The role of M₂‐muscarinic receptors in mediating contraction of the pig urinary bladder in vitro

Abstract

1 In urinary bladder, M 2 -muscarinic receptors predominate, but it is the smaller population of M 3 -receptors which mediate detrusor contraction. This study examines the M 2 : M 3 ratio and the role of M 2 -receptors in contraction of pig urinary bladder. 4 On normal detrusor in vitro, 4-DAMP and methoctramine caused surmountable antagonism of responses to carbachol with pK B values of 9.37+0.07 and 6.05+0.05 respectively. Darifenacin caused unsurmountable antagonism, the apparent pK B value being 8.61+0.10. 5 In tissues where the M 3 -receptors had been inactivated and cyclic AMP levels elevated, 4-DAMP and darifenacin were less potent, with apparent pK B values of 8.72+0.08 and 6.74+0.07. In contrast, methoctramine was more potent, the apparent pK B value increasing signi®cantly to 6.86+0.06. 6 These data suggest that the pig bladder possesses a similar muscarinic receptor population to the human bladder and that the M 3 -receptor subtype mediates contraction of the normal detrusor muscle. However an involvement of M 2 -receptors in contraction can be observed following pharmacological manipulation of the receptor population.

M3 muscarinic receptors mediate contraction of human urinary bladder

“…These data demonstrate that contraction of human bladder in response to carbachol is mediated predominantly if not exclusively by the M 3 muscarinic receptor. This situation mimics closely the previously reported ®ndings in rats (Choppin et al, 1998;Hegde et al, 1997;Longhurst et al, 1995;Longhurst & Levendusky, 2000;Tong et al, 1997), mice (Choppin & Eglen, 2001b), pigs (Yamanishi et al, 2000) and dogs (Choppin & Eglen, 2001a). These data suggest that a drug for the e ective treatment of overactive bladder should have high a nity for M 3 receptors.…”

“…A similar situation is found in the bladder of rats, rabbits, guinea-pigs (Wang et al, 1995) and pigs (Goepel et al, 1998;Yamanishi et al, 2000). The contractile response to the exogenous muscarinic agonist carbachol and to endogenous agonist released by ®eld stimulation, however, occurs predominantly if not exclusively via M 3 receptors in rats (Choppin et al, 1998;Hegde et al, 1997;Longhurst et al, 1995;Longhurst & Levendusky, 2000;Tong et al, 1997), mice (Choppin & Eglen, 2001b), pigs (Yamanishi et al, 2000) and dogs (Choppin & Eglen, 2001a).…”

M2 mediated contractions of human bladder from organ donors is associated with an increase in urothelial muscarinic receptors

“…M 2 and M 3 receptor subtypes predominate in the detrusor muscle, with the population of the M 2 subtype receptor in detrusor muscle greater than the M 3 subtype. Previous immunoprecipitation data with subtype-selective antibodies and radioligand binding studies have reported a ratio of M 2 to M 3 receptors in the detrusor to be approximately three to one for human, guinea pig, and rabbit bladders and selective radioligand binding data indicates a similar ratio for the pig bladder [Yamanishi et al, 2000]. Despite higher density of M 2 receptors, contraction has been found to be primarily mediated by M 3 receptors under normal conditions in all species studied.…”

Signal Transduction Underlying Carbachol-Induced Contraction of Human Urinary Bladder

“…M 2 and M 3 muscarinic receptors coexist in the bladder of various mammalian species, including humans, but the expression of M 2 receptors is much greater than that of the M 3 receptors (Wang et al, 1995;Goepel et al, 1998;Yamanishi et al, 2000;Kories et al, 2003). Nevertheless, the contractile response to the exogenous agonist carbachol and to endogenous agonist released by field stimulation have been attributed predominantly if not exclusively to M 3 receptors in rats (Longhurst et al…”