Studies on the uptake and release of propranolol and the effects of propranolol on catecholamines in cultures of bovine adrenal chromaffin cells.

Uptake and release of [3H]l-propranolol and the effects of propranolol on the uptake and release of [3H]norepinephrine were studied in cultures of isolated bovine adrenal chromaffin cells. [3H]l-Propranolol uptake increased with increasing [3H]l-propranolol concentration from 10(-7) M to 10(-3) M and was not saturable in this concentration range. [3H]l-Propranolol uptake was equally inhibited by l- and d-propranolol, indicating that the uptake is not stereoselective. [3H]l-Propranolol uptake differed from [3H]norepinephrine uptake in two respects: [3H]l-propranolol uptake was 44-50 times greater than [3H]norepinephrine uptake at early non-equilibrium time periods, and [3H]l-propranolol uptake was not Na+ dependent and was not inhibited by desipramine, indicating that [3H]l-propranolol is not taken up by the biogenic amine transport system. In cells preloaded with [3H]l-propranolol, two agents, veratridine and tyramine, stimulated an increased release of [3H]l-propranolol into the medium. However, veratridine-induced [3H]l-propranolol release was inhibited only slightly by the Na+ channel blocker tetrodotoxin, and tyramine-induced [3H]l-propranolol release was not inhibited by desipramine. In addition, K+, carbachol and the physiological mediator of adrenal catecholamine release, acetylcholine, failed to evoke [3H]l-propranolol release. Therefore, it is unlikely that propranolol is released in response to physiological stimulation of adrenal chromaffin cells in animals administered propranolol in vivo. l-Propranolol inhibited [3H]norepinephrine uptake by chromaffin cells with an IC50 for l-propranolol of 5 X 10(-6) M; d-propranolol was equally potent for this effect at lower propranolol concentrations. By themselves, neither l- nor d-propranolol had any effect on [3H]norepinephrine release from the cells. However, l-propranolol inhibited carbachol-induced [3H]norepinephrine release with an IC50 for l-propranolol of 5 X 10(-7) M to 10(-6) M. At these lower concentrations, d-propranolol had no effect on carbachol-induced [3H]norepinephrine release, indicating that the inhibition by l-propranolol may be mediated via beta-adrenoceptors on chromaffin cells.