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

1. The combination of two methylation inhibitors 3-deazaadenosine (10(-4) or 4 x 10(-4) M) plus L-homocysteine (2 x 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). 2. 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 x 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. 3. 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. 4. 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.