title: Pharmacological characterization of alpha 2-adrenoceptor-mediated responses in pig nasal mucosa.
abstract: 1. Pig nasal mucosal strips were incubated with alpha-adrenoceptor antagonists followed by alpha2-adrenoceptor agonist concentration-response curves. 2. Contractions elicited by the alpha2-adrenoceptor agonists BHT-920 (pD2 = 6.16 +/- 0.07), UK 14,304 (pD2 = 6.89 +/- 0.13) and PGE-6201204 (pD2 = 7.12 +/- 0.21) were blocked by the alpha2-adrenoceptor antagonist yohimbine (0.1 microm). In contrast, the alpha1-adrenoceptor antagonist prazosin (0.03 microm) had no effect on the BHT-920-, UK 14,304- and PGE-6201204-induced contractions, but blocked the contractile response to the alpha(1)-adrenoceptor agonist phenylephrine (pD2 = 5.38 +/- 0.04) and the mixed alpha1- and alpha2-adrenoceptor agonist oxymetazoline (pD(2) = 6.30 +/- 0.22). 3. The alpha2-adrenoceptor antagonist yohimbine (0.01-0.1 microm, pA2 = 8.04), alpha2B/C-adrenoceptor antagonist ARC 239 (10 microm, pK(b) = 6.33 +/- 0.21), alpha2A/C-adrenoceptor antagonist WB 4101 (0.3 microm, pK(b) = 8.01 +/- 0.24), alpha2A-adrenoceptor antagonists BRL44408 (0.1 microm, pK(b) = 6.82 +/- 0.34) and RX 821002 (0.1 microm, pKb = 8.31 +/- 0.35), alpha2C-adrenoceptor antagonists spiroxatrine (1 microm, pKb = 7.32 +/- 0.32), rauwolscine (0.1 microm, pKb = 8.16 +/- 0.14) and HV 723 (0.3 microm, pKb = 7.68 +/- 0.14) inhibited BHT-920-induced contractions in pig nasal mucosa. 4. The present antagonist potencies showed correlations with binding affinity estimates (pKi) obtained for these antagonists at the human recombinant alpha2A- and alpha2C-adrenoceptors (r = 0.78 and 0.83, respectively) and with binding affinity estimates (pKd) obtained in pig native alpha2A- and alpha2C-monoreceptor assays (r = 0.85 and 0.78, respectively). No correlation was observed for the alpha2B-subtype. 5. In conclusion, contractile responses to phenylephrine, BHT-920, UK 14,304, PGE-6201204 and oxymetazoline indicate that alpha1- and alpha2-adrenoceptors are present and mediate vasoconstriction in pig nasal mucosa. Furthermore, correlation analysis comparing antagonist potency in pig nasal mucosa with affinities for human recombinant alpha2-adrenoceptors and native pig alpha2-adrenoceptors suggest that alpha2A- and alpha2C-adrenoceptor subtypes constrict pig nasal mucosa vasculature.
authors.affiliation: Allergy Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Corboz
authors.forename: L M
authors.initials: LM
authors.lastname: Varty
authors.forename: C A
authors.initials: CA
authors.lastname: Rizzo
authors.forename: J C
authors.initials: JC
authors.lastname: Mutter
authors.forename: M A
authors.initials: MA
authors.lastname: Rivelli
authors.forename: Y
authors.initials: Y
authors.lastname: Wan
authors.forename: S
authors.initials: S
authors.lastname: Umland
authors.forename: H
authors.initials: H
authors.lastname: Qiu
authors.forename: J
authors.initials: J
authors.lastname: Jakway
authors.forename: K D
authors.initials: KD
authors.lastname: McCormick
authors.forename: M
authors.initials: M
authors.lastname: Berlin
authors.forename: J A
authors.initials: JA
authors.lastname: Hey
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013552:Swine
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D018341:Receptors, Adrenergic, alpha-2