Received for publication October 18, 2005.
Revised October 20, 2005.
Accepted for publication October 20, 2005.

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

Abstract

The signal transduction mechanisms activated by muscarinic receptor subtypes mediating rat urinary bladder contraction are incompletely understood. Normal rat bladder contractions are mediated by the M₃ muscarinic receptor subtype, 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 PI-PLC with ET-18-OCH₃ reduces carbachol potency and reduces darifenacin affinity, while inhibition of PC-PLC with D609 attenuates the carbachol maximal contraction. Inhibition of rho kinase with Y-27632 reduces carbachol potency and increases darifenacin affinity. Inhibition of rho kinase, PKA and PKG with HA-1077 reduces the carbachol maximal contraction, carbachol potency and darifenacin affinity. Inhibition of PKC with chelerythrine increases darifenacin affinity while inhibition of rho kinase, PKA, PKG, and PKC with H7 reduces the carbachol maximum, carbachol potency while increasing darifenacin affinity. Inhibition of rho kinase, PKA and PKG with H89 reduces carbachol maximum and carbachol potency. Both the M₂ and the M₃ receptor subtype are involved in normal rat bladder contractions. The M₃ subtype appears to mediate contraction by activation of PI-PLC, PC-PLC, and PKA, while 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.

Key words: Rho Kinase, carbachol, phospholipases, protein kinases, signal transduction, urinary bladder

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