The goal of the study is to obtain a better understanding of the role of adenosine in modulating cardiac function during episodes of cardiac stress. Data obtained under conditions of severe cardiac stress (e.g., hypoxia, ischemia) indicate that tissue adenosine levels increase and may modulate coronary flow, automaticity, A-V nodal conduction, and/or inotropic responses.
The specific aims are to determine cardiac adenosine levels during the stress of anaphylaxis, and to assess the role of adenosine in determining the severity of the cardiac anaphylactic reaction. Others have shown that isolated perfused guinea pig hearts sensitized with ovalbumin-specific antibody respond to an antigen challenge with increases in beating rate, vascular resistance, and incidence of A-V nodal block and a transient increase followed by depression of contractile force. Histamine, leukotrienes, and other endogenous substances appear to mediate various components of this anaphylactic reaction. Our preliminary studies show that adenosine release from the guinea pig heart is increased during anaphylaxis. In the proposed studies, the magnitude and time course of changes in the adenosine content of coronary effluent from these preparations will be measured before and after antigen challenge. These changes will be correlated with the antigen-induced alterations in functional variables and the release of histamine and leukotrienes. To assess adenosine's modulatory role during anaphylaxis, we will determine whether antagonism of the action of endogenous adenosine (by theophylline) or alterations in the level of endogenous adenosine will modify the antigen-induced changes in functional variables and/or the release of the mediators. Levels of endogenous adenosine will be increased by addition of the adenosine deaminase inhibitor, EHNA, or by decreasing the perfusate flow, pressure, and/or 02 content. Levels will be decreased by addition of adenosine deaminase. We will also conduct experiments to determine whether exogenous adenosine alters the cardiac effect of exogenous histamines and leukotrienes and whether exogenous adenosine alters the release of these mediators during anaphylaxis. The results of these studies will provide important information about cardiac anaphylaxis and the potential modulatory role of adenosine in the stressed heart.
| Heller, L J; Regal, J F (1991) Reduced anaphylactic responsiveness of strain 2 guinea pigs. Proc Soc Exp Biol Med 198:838-45 |
| Heller, L J; Regal, J E (1990) Relationship between alterations in atrial and ventricular histamine content and cardiac function during cardiac anaphylaxis of isolated guinea pig hearts. Int Arch Allergy Appl Immunol 91:285-90 |
| Heller, L J; Trachte, G J; Regal, J F (1989) Role of adenosine in hypoxic alterations of anaphylaxis of isolated guinea pig hearts. Am J Physiol 257:H1378-88 |
| Heller, L J; Regal, J F (1988) Effect of adenosine on histamine release and atrioventricular conduction during guinea pig cardiac anaphylaxis. Circ Res 62:1147-58 |
