UPTAKE OF PROPRANOLOL BY ISOLATED GUINEA-PIG ATRIA

¹ Department of Pharmacology, Harvard Medical School, Boston, Massachusetts

Fluorometric and radiometric assays for propranolol were developed in order to determine whether the antagonist is measurably taken up by isoproterenol receptors in cardiac tissue. The equilibrium constant for dl-H³-propranolol interaction with receptors was estimated from competitive propranolol-isoproterenol antagonism, as 3 x 10^-9 M. The d-isomer of propranolol appeared 2% as active as the ^l-isomer. Receptor blockade by propranolol occurred slowly at a rate which increased with concentration; blockade disappeared more slowly and was concentration-independent. Atria concentrated H³-propranolol from 3 to 30 x 10^-9 M solutions at an exponentially decreasing rate for 90 min, and released it at a slower multiphasic rate; both processes were nearly concentration-independent and unaffected by isoproterenol. Atria equilibrated in 10^-11 to 10^-4 M propranolol concentrated the drug 30-fold in a nonsaturable compartment. Uptake by unknown sites obscured uptake by receptors, and the nonspecific uptake was little affected by the presence of Dibenamine, another antagonist (MJ-1999) which occupies isoproterenol receptors, cocaine, reserpine, ouabain or isoproterenol. However, a saturable component of propranolol uptake by fragments of atrial cells was observed. An estimate of the upper limit of receptor capacity in atria is made and compared to previous estimates of the receptor capacity of striated and smooth muscles. Receptors occupy only a tiny fraction of the surface area of cardiac cells.