title: Prostanoid receptors mediating contraction in rat, macaque and human bladder smooth muscle in vitro.
abstract: Selective prostaglandin EP1 antagonists have been suggested for the treatment of bladder dysfunction. This study assessed the contractile prostanoid receptor subtypes in human and non-human bladder in vitro. Classical tissue bath studies were conducted using bladder strips exposed to prostanoid agonists and antagonists. Prostaglandin E2 (PGE2) contracted rat, macaque and human bladder smooth muscle strips (pEC50 7.91±0.06 (n=7), 6.40±0.13 (n=7), and 6.07±0.11 (n=5), respectively). The EP1 receptor antagonist, PF2907617 (300nM), caused a rightward shift of the PGE2 concentration-response curve in the rat bladder only (pKB 8.40±0.15, n=3). PGE2 responses in rat and macaque bladders, but not human, were antagonised by the EP3 antagonist CJ24979 (1µM). Sulprostone, a mixed EP1/EP3/FP receptor agonist, induced potent contractions of rat bladder muscle (pEC50 7.94±0.31, n=6). The FP receptor agonist, prostaglandin F2α (PGF2α), induced bladder contraction in all species tested, but with a lower potency in rat. The selective FP receptor agonist latanoprost caused potent contractions of macaque and human bladder strips only. SQ29548, a selective TP antagonist, and GW848687X, a mixed EP1/TP antagonist caused rightward shifts of the concentration-response curves to the selective TP agonist, U46619 (pKB estimates 8.53±0.07 and 7.56±0.06, n=3, respectively). Responses to U46619 were absent in rat preparations. These data suggest significant species differences exist in bladder contractile prostanoid receptor subtypes. We conclude that the EP1 subtype does not represent the best approach to the clinical treatment of bladder disorders targeting inhibition of smooth muscle contraction.
authors.affiliation: Genitourinary Biology, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. Electronic address: james.root@astrazeneca.com.
authors.forename: James A
authors.initials: JA
authors.lastname: Root
authors.affiliation: Genitourinary Biology, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.
authors.forename: Dorren A
authors.initials: DA
authors.lastname: Davey
authors.affiliation: Genitourinary Biology, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Af Forselles
mesh_terms: D000368:Aged; D000818:Animals; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D006801:Humans; D008251:Macaca; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology*; D019459:Urothelium / Q000187:drug effects / Q000502:physiology
chemical_list: D011982:Receptors, Prostaglandin; D013779:Tetrodotoxin; D015232:Dinoprostone
keywords: Human; Macaque; Prostaglandin; Rat; Urinary bladder; Urothelium