Transduction. II. Denervated Rat Bladder

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

Normal rat bladder contractions are mediated by the M₃ muscarinic receptor subtype. The M₂ receptor subtype mediates contractions of the denervated, hypertrophied bladder. This study determined signal transduction mechanisms mediating contraction of the denervated rat bladder. Denervated bladder muscle strips were exposed to inhibitors of enzymes thought to be involved in signal transduction in vitro followed by a cumulative carbachol concentration-response curve. Outcome measures were the maximal contraction, the potency of carbachol, and the affinity of 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) has no effect on denervated bladder contractions, 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 maximum and potency. Inhibition of rho kinase with (R)-(+)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride (Y-27632) reduces carbachol maximum, 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 maximum and potency. Inhibition of PKC with chelerythrine increases darifenacin affinity, whereas inhibition of rho kinase, PKA, PKG, and protein kinase C (PKC) with 1-(5-isoquinolinesulfonyl)-2-methylpiperazine·2HCl (H7) reduces the carbachol potency while increasing darifenacin affinity. Inhibition of rho kinase, PKA, and PKG with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide·2HCl (H89) increases darifenacin affinity. This study demonstrates that different signal transduction mechanisms mediate the contractile response in the denervated rat bladder than in normal rat bladder. In normal rat bladder, PI-PLC and PC-PLC mediate the contraction, but in denervated bladder only PC-PLC is involved. In the denervated bladder, the rho kinase pathway is more dominant than in normal bladders. PKA seems to mediate a contractile response in normal bladders, whereas it seems to inhibit contraction in denervated bladders.

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]