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

In the rabbit bladder,pregnancy and prolonged bladder contractions decrease both muscarinic receptor density and contractile response, whereas newborn s show enhanced muscarinic contractile response. Although the M-2 receptor predominates in rabbit bladder, we and others have shown that the affinity of a series of subtype selective muscarinic antagonists for inhibition of m uscarinic agonist-induced contractions is most consistent with the pharmaco logically defined M-3 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 cha nges in receptor density and contractility are due to a selective decrease in either the M-2 or M-3 muscarinic receptor subtype. To determine organ sp ecificity, the heart and uterus were also studied. Gravid rabbits of 3 week s' gestation and their fetal rabbits were studied. In male rabbits, bladder contractions were induced for 4 hr by ligating the catheterized penis at i ts base. Muscarinic receptor density and subtype distribution were determin ed 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 induce d bladder contractions. Immunoprecipitation showed greater M-2 receptors th an M-3 in all tissues studied, whereas M-1 and M-4 receptors were undetecta ble. There was no difference from control in the ratio of M-2 to M-3 recept or in any tissues except that a greater proportion of M-3 receptors was fou nd in male vs, female bladders. Changes in contractile response to choliner gic 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 M-3 receptor subtype that mediates bladder smooth musc le contraction. (C) 1999 Wiley-Liss, Inc.