Determination of agonist affinity for cardiac beta-adrenoceptors during reserpine-induced supersensitivity

The positive inotropic responses to orciprenaline of paced left atria and papillary muscles and the positive chronotropic responses of spontaneously beating right atria of guinea-pigs were recorded. Tissues from guinea-pigs pretreated with reserpine exhibited supersensitivity to beta-adrenoceptor stimulation as demonstrated by the significantly lower EC50 values to orciprenaline. The antagonism of these responses by Ro 03-7894 was characteristic of irreversible beta-adrenoceptor blockade--depression of maximum response and resistant to washout. The dissociation constants (KA) of orciprenaline were determined from the concentration-response curves obtained before and after Ro 03-7894, and no difference was found between tissues from untreated and reserpine-pretreated animals. KA values were also determined from the functional antagonism of the responses by carbachol. The degree of antagonism was less after reserpine pretreatment, but there was no increase in KA value. The reserpine-induced supersensitivity does not therefore appear to be due to an increase in agonist affinity for the cardiac beta-adrenoceptor.