Effects of histamine H₁- and H₂-receptor antagonists on cardiovascular function during systemic anaphylaxis in guinea pigs

Abstract

The heart is a target organ of anaphylaxis. In isolated perfused hearts, an anaphylactic reaction is characterized by arrhythmias, coronary constriction, and severe impairment of ventricular contractile force. Various mediators such as PAF, thromboxane A₂ and leukotrienes, are responsible for anaphylactic coronary constriction and negative inotropic effects. The cardiac effects of anaphylactic histamine release are related to the stimulation of two antagonistic receptor types. Histamine induces atrioventricular conduction delay and constriction of the epicardial coronary vessels via H₁-receptor stimulation. H₂-receptors, however, mediatecoronary vasodilation and an increase in heart rate and myocardial contractility. It may therefore be concluded that administration of histamine H₂-receptor antagonists is disadvantageous. During anaphylactic states, the cardiodepressive effects of the other mediators of anaphylaxis are unmasked, resulting in a sustained coronary constriction and impairment of myocardial contractility. To verify this speculation, we investigated the effects of H₁- and H₂-receptor antagonists on cardiovascular function of guinea pigs during systemic anaphylaxis.

In guinea pigs, sensitization was produced by subcutaneous application of ovalbumin. Fourteen days after sensitization, the effects of an intravenous infusion of ovalbumin were tested in the anesthetized artificially ventilated guinea pigs. The renewed administration of the antigen induced severe cardiac dysfunction. Within a few minutes, cardiac output markedly decreased and left ventricular end-diastolic pressure increased significantly, indicating left ventricular pump failure. In the same time range, ECG recordings uniformly showed signs of acute myocardial ischemia. In addition, arrhythmias occurred in terms of an atrioventricular block. After 4 min, blood pressure rapidly declined. All animals died within 12 min. Pretreatment with the selective H₁-receptor antagonist astemizol (5 mg/kg i.v.) delayed the onset of myocardial ischemia, arrhythmias and cardiac pump failure. After 10 min, however, left ventricular contractility and blood pressure steadily declined, leading to severe hypotension within 30 min. In the case of a pretreatment with astemizol (5 mg/kg i.v.) and the H₂-receptor antagonist famotidine (10 mg/kg i.v.), no relevant changes of cardiovascular function were seen compared to pretreatment with astemizol alone. It is therefore concluded that endogenous histamine, via H₁-receptor stimulation plays an important part during the early phase of systemic anaphylaxis, whereas mediators other than histamine are involved at a later stage of the process. Furthermore, H₂-receptor-mediated effects are of minor importance in cardiovascular manifestation of anaphylaxis. Pretreatment with H₂-receptor antagonists has no detrimental effects on cardiovascular function during anaphylactic reactions in guinea pigs underin vivo conditions.