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

• Published in: British journal of pharmacology 1998-07, Vol.124 (5), p.865-872
• Main Authors: Palea, S, Toson, G, Pietra, C, Trist, D G., Artibani, W, Romano, O, Corsi, M
• Format: Article
• Language: English
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology; acetylcholine release; Alprostadil - pharmacology; Biological and medical sciences; Biphenyl Compounds - pharmacology; detrusor; Dinoprost - pharmacology; Dinoprostone - pharmacology; Electric Stimulation; electrical field stimulation; Fundamental and applied biological sciences. Psychology; Heptanoic Acids - pharmacology; Human urinary bladder; Humans; In Vitro Techniques; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Prostaglandin Antagonists - pharmacology; Prostaglandin D2 - pharmacology; prostaglandin E2; prostaglandin F2α; prostanoid receptors; Receptors, Prostaglandin - agonists; Receptors, Prostaglandin - antagonists & inhibitors; Receptors, Prostaglandin E - antagonists & inhibitors; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Thromboxane - agonists; Receptors, Thromboxane - antagonists & inhibitors; smooth muscle contraction; Thromboxane A2 - pharmacology; Thromboxane A2 - physiology; TXA2 receptors; Urinary Bladder - drug effects; Urinary Bladder - physiology; U‐46619; vapiprost; Vertebrates: urinary system; Xanthenes - pharmacology; Xanthones
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0701903

Cumulative concentration‐response curves (CRC) to prostaglandin E1 (PGE1), PGE2, PGD2 and PGF2α (0.01–30 μM) and to the thromboxane A2 (TXA2) receptor agonist U‐46619 (0.01–30 μM) were constructed in human isolated detrusor muscle strips both in basal conditions and during electrical field stimulation. All the agonists tested contracted the detrusor muscle. The rank order of agonist potency was: PGF2α>U‐46619>PGE2 whereas weak contractile responses were obtained with PGD2 and PGE1. Any of the agonists tested was able to induce a clear plateau of response even at 30 μM. The selective TXA2 antagonist, GR 32191B (vapiprost), antagonized U‐46619‐induced contractions with an apparent pKB value of 8.27±0.12 (n=4 for each antagonist concentration). GR 32191B (0.3 μM) did not antagonize the contractile responses to PGF2α and it was a non‐surmountable antagonist of PGE2 (apparent pKB of 7.09±0.04; n=5). The EP receptor antagonist AH 6809 at 10 μM shifted to the right the CRC to U‐46619 (apparent pKB value of 5.88±0.04; n=4). Electrical field 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 μM) and atropine (1 μM). U‐46619 (0.01–3 μM) potentiated the twitch contraction in a dose‐dependent manner and this effect was competitively antagonized by GR 32191B with an estimated pKB of 8.54±0.14 (n=4 for each antagonist concentration). PGF2α in the range 0.01–10 μM (n=7), but not PGE2 and PGE1 (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 unaffected by 0.3 μM GR 32191B (n=5). Cumulative additions of U‐46619 (0.01–30 μM) were without effect 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 μM; n=3). Moreover, pretreatment of the tissue with 0.3 μM U‐46619 did not potentiate the smooth muscle response to 7 μM bethanecol (n=2). We concluded that TXA2 can induce direct contraction of human isolated urinary bladder through the classical TXA2 receptor. Prostanoid receptors, fully activated by PGE2 and PGF2α 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 PGE2 seem to indicate the presence of a new EP receptor subtype. Moreover, we suggest the presence of prejuctional TXA2 and FP re