Protective role of bradykinin in cardiac anaphylaxis. Coronary-vasodilating and antiarrhythmic activities mediated by autocrine/paracrine mechanisms.

Cardiac anaphylaxis, an acute ischemic dysfunction comprising coronary vasoconstriction and arrhythmias, is a model of clinically recognized immediate hypersensitivity reactions affecting the heart. Bradykinin, a mediator of hypersensitivity, is also a potent coronary vasodilator, acting via nitric oxide and prostacyclin production. Because ischemia increases bradykinin outflow from the heart, we questioned whether bradykinin might mitigate anaphylactic coronary vasoconstriction. Antigen challenge of hearts isolated from presensitized guinea pigs was associated with an approximately 30% increase in bradykinin overflow. Furthermore, (1) when the half-life of bradykinin was prolonged with the kininase II/angiotensin-converting enzyme inhibitors captopril and enalaprilat, anaphylactic coronary vasoconstriction was attenuated and reversed, and arrhythmias were alleviated; (2) the bradykinin B2-receptor antagonist HOE 140 prevented these effects; and (3) HOE 140 exacerbated both anaphylactic coronary vasoconstriction and arrhythmias. During cardiac anaphylaxis, the coronary overflow of cGMP, a marker of nitric oxide production, and 6-ketoprostaglandin F1 alpha, a stable prostacyclin metabolite, increased two-fold and fourfold, respectively. Because neither enalaprilat nor HOE 140 affected these changes, the enhanced overflow of cGMP and 6-ketoprostaglandin F1 alpha is likely to reflect the actions of other hypersensitivity mediators (eg, histamine and leukotrienes). We postulate that bradykinin plays a protective role in cardiac anaphylaxis by accumulating at the luminal surface of the coronary endothelium and promoting, in an autocrine mode, a B2-receptor-mediated production of nitric oxide and prostacyclin in concentrations sufficient to elicit a paracrine effect on coronary vascular smooth muscle, thus opposing the vasoconstricting effects of other anaphylactic mediators.