Adenosine receptors mediate both contractile and relaxant effects of adenosine in main pulmonary artery of guinea pigs

In guinea pig main pulmonary artery precontracted with noradrenaline, adenosine exerted an initial phasic contraction followed by a tonic contraction and a slow relaxation. After selective blockade by 1,3-dipropyl-8-cyclopentylxanthine (DPCPX: 10 nM) of A₁ receptors, adenosine only elicited a rapid relaxation. This initial response was characterized by use of adenosine (AR) and its analogues N⁶-cyclopentyl-adenosine (CPA), R-N⁶-phenyllsopropyladeno-sine (R-PIA), 2-chloroadenosine (CADO), 5-N-ethyl-carboxamidoadenosine(NECA), N⁶-2-(4-aminophenyl) ethyl adenosine (APNEA) and 2-p-((carboxyethyl)phenethylamino)-5-carboxamidoadenosine (CGS 21 680). The order of potency of the adenosine analogues for purine-induced phasic contraction was CPA > R-PIA > NECA = APNEA > AR > CGS 21 680 suggesting the involvement of activation of A₁ type adenosine receptors in the contraction phase. DPCPX antagonized the CPA-induced contraction with a pA₂ = 9.27 ± 0.26, but the Schild plot slope parameter was significantly lower than unity (0.58 ± 0.09). In contrast, in electrically driven guinea pig atrial myocardium (a tissue reported to possess A1 receptors), the DPCPX-CPA antagonism was purely competitive (pA₂ = 8.95 ± 0.06; slope = 0.93 ± 0.06). In the presence of 300 nM DPCPX, the rank order of potency for the purine-induced fast relaxation was NECA > CADO = AR > CGS 21 680 = R-PIA > CPA. The NECA- and adenosine-induced relaxation was influenced neither by 300 nM CP 66 713 (an antagonist at A_2a receptors), nor by endothelial removal and inhibition of nitric oxide synthase (100 M N^G-nitro-L-arginine: L-NOARG). The adenosine-induced relaxation was antagonized by 8-phenyltheophylline (8-PT), a potent A₁/A₂ antagonist. However, the rapid relaxation elicited by adenosine in the presence of 8-PT, was reversed and contraction developed. It is concluded that adenosine causes contraction via dual action on A₁ adenosine receptors and on xanthine-resistant sites. Our experiments with APNEA (a prototypic A₃ receptor agonist) did not support the suggestion that A₃ receptors are implicated in the xanthine-resistant component of adenosine-induced contraction, as DPCPX (300 nM) completely abolished and even reversed the APNEA-induced contraction. In addition, cromolyn (a mast cell stabilizing agent) did not influence the xanthine-resistant contraction induced by adenosine in the presence of DPCPX, 8-PT and dipyridamole (an adenosine uptake inhibitor). On the basis of the rank order of agonist potency, the receptors involved in the adenosine-induced rapid relaxation most likely is of the A_2b subtype. The opposing action of the xanthine-resistant contraction, however, did not allow a definitive pharmacological characterization of the receptor mediating relaxation.