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 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 muscarinic agonist-induced contractions is most consistent with the pharmacologically 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 changes 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 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 M 2 receptors than M 3 in all tissues studied, whereas M l and M 4 receptors were undetectable. There was no difference from control in the ratio of M 2 to M 3 receptor in any tissues except that a greater proportion of M 3 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 M 3 receptor subtype that mediates bladder smooth muscle contraction. Neurourol.

The risk of lower urinary tract symptoms five years after the first delivery*

“…Studies in rats, rabbits, and guinea pigs have shown that the increased estrogen and progesterone levels during pregnancy generate bladder hypertrophy and increase capacity, possibly through degenerative and regenerative changes in the autonomic innervation of the lower urinary tract [Owman, 1981;Batra and Andersson, 1989;Qayyum et al, 1989;Lee et al, 1993;Hsia and Shortli¡e 1995;Tong et al, 1995;Baselli et al, 1999;Grandadam et al, 1999].…”

“…Postganglionic nerve endings innervate the smooth muscle of the bladder and urethra in humans [Gosling et al, 1998] and possibly the striated rhabdosphincter in animals [Elbadawi and Schenk, 1974]. Transmission in the bladder ganglia is mainly mediated via nicotinic receptors (acetylcholine release), whereas postganglionic transmission occurs mainly via di¡erent muscarinic receptor subtypes (acetylcholine release) [deGroat, 1976;Baselli et al, 1999].…”

“…In the bladder of the rat and rabbit, the muscarinic receptor density and contractile response are decreased during pregnancy, resulting in hypotonia of the smooth muscle and an increased bladder capacity [Tong et al, 1995;Baselli et al, 1999]. A larger bladder capacity has been associated with reduced invaginations (caveolae) and signaling protein in the cell membrane of the detrusor muscle cells in the pregnant rat [Bakircioglu et al, 2000].…”

Effect of human chorionic gonadotrophin on in vitro contractions of stimulated detrusor muscle strips of female rats

“…3,5,11,14,16,25,26 Various studies have shown that the maximum cystometric capacity is significantly increased in pregnancy with decreased voided urine volumes and that the bladder muscarinic receptor density is reduced with a consequent and marked decrease in cholinergic contractile response and a relative increase in the purinergic component. 4,10,25 The decreased bladder contractility was traditionally believed to be a non-specific response to uterine quiescence in pregnancy secondary to the close anatomical relationship between the two organs. More recently, this was considered as an abnormal detrusor reaction to first-trimester hormonal changes similar to hyperemesis gravidarum.…”

“…3,[5][6][7][8] Experimental and clinical studies have shown that pregnancy induces substantial changes in the urinary bladder resulting in decreased contractility and suggest that the specific hormonal changes during pregnancy may be primarily responsible. 1,2,4,5,9,10 Estrogen, progesterone and relaxin are implicated for their ability to influence the function of the urinary bladder. [1][2][3][4][5]7,9,[11][12][13][14] However, relatively little information exists to support a clear association between hormonal levels and lower urinary tract symptomatology in longitudinal studies of pregnant women.…”