Altered inotropic and chronotropic effects of noradrenaline on isolated rat atria exposed to chagasic sera. Influences of cocaine, normetanephrine and U-0521 (3'-4'-dihydroxy-2-methyl propiophenone

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Abstract
The effects of chagasic sera containing an antibody (EVI antibody), which reacts with the plasma membrane of striated muscle fibres and endothelial cells, on the inotropic and chronotropic influences of noradrenaline upon isolated rat atria suspended in different media, were explored. Also explored were the action of cocaine, normetanephrine and U-0521 (3′-4′-dihydroxy-2- methyl propiophenone) on the atrial effects of the agonist in preparations immersed in Krebs-Ringer bicarbonate, alone and with the addition of normal human sera or EVI positive human chagasic sera (EVI(+)S). The positive inotropic action of a single dose of noradrenaline (3.0 x 10−7 mol·litre−1) was significantly smaller in spontaneously beating auricles exposed to the EVI(+)S. Cumulative dose-response curves for the agonist showed depression and reduced slope suggesting that EVI(+)S may nihilate the effect of the amine by means of a "noncompetitive-like" mechanism. A similar diminished reactivity towards noradrenaline was found regarding atrial contractile rate. Incubation in a solution with U-0521 enhanced the maximal augmentation of atrial isometric tension evoked by the amine in the three media whereas cocaine failed to elicit significant changes. However, normal human sera not only restored but actually potentiated the inotropic influence of noradrenaline although only in auricles bathed with a solution containing EVI(+)S. None of these three agents altered the reduced chronotropic effect of the agonist exposed to the EVI antibody. Contractile influences on atria paced at single fixed rates were similar to those observed in spontaneously beating preparations. The experimental findings suggest that: a) at the contractile frequencies in the present studies neuronal uptake is neither an important mechanism for terminating the contractile effect of exogenously added noradrenaline, nor a factor involved in the altered action of the agonist in the presence of EVI(+)S; and b) the importance of extraneuronal uptake of noradrenaline became clear after the incubation in a media containing EVI(+)S. It is, therefore plausible to suggest that the EVI antibody might influence the contractile effect of the agonist through a reversible enhancement of extraneuronal uptake. This would in turn modify the interaction between the amine and adrenoceptive sites needed for the full positive inotropic effectiveness of noradrenaline. The possible significance of these findings in the alterations observed in chronic Chagas heart disease is discussed.

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