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- > 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 (H-2)-receptor antagonist cimetidine (60-mu-M) reversed the antigen-induced increase in CF to a decrease. In contrast, H-1-receptor blockade by mepyramine (6-mu-M) had no effect. Methysergide (10-mu-M) and ketotifen (0.1-mu-M) evoked a mild suppression during all three phases. Indomethacin (10-mu-M) was almost inactive while tolfenamic acid (1-mu-M) was slightly active in this respect during phase 2. Addition of the 5-lipoxygenase inhibitor AA 861 (1-mu-M) 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 H-2-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.