title: Evidence for an atypical receptor mediating the augmented bronchoconstrictor response to adenosine induced by allergen challenge in actively sensitized Brown Norway rats.
abstract: The bronchoconstrictor response to adenosine is markedly and selectively increased following ovalbumin (OA) challenge in actively sensitized, Brown Norway rats. We present a pharmacological analysis of the receptor mediating this response. Like adenosine, the broad-spectrum adenosine receptor agonist, NECA, induced dose-related bronchoconstriction in actively sensitized, OA-challenged animals. In contrast, CPA, CGS 21680 and 2-Cl-IB-MECA, agonists selective for A(1) A(2A) and A(3) receptors, respectively, induced no, or minimal, bronchoconstriction. Neither the selective A(1) receptor antagonist, DPCPX, nor the selective A(2A) receptor antagonist, ZM 241385, blocked the bronchoconstrictor response to adenosine. MRS 1754, which has similar affinity for rat A(2B) and A(1) receptors, failed to block the bronchoconstrictor response to adenosine despite blockade of the A(1) receptor-mediated bradycardia induced by NECA. 8-SPT and CGS 15943, antagonists at A(1), A(2A), and A(2B) but not A(3) receptors, inhibited the bronchoconstrictor response to adenosine. However, the degree of blockade (approximately 3 fold) did not reflect the plasma concentrations, which were 139 and 21 times greater than the K(B) value at the rat A(2B) receptor, respectively. Adenosine and NECA, but not CPA, CGS 21680 or 2-Cl-IB-MECA, induced contraction of parenchymal strip preparations from actively sensitized OA-challenged animals. Responses to adenosine could not be antagonized by 8-SPT or MRS 1754 at concentrations >50 times their affinities at the rat A(2B) receptor. The receptor mediating the bronchoconstrictor response to adenosine augmented following allergen challenge in actively sensitized BN rats cannot be categorized as one of the four recognized adenosine receptor subtypes.
authors.affiliation: Research Department, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: J P
authors.initials: JP
authors.lastname: Hannon
authors.forename: B
authors.initials: B
authors.lastname: Tigani
authors.forename: C
authors.initials: C
authors.lastname: Wolber
authors.forename: I
authors.initials: I
authors.lastname: Williams
authors.forename: L
authors.initials: L
authors.lastname: Mazzoni
authors.forename: C
authors.initials: C
authors.lastname: Howes
authors.forename: J R
authors.initials: JR
authors.lastname: Fozard
mesh_terms: D000241:Adenosine / Q000494:pharmacology* / Q000502:physiology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000403:Airway Resistance / Q000187:drug effects / Q000502:physiology; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D001985:Bronchial Provocation Tests / Q000379:methods; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D007114:Immunization; D007279:Injections, Subcutaneous; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects / Q000502:physiology; D008297:Male; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology*; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D011914:Rats, Inbred BN; D018047:Receptors, Purinergic P1 / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D000485:Allergens; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014665:Vasodilator Agents; D019830:Adenosine-5'-(N-ethylcarboxamide); D010047:Ovalbumin; D000241:Adenosine