RELEASE OF CALCITONIN-GENE-RELATED PEPTIDE IN CARDIAC ANAPHYLAXIS

We have investigated the antigen-stimulated release of calcitonin gene -related peptide (CGRP) from ovalbumin-sensitized guinea-pig isolated hearts and the interaction with other mediators of anaphylaxis release d concomitantly. It was found that antigen challenge caused a signific ant increase of CGRP release (from basal 31.2 +/- 2.9 to 51.6 +/- 4.9 fmol/5 min). Anaphylactic CGRP release was significantly attenuated in the presence of the cyclooxygenase inhibitor indomethacin while the 5 -lipoxygenase inhibitor Bay-X1005 )-2-[4-quinolin-2-yl-methoxy)phenyl] -2-cyclopentyl acetic acid) had no significant effect. Combined treatm ent with the histamine receptor (H-1, H-2) antagonists mepyramine and cimetidine also significantly attenuated anaphylactic release of CGRP Under control conditions antigen injection increased release of cystei nyl-leukotrienes (LT), thromboxane (TXB(2)) and 6-keto-prostaglandin ( PG)F-1 alpha from basal values of 0.96 +/- 0.09, 2.7 +/- 0.7 and 3.4 /- 0.28 ng/5 min respectively, to 5.9 +/- 0.9, 48.4 +/- 3.4 and 6.9 +/ - 1.4 ng/5 min. Indomethacin abolished the release of cyclooxygenase p roducts of arachidonate metabolism and simultaneously increased cystei nyl-LT release significantly (8.8 +/- 1.4 ng/5 min). Conversely Bay-X1 005 completely abolished cysteinyl-LT release and had no significant e ffect on anaphylactic release of TXB(2) and 6-keto-PGF(1 alpha). Simul taneous blockade of H-1 and H-2 receptors abolished release of 6-keto- PGF(1 alpha), while release of TXB(2) and cysteinyl-LT was not signifi cantly affected. The results indicate that CGRP is not a primary media tor of the immediate hypersensitivity reaction of the heart, but is in turn released by arachidonic acid metabolites of the cyclooxygenase p athway and histamine. In contrast, LT obviously do not contribute to a naphylactic CGRP release. CGRP is a potent coronary vasodilator and co uld act as endogenous functional antagonist of vasoconstrictor mediato rs also released during cardiac anaphylaxis such as cysteinyl-LT, plat elet activating factor and TXA(2).