DIFFERENTIAL-EFFECTS ON SYMPATHETIC NEUROTRANSMISSION OF MAST-CELL DEGRANULATION BY COMPOUND-48 80 OR ANTIGEN IN THE RAT ISOLATED-PERFUSED HEART/

The aim of the present study was to investigate whether or not release of endogenous mast cell mediators modulates exocytotic noradrenaline overflow. Therefore, we perfused rat isolated hearts with the right sy mpathetic innervation intact and investigated the effect of mast cell degranulation on the efflux of noradrenaline. Compound 48/80 (48/80), a mast cell degranulating agent, caused a large release of histamine a nd serotonin and a facilitation of evoked noradrenaline overflow. When 48/80 was introduced into the perfu sion medium 4 min before sympathe tic nerve stimulation (SNS), evoked noradrenaline overflow was increas ed by about 60%. In the presence of the uptake 1-blocker cocaine, faci litation was attenuated (increase by only 30%). This effect was abolis hed by the histamine H-2 receptor antagonist cimetidine or the inhibit or of nitric oxide synthesis N-G-nitro-(L)-(-)-arginine. When the pree xposure time to 48/80 was reduced to 30 s, the facilitation was less p ronounced (15%) and inverted to an inhibition in the presence of cocai ne (plus idazoxan) by 17% and/or cimetidine (by about 30%). The result ing inhibition of noradrenaline efflux was attenuated by the serotonin 5-HT1/2 receptor antagonist methiothepin or the 5-HT2 antagonist keta nserin. Infusion of ovalbumin into hearts of not specifically sensitiz ed, but sham treated rats (in vivo injection of a saline-alumina mixtu re 10-12 days before the in vitro experiment) did not affect histamine , serotonin or (basal and evoked) noradrenaline efflux. In hearts from rats that were previously sensitized by an injection of an ovalbumin- alumina adsorbate, ovalbumin induced a marked increase of histamine an d serotonin efflux. When the infusion of the antigen started 30 s befo re SNS, evoked noradrenaline overflow M as inhibited by about 60%. The inhibition was unaffected by histamine receptor antagonists, but atte nuated by purinoceptor (suramin plus 1,3-dipropyl-8-cyclopentylxanthin e), or serotonin receptor (methiothepin, rauwolscine or ketanserin) an tagonists. When the preexposure time to ovalbumin was prolonged to 4 m in before SNS, no significant change of stimulation-induced noradrenal ine overflow was observed. Basal, immunologically and non-immunologica lly induced histamine and serotonin efflux were not significantly affe cted by SNS or any of the drugs tested. The results indicate a complex influence of various mediators released upon mast cell degranulation induced by two different stimuli on exocytotic noradrenaline release f rom rat heart. Depending on the stimulus and on the time interval betw een the start of the application of the mast cell degranulating agent and SNS,a histamine- and nitric oxide-mediated facilitation, or a sero tonin- and purine-mediated inhibition prevails.