Blockade by methylation inhibitors of the anaphylactic response of guinea‐pig lung strips

Abstract

The combination of two methylation inhibitors 3‐deazaadenosine (10−4 or 4 × 10−4 m) plus l‐homocysteine (2 × 10−4 m) caused a time‐dependent inhibition of antigen‐induced contraction, formation of thromboxane B2 (TxB2) and release of histamine from lung parenchyma strips taken from guinea‐pigs actively sensitized with ovalbumin (OA). The methylation inhibitors also prevented the lung strip contractions induced by the mediators platelet‐activating factor (Paf‐acether, 10−6 m), leukotriene D4 (LTD4, 10−8 and 3 × 10−8 m), and in part to arachidonic acid (10−6 and 10−5 m), under conditions where the contractions to histamine (10−6‐10−4 m) were virtually unaffected. TxB2 formation induced by these mediators or by OA was more affected by the methylation inhibitors than the lung strip contractions, indicating that prostaglandin formation is more sensitive to these inhibitors than the myotropic activity. In contrast, the suppressive effect of the methylation inhibitors on histamine secretion by parenchyma lung strips induced by OA followed the inhibition of the contraction. These results show that inhibitors of methyltransferases interfere with the myotropic responses and with the release of mediators by actively sensitized guinea‐pig lung strips stimulated with antigen, and suggest a major role for a methylation process in mediating the contraction of and mediator release by the lung parenchyma.

S-Adenosylhomocysteine Levels Are Not Involved in the Spasmolytic Activity of 3-Deazaadenosine in Guinea-Pig Lung Parenchyma

“…However, under these conditions, MDL 28,842 did not inhibit the contractile response to LTD4 or histamine, whereas 3-DAA inhibited both, as reported by Randon et al [5]. Also in agreement with these inves tigators, 3-DAA and L-HC had a greater effect on LTD4 than on histamine-induced contractions, although without further stud ies it is not clear whether this difference would be seen at different concentrations of the two agonists.…”

“…Randon et al [5] concluded that the inhibitory effect of 3-DAA + L-HC was due to inhibition of methyltransferase activity as a result of increased tissue levels of SAH and/or 3-deazaadenosylhomocysteine. The data reported here do not exclude this mech anism, but suggest that it is the 3-deazaade nosylhomocysteine and not SAH which may be responsible for this inhibition.…”

“…In addi tion, in some cells, 3-DAA can be metabolized to 3-deazaadenosine 5'-nucleotides [8]. Inter pretation of the data of Randon et al [5] is also complicated by the fact that 3-DAA and L-HC have been shown to raise cyclic AMP (cAMP) levels in several cell systems [9,10], an effect which should lead to inhibition of contractile responses. The availability of a novel, potent and specific inhibitor of SAH hydrolase, MDL 28,842, (Z)-9-(5-deoxy-5-fluoro-B-Derythro-pent-4-enofuranosyl) adenine [11], has made it possible to test whether increased tissue levels of SAH alone inhibit the contrac tile effects of LTD4 on guinea-pig lung paren chymal strips, whether 3-DAA requires con version to 3-deazaadenosylhomocysteine to inhibit contractile responses and whether the activity of SAH hydrolase regulates the con tractile activity of LTD4 in guinea-pig lung parenchymal strips.…”

“…Randon et al [5] showed that a combination of 3-DAA and L-HC inhibited the contractile effects of leuko triene D4 (LTD4) on guinea-pig lung paren chymal strips, with only a minor effect on histamine-induced contractions. They sug gested that méthylation processes are in volved in the contractile responses to LTD4 and that indirect inhibition of methyltransfer ases by 3-DAA and L-HC through inhibition of SAH hydrolase explained the inhibition of LTD4-induced contractions.…”

Effect of Y-20811, a Long-Lasting Thromboxane A₂ Synthetase Inhibitor, on Antigen-Induced Airway Hyperresponsiveness in Guinea Pigs

“…Guinea pigs were sensitized by the method previously used by Randon et al [14] and described as follows. Guinea pigs were in jected subcutaneously twice with an interval of 2 weeks with solu tion (saline) containing 10 pg of EA dispersed in 1 mg of AI(OH)3 gel.…”