Pharmacological characterization of thromboxane and prostanoid receptors in human isolated urinary bladder

Abstract

1 Cumulative concentration-response curves (CRC) to prostaglandin E 1 (PGE 1 ), PGE 2 , PGD 2 and PGF 2a (0.01 ± 30 mM) and to the thromboxane A 2 (TXA 2 ) receptor agonist U-46619 (0.01 ± 30 mM) were constructed in human isolated detrusor muscle strips both in basal conditions and during electrical ®eld stimulation. 2 All the agonists tested contracted the detrusor muscle. The rank order of agonist potency was: PGF 2a 4U-466194PGE 2 whereas weak contractile responses were obtained with PGD 2 and PGE 1 . Any of the agonists tested was able to induce a clear plateau of response even at 30 mM. 3 The selective TXA 2 antagonist, GR 32191B (vapiprost), antagonized U-46619-induced contractions with an apparent pK B value of 8.27+0.12 (n=4 for each antagonist concentration). GR 32191B (0.3 mM) did not antagonize the contractile responses to PGF 2a and it was a non-surmountable antagonist of PGE 2 (apparent pK B of 7.09+0.04; n=5). The EP receptor antagonist AH 6809 at 10 mM shifted to the right the CRC to U-46619 (apparent pK B value of 5.88+0.04; n=4). 4 Electrical ®eld stimulation (20 Hz, 70 V, pulse width 0.1 ms, trains of 5 s every 60 s) elicited contractions fully sensitive to TTX (0.3 mM) and atropine (1 mM). U-46619 (0.01 ± 3 mM) potentiated the twitch contraction in a dose-dependent manner and this e ect was competitively antagonized by GR 32191B with an estimated pK B of 8.54+0.14 (n=4 for each antagonist concentration). PGF 2a in the range 0.01 ± 10 mM (n=7), but not PGE 2 and PGE 1 (n=3 for each), also potentiated the twitch contraction of detrusor muscle strips (23.5+0.3% of KCl 100 mM-induced contraction) but this potentiation was una ected by 0.3 mM GR 32191B (n=5). 5 Cumulative additions of U-46619 (0.01 ± 30 mM) were without e ect on contractions induced by direct smooth muscle excitation (20 Hz, 40 V, 6 ms pulse width, trains of 2 s every 60 s, in the presence of TTX 1 mM; n=3). Moreover, pretreatment of the tissue with 0.3 mM U-46619 did not potentiate the smooth muscle response to 7 mM bethanecol (n=2). 6 We concluded that TXA 2 can induce direct contraction of human isolated urinary bladder through the classical TXA 2 receptor. Prostanoid receptors, fully activated by PGE 2 and PGF 2a are also present. All these receptors are probably located post-junctionally. The rank order of agonist potency and the fact that GR32191B, but not AH6809, antagonized responses to PGE 2 seem to indicate the presence of a new EP receptor subtype. Moreover, we suggest the presence of prejuctional TXA 2 and FP receptors, potentiating acetylcholine release from cholinergic nerve terminals.

Enhanced Sensitivity to Afferent Stimulation and Impact of Overactive Bladder Therapies in the Conscious, Spontaneously Hypertensive Rat

“…This is consistent with robust capsaicin desensitization in the protocol used for these studies. Alternatively, it may reflect capsaicin-insensitive effects of PGE 2 acting on smooth muscle (Palea et al, 1998) or other tissues, such as the urothelium (Wang et al, 2008), capable of modulating bladder function. Capsaicin pretreatment alone enhanced basal VV and MI in SHR consistent with previous studies in control rats (Maggi et al, 1988;Mitsui et al, 2001).…”

Evaluation of Prostaglandin E2 and E-Series Prostaglandin Receptor in Patients with Interstitial Cystitis

“…16,17 A previous study demonstrated that non-selective EP1/EP2 receptor antagonist decreased detrusor contraction in human isolated bladder. 18 However, the role of EP2 receptor in bladder function remains to be clarified. To our knowledge, the present study is the first report…”

Loxoprofen inhibits facilitated micturition reflex induced by acetic acid urinary bladder infusion of the rats

“…These data indicated that PGE 2 did not play a part of normal micturition and may play a part of the micturition refl ex during acetic acid infusion. PGE 2 infusion into the urinary bladder facilitated the micturition refl ex (11) and made contraction of the detrusor smooth muscles (19). PGE 2 could be released from the immune cells during the infl ammation and from fi broblast cells in the submucosal connective tissue (13,16).…”