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Am J Physiol Regul Integr Comp Physiol 283: R663-R668, 2002. First published June 6, 2002; doi:10.1152/ajpregu.00116.2002
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Vol. 283, Issue 3, R663-R668, September 2002

Interaction between muscarinic receptor subtype signal transduction pathways mediating bladder contraction

Alan S. Braverman1, Ronald J. Tallarida2, and Michael R. Ruggieri Sr.1,2

Departments of 1 Urology and 2 Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

M3 muscarinic receptors mediate cholinergic-induced contraction in most smooth muscles. However, in the denervated rat bladder, M2 receptors participate in contraction because M3-selective antagonists [para-fluoro-hexahydro-sila-diphenidol (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 receptor. 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 additive effects. In denervated bladders, synergistic effects were seen with the 10:1 and 1:1 (methoctramine:p-F-HHSiD wt/wt) combinations. After 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 receptors interact in a facilitatory manner to mediate contraction.

urinary bladder; synergy; denervation; second messengers


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