Adenosine reduces airway excitatory non‐cholinergic (e‐NC) contraction through both A₁ and A₂ adenosine receptor activation in the guinea pig

Abstract

The influence of adenosine and selective A1 and A2 agonists and antagonists was investigated on the cholinergic and the excitatory non-cholinergic (e-NC) contractions induced by electrical field stimulation in the guinea-pig bronchi. Adenosine (10 nM-1 mM) induced a concentration-dependent inhibition of the e-NC contraction (EC50 = 90 +/- 14 microM), whereas the cholinergic peak was only slightly affected. Preincubation of the tissue with the adenosine uptake blocker dipyridamole (10 microM) significantly shifted the concentration-inhibition curve to adenosine to the left (EC50 = 10 +/- 1 microM), suggesting an interaction with extracellular adenosine receptors of A1 and/or A2 subtype. To characterize the receptor type involved in this effect, selective adenosine derivatives were studied. The agonist to both A1 and A2 adenosine receptors, 5'-N-ethylcarboxamidoadenosine (NECA) was more potent than the selective A1 agonist, (-)-R-6-phenylisopropyladenosine (R-PIA), in inhibiting the e-NC contraction (EC50 = 0.10 +/- 0.04 and 0.60 +/- 0.12 microM, respectively, with a maximal inhibition of 70 and 45%, respectively). The concentration-response curve to NECA was shifted to the right by the A2 receptor selective antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) (10 microM) (EC50 = 1.4 +/- 0.5 microM) as well as by the specific A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (10 microM) (EC50 = 0.7 +/- 0.3 microM). The inhibitory effect induced by the association of both antagonists, DPCPX and DMPX, was considerably potentiated (EC50 > 22 +/- 2.5 microM). The effect of R-PIA was also shifted to the right by DPCPX (EC50 = 8.2 +/- 1.6 microM) but was not modified by DMPX. The contractile response to exogenous substance P was unaffected by NECA pretreatment (0.3 microM). Altogether, these results suggest that adenosine-induced inhibition of e-NC contraction of guinea-pig bronchi is mediated through activation of both A1 and A2 adenosine receptors linked to inhibition of the release of neuropeptides from C-fibre nerve endings.

Evidence for both adenosine A1 and A2A receptors activating single vagal sensory C‐fibres in guinea pig lungs

“…This would be in agreement with our findings that the jugular C‐fibre neurons contain tachykinins and project fibres that innervate the large airways (Undem et al 2004). Lagente et al (1997) have also noted that adenosine fails to evoke tachykinergic contractions in guinea pig isolated bronchi (Lagente et al 1997).…”

“…It is also possible that adenosine receptor stimulation may alter the function of respiratory jugular C‐fibres in a manner other than overt activation. In this context it is perhaps noteworthy that neurokinin‐containing fibres in guinea pig trachea are jugular C‐fibres (Riccio et al 1996) and both adenosine A 1 and A 2A receptor stimulation have been linked to inhibition of evoked neurokinin release from this tissue (Lagente et al 1997).…”

Adenosine A₁ and A₃ Receptor Agonists Inhibit Nonadrenergic, Noncholinergic Relaxations in the Guinea Pig Isolated Trachea

“…However, the A 1 antagonist DPCPX alone (0.1–100 n M ) reduced EFS-induced relaxations in a concentration-dependent fashion up to 25% (fig. 2) and did not antagonize the effect of CCPA at 10 n M , the standard dose recommended in the literature [41,42,43] (fig. 1).…”

“…Our observations suggest that, in the periphery, A 1 receptor activation may reduce not only the cholinergic excitatory neurotrasmission [41], but also the release of inhibitory neurotransmitters from intrinsic NANC nerves. Conversely, A 2 receptors have been found to facilitate cholinergic transmission by acting prejunctionally in rat isolated [25] airways.…”

“…tachykinergic) excitatory system, adenosine has been found to reduce the EFS-induced substance-P-mediated contraction in the guinea pig airways through the activation of prejunctional A 1 and A 2 receptors [41]. By contrast, another study questioned any involvement of adenosine in the modulation of the noncholinergic excitatory system in the airways of the same species [51].…”