Effects of 5-Lipoxygenase Inhibition on Cardiac Anaphylaxis in Isolated Guinea Pig Hearts

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Abstract
Synthesis of the cardioactive peptidoleukotrienes depends on the activity of 5-lipoxygenase. It is unclear whether inhibition of endogenous leukotriene biosynthesis can alter vasoconstriction and negative inotropic effects associated with inflammatory states in the heart. In an attempt to study this problem, two 5-lipoxygenase inhibitors, the novel compound RG 6866, N-methyl-4-benzyloxyphenyl acetohydroxamic acid, and AA 861 have been examined in Langendorff-perfused guinea pig hearts undergoing cardiac anaphylaxis and compared to indometacin and LY 171883, a cyclooxygenase inhibitor and a leukotriene antagonist, respectively. In paced hearts perfused at constant pressure, RG 6866 had no apparent direct effects, infused intracardially at 20 μg/min, about 3 μmol/l. LY 171883, but not RG 6866 or indometacin, antagonized coronary vasoconstriction by exogenous leukotriene D4. When hearts were challenged with antigen (ovalbumin 1 mg i.e.) in the presence of antihistamines, a significant reduction in coronary flow occurred within 30 s which was maximal at 2–3 min, –48 ± 3%, and persisted for at least 10 min. An initial positive inotropic effect was followed by a 25% fall in developed pressure. Both 5-lipoxygenase inhibitors blocked effects of antigen challenge on coronary flow: RG 6866, –4 ± 3%, AA 861, –11 ± 3 %; reduction at 2 min. The late negative inotropic effect was also blocked. The combined 5-lipoxygenase inhibitor/leukotriene antagonist, RG 5901, and the leukotriene antagonist, LY 171883, were also effective, but not indometacin. These results provide further evidence for the contribution of leukotrienes to cardiac anaphylaxis. More importantly, these findings suggest that 5-lipoxygenase inhibitors can be beneficial in situations where endogenous leukotrienes produce coronary vasoconstriction and myocardial depression.