Developmental Changes in Mechanical Responses and Receptor Subtypes

Endothelin-1 (ET-1) and endothelin-3 (ET-3) produced positive inotropic effects on electrically stimulated left atria and increased the frequency of spontaneously beating right atria of adult rats. The potency of the inotropic effect of ET-1 was greater than that of ET-3, but the potencies of the chronotropic effects of ET-1 and ET-3 were not significantly different. In the neonatal atria, ET-1 and ET-3 also induced positive inotropic and chronotropic responses. ET-1 and ET-3 showed weak or no cardiotonic effects on the adult ventricles, whereas they caused marked positive inotropy in the neonatal ventricles. The characteristics of binding sites for ET-1 and ET-3 were very similar between the atria and the ventricles of the rat neonate. Saturation and competition binding experiments have shown that neonatal cardiac membranes from both atria and ventricle have two distinct binding sites for endothelin, that is, a low-affinity and a high-affinity site. ET-1 was found to bind to the low-afflinity sites with a significantly lower Kd than ET-3, whereas the estimated Kd values for ET-1 and ET-3 at the high affinity sites were similar. In contrast, the binding sites in adult atria were different from those of the ventricles: only a single binding site for both ET-1 and ET-3 was detected. Adult atrial membranes, on the other hand, had two distinct binding sites similar to those of neonatal membranes. The attenuation of the cardiotonic effects of ET-1 and ET-3 in ventricular muscle during development may be attributable to the changes that occur in the population of endothelin receptor subtypes. (Circulation Research 1991;69:918-926)