Characterization and modulation of antigen-induced effects in isolated rat heart.
The response to antigen (trinitro-phenyl-haptenized ovalbumin) and the modulatory role of several antiallergic drugs was studied in isolated hearts from actively sensitized rats. Antigen induced a triphasic effect on coronary flow (CF) and left ventricular pressure (LVP) characterized by short-term increase (0-1.5 min = phase 1) and a severe decrease (1.5-7.5 min = phase 2) followed by a less pronounced long-lasting decrease (7.5- greater than 20 min = phase 3). The first phase was accompanied with a substantial release of 5-hydroxytryptamine (5-HT), histamine, and leukotrienes measured in cardiac effluents. The histamine2 (H2)-receptor antagonist cimetidine (60 microM) reversed the antigen-induced increase in CF to a decrease. In contrast, H1-receptor blockade by mepyramine (6 microM) had no effect. Methysergide (10 microM) and ketotifen (0.1 microM) evoked a mild suppression during all three phases. Indomethacin (10 microM) was almost inactive while tolfenamic acid (1 microM) was slightly active in this respect during phase 2. Addition of the 5-lipoxygenase inhibitor AA 861 (1 microM) resulted in complete suppression of the antigen-induced decrease in CF. The leukotriene antagonist FPL 55712 (5 and 50 nM) evoked a dose-dependent suppression with respect to the anaphylactic phases 2 and 3. A similar reduction was obtained with sodium cromoglycate (1 mM). AA 861, FPL 55712, and sodium cromoglycate also suppressed the antigen-induced decrease in LVP. The antigen-induced histamine release was not affected by the aforementioned drugs. Our results provide evidence that H2-receptor blockade during cardiac anaphylaxis enhances coronary constriction and may be detrimental in this condition. On the other hand, leukotriene antagonists and 5-lipoxygenase inhibitors may exert beneficial effects during cardiac anaphylaxis. Further experiments in this area are needed to clarify the precise role of mast cell-generated mediators in cardiac anaphylaxis possibly leading to new therapeutic approaches in this life-threatening disorder.
Vleeming
W
W
Department of Pharmacotherapy, Faculty of Pharmacy, University Utrecht, The Netherlands.
van Rooij
H H
HH
Wemer
J
J
Porsius
A J
AJ
D000707:Anaphylaxis / Q000503:physiopathology*; D000818:Animals; D016525:Antigenic Modulation / Q000502:physiology*; D000941:Antigens / Q000276:immunology / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D003326:Coronary Circulation / Q000502:physiology; D006321:Heart / Q000503:physiopathology*; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D006967:Hypersensitivity / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology*; D066298:In Vitro Techniques; D015289:Leukotrienes / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D009764:o-Phthalaldehyde
D000941:Antigens; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D012701:Serotonin; D007073:Immunoglobulin E; D009764:o-Phthalaldehyde; D006632:Histamine; D010047:Ovalbumin