Effects of Adenosine on Histamine Release from Human Lung Fragments

Abstract

The actions of adenosine on histamine release of human lung fragments were investigated. Histamine release was stimulated either with the calcium ionophore A 23187 or with concanavalin A. Adenosine and its analogue 5′-N-ethyl-carboxamidoadenosine alone had no significant effect on basal release or on the release elicited by A 23187 or concanavalin A. However, in the presence of the adenosine receptor antagonist 8-[4-[[[[(2-aminoethyl)amino]-carbonyl] methyloxy]-phenyl]-1,3-dipropylaxanthine (XAC), which itself did not affect the release, adenosine increased the stimulated histamine release. On the other hand, in the presence of the nucleoside transport inhibitor S-(p-nitro-benzyl)-6-thioninosine (NBTI), adenosine caused a reduction in stimulated histamine release. NBTI itself caused a stimulation of release. Thus, a stimulatory effect of adenosine was seen in the presence of XAC, whereas an inhibitory effect was unmasked by NBTI. From these data it is concluded that adenosine exerts two opposing effects on histamine release in the human lung which neutralize each other: it inhibits release via a site antagonized by XAC, which presumably represents an A₂ adenosine receptor, and it stimulates release via a mechanism that is blocked by NBTI, suggesting that adenosine needs to reach the interior of cells to exert this effect. The slight stimulatory effect of NBTI alone demonstrates that trapping intracellularly formed adenosine inside mast cells leads to sufficient concentrations of adenosine to stimulate histamine release. These findings suggest an important bimodal role of adenosine in regulating histamine release in the human lung.

Activation of Adenosine A2a Receptors Inhibits Mast Cell Degranulation and Mast Cell‐Dependent Vasoconstriction

“…In the presence of adenosine (10 and 100 nM), mast cell degranulation in response to inosine application by micropipette was not observed. These findings are in agreement with prior observations that adenosine pretreatment inhibits mast cell degranulation (16). However, ruthenium red detects only degranulated mast cells and therefore could not detect the presence of selective mast cell secretion without degranulation.…”

“…Inosine is selective in its activation of the A 3 receptor subtype (12). An A 2 -mediated inhibitory role of adenosine on mast cell degranulation has also been reported in vivo (8,16). The inhibitory role was proposed after noting that adenosine could decrease histamine release from human lung fragments and that antagonists of A 2 receptors could potentiate (8,16).…”

Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation.

“…More recent studies indicate that adenosine analogs that activate A 3 adenosine receptors produce mast cell-dependent vascular responses (10,33). It has also been noted that reoxygenation after myocardial hypoxia produces degranulation of myocardial mast cells (34). The vascular and cardiac responses to nucleosides or hypoxia may be mediated in part by adenosine and inosine acting on A 3 receptors of tissue resident mast cells.…”

Purinergic Signaling in the Airways

“…Mast Cells. Adenosine was reported to both inhibit and potentiate IgE-dependent histamine and 5-HT release from lung mast cells; A 2 receptors are involved (Hughes et al, 1984;Ott et al, 1992). Immunological identification of A 2B receptors was reported in human lung mast cells (Feoktistov et al, 2003).…”

“…Adenosine, acting through A 2 receptors, was reported to both stimulate and inhibit histamine release from mast cells in the lung (Hughes et al, 1984;Ott et al, 1992). Inhaled adenosine, but not guanosine, is a potent bronchocon-850 strictor in asthma (Cushley et al, 1983).…”