Effects of cannabinoid receptor agonists on neuronally‐evoked contractions of urinary bladder tissues isolated from rat, mouse, pig, dog, monkey and human

Abstract

1 This study investigated the cannabinoid receptor, known to inhibit neuronally-evoked contractions of the mouse isolated urinary bladder, in bladder sections isolated from mouse, rat, dog, pig non-human primate or human. 2 The CB 1 -like pharmacology of the cannabinoid receptor in mouse isolated bladder observed previously was con®rmed in this study by the rank order of agonist potencies: CP 559405WIN 55212-24HU 2104JWH 0154anandamide, the high anity of the CB 1 selective antagonist, SR 141716A (apparent pK B 8.7), and the low anity of the CB 2 antagonist, SR 144528 (apparent pK B 56.5). In these studies, SR 141716A (10 ± 100 nM) signi®cantly potentiated electrically-evoked contractions in this tissue by an undetermined mechanism. 3 A similar rank order of agonist potencies was determined in rat isolated bladder sections (CP 55,. In this tissue, the maximal inhibitory eect of all agonists was lower than in the mouse bladder. Indeed, the eects of both HU 210 and anandamide were too modest to quantify potency accurately. 4 In the rat isolated bladder, SR 141716A (30 nM) or SR 144528 (100 nM), reversed the inhibitory eect of WIN 55212-2 (apparent pK B =8.4 and 8.0, respectively) or JWH 015 (apparent pK B =8.2 and 7.4, respectively). These ®ndings may demonstrate pharmacological dierences between the rat and mouse orthologues of the CB 1 receptor. Alternatively, they may be attributed to a mixed population of CB 1 and CB 2 receptors that jointly in¯uence neurogenic contraction of the rat bladder, but cannot be dierentiated without more selective ligands. 5 WIN 55212-2 had no eect on electrically-evoked contractions of bladder sections isolated from dog, pig, cynomolgus monkey and human. These ®ndings suggest that the eect of cannabinoid agonists to inhibit neurogenic contraction of the mouse and rat bladder is not conserved across all mammalian species.

Pharmacological characterization of cannabinoid receptor activity in the rat‐isolated ileum myenteric plexus‐longitudinal muscle preparation

“…In the rat MPLM, the pEC50 values of all four agonists to inhibit the twitch contractions and their rank order of pEC50 values were consistent with those previously reported at the guinea pig, human, mouse and rat CB1, but not CB2 receptor Showalter et al, 1996;Rinaldi-Carmona et al, 1998;Martin et al, 2000). These findings, together with the demonstration that rimonabant caused similar concentration-dependent, but agonistindependent, parallel and surmountable dextral shifts of the agonist concentration-response curves with pKB values within its reported range of pKB/pKi values at the CB1 receptor (7.93 to 8.74 ;Felder et al, 1995;Rinaldi-Carmona et al, 1994;Showalter et al, 1996), suggested that the inhibition produced by each agonist was mediated by the activation of the CB1 receptor.…”

Cannabinoid receptor expression in the bladder is altered in detrusor overactivity

“…In addition, the majority of available studies have only looked at efferent functions of the bladder and have found electrically-evoked contractions of bladder strips to be reduced after the addition of a CB1 agonist [4,10,11]. Cystometric studies supporting the role of cannabinoids on efferent functions have shown that CB agonists increased micturition threshold and voiding interval [12][13][14].…”

Prejunctional and peripheral effects of the cannabinoid CB1 receptor inverse agonist rimonabant (SR 141716)

“…Later studies confirmed a rimonabantsensitive inhibition of neuronally stimulated contractions of isolated bladder in mouse and extended these findings to rats. On the other hand, no such inhibition was seen in the isolated bladder of dogs, pigs, cynomolgus monkeys, or humans, indicating that the inhibitory effect of cannabinoids on bladder contractility is species dependent (Martin et al 2000). In line with the in vitro data from rodents, in vivo studies in rats demonstrated a cannabinoid-induced reduction of micturition thresholds, which became even more prominent under conditions of bladder inflammation or after sympathectomy.…”