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(Circulation Research. 1995;76:434-440.)
© 1995 American Heart Association, Inc.

Articles

Protective Role of Bradykinin in Cardiac Anaphylaxis

Coronary-Vasodilating and Antiarrhythmic Activities Mediated by Autocrine/Paracrine Mechanisms

Lisa E. Rubin, Roberto Levi

From the Department of Pharmacology, Cornell University Medical College, New York, NY.

Correspondence to Roberto Levi, MD, Department of Pharmacology, Cornell University Medical College, 1300 York Ave, New York, NY 10021.

Abstract 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 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, a stable prostacyclin metabolite, increased twofold and fourfold, respectively. Because neither enalaprilat nor HOE 140 affected these changes, the enhanced overflow of cGMP and 6-ketoprostaglandin F₁ 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.

Key Words: bradykinin • cardiac anaphylaxis • myocardial ischemia • HOE 140 • nitric oxide

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