The effect of pregnancy and contractile activity on bladder muscarinic receptor subtypes

Abstract

In the rabbit bladder, pregnancy and prolonged bladder contractions decrease both muscarinic receptor density and contractile response, whereas newborns show enhanced muscarinic contractile response. Although the M2 receptor predominates in rabbit bladder, we and others have shown that the affinity of a series of subtype selective muscarinic antagonists for inhibition of muscarinic agonist–induced contractions is most consistent with the pharmacologically defined M3 receptor directly mediating smooth muscle contraction. Bladders from fetal rabbits, gravid rabbits, and male rabbits exposed to 4 hr of induced spontaneous contractions were used to determine whether changes in receptor density and contractility are due to a selective decrease in either the M2 or M3 muscarinic receptor subtype. To determine organ specificity, the heart and uterus were also studied. Gravid rabbits of 3 weeks' gestation and their fetal rabbits were studied. In male rabbits, bladder contractions were induced for 4 hr by ligating the catheterized penis at its base. Muscarinic receptor density and subtype distribution were determined by radioligand binding and immunoprecipitation. Receptor density was 24% lower in gravid bladder body, unchanged in gravid bladder base, 54% lower in gravid uterus, 115% higher in fetal bladders, and 34% lower after induced bladder contractions. Immunoprecipitation showed greater M2 receptors than M3 in all tissues studied, whereas Ml and M4 receptors were undetectable. There was no difference from control in the ratio of M2 to M3 receptor in any tissues except that a greater proportion of M3 receptors was found in male vs. female bladders. Changes in contractile response to cholinergic stimulation in the gravid, fetal, and experimental detrusor instability model are associated with changes in total receptor density and not solely with changes in the M3 receptor subtype that mediates bladder smooth muscle contraction. Neurourol. Urodynam. 18:511–520, 1999. © 1999 Wiley‐Liss, Inc.

Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence

“…The results were interpreted to mean that pregnancy induced an increase in the purinergic and a decrease in the cholinergic components of the urinary bladder response to field stimulation (Levin et al, 1991). A reduction of the muscarinic receptor density in the pregnant rabbit bladder was confirmed by other investigators (Baselli et al, 1999).…”

Increased maternal intraabdominal pressure alters the contractile properties of fetal rabbit bladder

“…Cholinergic hypersensitivity may result from changes in the density of muscarinic receptors, which can be regulated by modifying the degree of receptor activation. Because the density of muscarinic receptor is physiologically 115% higher in fetal rabbit bladders than that of adult bladders [22], the density of cholinergic receptors is expected to be increased under the effect of increased IAMNP. This kind of cholinergic hypersensitivity may also imply increased density of muscarinic receptors, which occurs after prolonged exposure to muscarinic receptor antagonists.…”

Development of fetal nicotine and muscarinic receptors in utero

“…The M 2 receptor is the predominant subtype in the bladder and uterus. The bladder of the fetal rabbit has been shown to respond to muscarinic stimulation (19,20). The development of sheep fetuses is associated with increased contractile activation between 65 and 140 gestational days, and atropine-increased bladder capacity is observed at 120 days' gestation (21)(22)(23).…”