calcimycin and 4-nitrobenzylthioinosine

The actions of adenosine on histamine release of human lung fragments were investigated. Histamine release was stimulated either with the calcium ionophore A23187 or with concanavalin A. Adenosine and its analogue 5'-N-ethylcarboxamidoadenosine 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-dipropylxanthine (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-nitrobenzyl)-6-thioinosine (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.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Calcimycin; Carrier Proteins; Concanavalin A; Histamine Release; Humans; In Vitro Techniques; Lung; Mast Cells; Membrane Proteins; Nucleoside Transport Proteins; Receptors, Purinergic; Thioinosine

1. Adenosine and its metabolically stable analogue N-ethyl-carboxamidoadenosine (NECA) enhance histamine release from rat peritoneal mast cells when these are stimulated by calcium-mobilizing agents. NECA and adenosine shift the concentration-response curve of the calcium ionophore A23187 to lower concentrations. 2. The potencies of NECA or adenosine in enhancing A23187-induced histamine release are dependent on the level of stimulated release in the absence of adenosine analogues. At high levels of release their potencies are up to 20 times higher than at low levels. Consequently, averaged concentration-response curves of adenosine and NECA for enhancing histamine release are shallow. 3. The adenosine transport blocker S-(p-nitrobenzyl)-6-thioinosine (NBTI) has no effect by itself at low levels of stimulated histamine release, but abolishes the enhancing effect of adenosine. At high levels of release, however, NBTI alone enhances the release of histamine. 4. It is concluded that adenosine and calcium reciprocally enhance the sensitivity of the secretory processes to the effects of the other agent. The levels of intracellular adenosine obtained by trapping adenosine inside stimulated mast cells are sufficient to enhance histamine release substantially, suggesting that this effect may play a physiological and pathophysiological role.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Calcimycin; Calcium Channel Agonists; Histamine Release; In Vitro Techniques; Male; Mast Cells; Peritoneal Cavity; Rats; Thioinosine

5'-N-ethylcarboxamideadenosine (NECA) greater than 2-chloroadenosine greater than adenosine greater than (-)-N6-(R-phenyl-isopropyl)-adenosine greater than (+)-N6-(S-phenylisopropyl)-adenosine, in that order of potency, inhibited in vitro antigen-induced histamine release from human basophils in a dose-dependent fashion. Inhibition occurred only during the first stage of antigen-induced histamine release and the nucleosides failed to inhibit the release caused by the Ca2+ ionophore, A23187. 6-nitrobenzylthioinosine and dipyridamole, which inhibit adenosine uptake, and erythro-9-(2-hydroxy-3-nonyl)adenine, which blocks adenosine metabolism, did not impair the inhibition caused by NECA and adenosine. 8-phenyltheophylline and theophylline, two competitive antagonists of adenosine receptors, blocked the inhibition caused by NECA and adenosine. These data suggest that NECA and other adenosine analogs activate a specific cell surface adenosine receptor which possesses properties similar to those of an adenosine A2/Ra receptor.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Adenylyl Cyclases; Basophils; Biological Transport; Calcimycin; Histamine Release; Humans; Receptors, Cell Surface; Receptors, Purinergic; Structure-Activity Relationship; Theophylline; Thioinosine