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 sympathetic 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 and serotonin and a facilitation of evoked noradrenaline overflow. When 48/80 was introduced into the perfusion medium 4 min before sympathetic nerve stimulation (SNS), evoked noradrenaline overflow was increased by about 60%. In the presence of the uptake 1-blocker cocaine, facilitation was attenuated (increase by only 30%). This effect was abolished by the histamine H2 receptor antagonist cimetidine or the inhibitor of nitric oxide synthesis NG-nitro-(L)-(-)-arginine. When the preexposure time to 48/80 was reduced to 30 s, the facilitation was less pronounced (15%) and inverted to an inhibition in the presence of cocaine (plus idazoxan) by 17% and/or cimetidine (by about 30%). The resulting inhibition of noradrenaline efflux was attenuated by the serotonin 5-HT1/2 receptor antagonist methiothepin or the 5-HT2 antagonist ketanserin. Infusion of ovalbumin into hearts of not specifically sensitized, but sham treated rats (in vivo injection of a saline-alumina mixture 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 and serotonin efflux. When the infusion of the antigen started 30 s before SNS, evoked noradrenaline overflow was inhibited by about 60%. The inhibition was unaffected by histamine receptor antagonists, but attenuated by purinoceptor (suramin plus 1,3-dipropyl-8-cyclopentylxanthine), or serotonin receptor (methiothepin, rauwolscine or ketanserin) antagonists. When the preexposure time to ovalbumin was prolonged to 4 min before SNS, no significant change of stimulation-induced noradrenaline overflow was observed. Basal, immunologically and non-immunologically induced histamine and serotonin efflux were not significantly affected 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 from rat heart. Depending on the stimulus and on the time interval between the start of the application of the mast cell degranulating agent and SNS, a histamine- and nitric oxide-mediated facilitation, or a serotonin- and purine-mediated inhibition prevails.
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Pharmakologisches Institut der Universität, Mainz, Germany.
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D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects*; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D002927:Cimetidine / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D004347:Drug Interactions; D006636:Histamine Release / Q000187:drug effects; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology; D008719:Methiothepin / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D019335:Nitroarginine; D009638:Norepinephrine / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage / Q000633:toxicity*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D003189:p-Methoxy-N-methylphenethylamine / Q000008:administration & dosage / Q000633:toxicity*
D019335:Nitroarginine; D012701:Serotonin; D003189:p-Methoxy-N-methylphenethylamine; D008719:Methiothepin; D002927:Cimetidine; D010047:Ovalbumin; D001120:Arginine; D007650:Ketanserin; D003042:Cocaine; D009638:Norepinephrine