Adenosine A1 and A3 receptor agonists inhibit nonadrenergic, noncholinergic relaxations in the guinea pig isolated trachea

Background: Adenosine affects the tone and reactivity of airways by activating specific membrane receptors, named A(1), A(2a), A(2b) and A(3). It affects cellular activities either directly by regulating membrane ion exchanges and polarization, or indirectly by modifying neurotransmitter release.

Objectives: We assessed the effect of A(1) and A(3) receptor activation on electrically induced nonadrenergic, noncholinergic (NANC) relaxations in the guinea pig isolated trachea and the localization of A(1) and A(3) receptors in tracheal inhibitory neurons.

Methods: NANC responses at 3 Hz were evaluated in the presence of 2-chloro-N(6)-cyclopentyladenosine (CCPA), a selective A(1) agonist, and 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA), a selective A(3) agonist, before and after the administration of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective A(1) antagonist, or 9-chloro-2-(2-furanyl)-5-((phenylacetyl)amino[1,2,4]triazolo[1,5-c])quinazoline (MRS 1220), a selective A(3) antagonist, respectively. For immunohistochemistry, tissues were exposed to antibodies to HuC/D, a general neuronal marker, neuronal nitric oxide synthase (nNOS), and A(1) or A(3) adenosine receptors and processed by indirect immunofluorescence.

Results: CCPA (10 nM-3 microM) inhibited NANC relaxations. DPCPX (10 nM) failed to antagonize the effect of CCPA, but inhibited per se NANC relaxations (range 0.1-100 nM). CCPA (10 nM-10 microM) contracted unstimulated tracheal preparations, an effect antagonized by 10 nM DPCPX, with a pK(B) value of 8.43. Cl-IB-MECA (10 nM-3 microM) inhibited NANC relaxations through a mechanism antagonized by MRS 1220 (100 nM). A(1)- and A(3)-positive neurons containing nNOS were detected in tracheal sections.

Conclusions: Enogenous adenosine may induce airway hyperresponsiveness by inhibiting NANC relaxations via A(1) and A(3) receptors.