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Am J Physiol Regul Integr Comp Physiol (June 6, 2002). doi:10.1152/ajpregu.00116.2002
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Articles in PresS, published online ahead of print June 6, 2002
Am J Physiol Regu Physiol, 10.1152/ajpregu.00116.2002
Submitted on February 20, 2002
Accepted on May 31, 2002

Interaction Between Muscarinic Receptor Subtype Signal Transduction Pathways Mediating Bladder Contraction

Alan S Braverman1, Ronald J Tallarida2, and Michael R Ruggieri, Sr.3*

1 Department of Urology, Temple University School of Medicine, Philadelphia, PA, USA
2 Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA
3 Department of Urology, Temple University School of Medicine, Philadelphia, PA, USA; Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA

* To whom correspondence should be addressed. E-mail: rugg1{at}msn.com.

M3 muscarinic receptors mediate cholinergic induced contraction in most smooth muscles. However, in the denervated rat bladder, M2 receptors participate in contraction, since M3-selective antagonists (p-F-HHSiD and 4-DAMP) have low affinities. However, the affinity of the M2-selective antagonist, methoctramine in the denervated bladder is consistent with M3 receptor mediating contraction. It is possible that two pathways interact to mediate contraction; one mediated by the M2 receptor and one by the M3. To determine whether an interaction exists, the inhibitory potencies of combinations of methoctramine and p-F-HHSiD for reversing cholinergic contractions were measured. In normal bladders, all combinations gave simple additive effects. In denervated bladders, synergistic effects were seen with the 10:1 and 1:1 (methoctramine:p-F-HHSiD w/w) combinations. Following application of the sarcoplasmic reticulum ATPase inhibitor thapsigargin to normal tissue, the 10:1 and 1:1 ratios became synergistic, mimicking denervated tissue. Thus in normal bladders both M2 and M3 receptors can induce contraction. In the denervated bladder, the M2 and the M3 receptor interact in a facilitatory manner to mediate contraction.




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