Previous studies have shown that an anaphylactic reaction in the isolated perfused heart is characterized by drastic coronary constriction, arrhythmias, and severe impairment of contractility. In vivo anaphylaxis is associated with myocardial ischemia and rapid cardiovascular failure. Recently, not only histamine but also platelet activating factor (PAF) has been implicated in cardiac manifestation of anaphylaxis. The present study was designed to separate the effects of PAF from those of histamine on cardiovascular function during systemic anaphylaxis. In guinea pigs, sensitization was produced by subcutaneous (s.c.) application of ovalbumin. Fourteen days after sensitization, the effects of an intravenous (i.v.) infusion of ovalbumin were tested in anesthetized artificially ventilated guinea pigs. The renewed application of the antigen induced severe cardiac dysfunction. Within 3 min, cardiac output (CO) had already decreased by 90% and left ventricular end-diastolic pressure (LVEDP) increased significantly, indicating left ventricular pump failure. Concurrently, ECG recordings uniformly showed signs of acute myocardial ischemia. In addition, arrhythmias occurred in terms of atrioventricular block. After 4 min, blood pressure (BP) rapidly decreased. All animals died within 10 min. Pretreatment with the H1-receptor antagonist mepyramine (1 mg/kg i.v.) in combination with the H2-receptor antagonist cimetidine (10 mg/kg i.v.) delayed onset of myocardial ischemia, arrhythmias and cardiac pump failure. After 10 min, however, LV contractility and BP steadily decreased, leading to severe hypotension within 30 min. If the selective PAF antagonist WEB 2086 (1 mg/kg i.v.) was administered in addition to cimetidine and mepyramine, myocardial ischemia and LV contractile failure were markedly inhibited further. In contrast, pretreatment with WEB 2086 alone had no beneficial effects on the anaphylactic cardiovascular changes. Therefore, we conclude that histamine is the predominant mediator during the early phase of systemic anaphylaxis whereas PAF-mediated effects are involved in cardiac dysfunction during the protracted late phase of anaphylaxis.