title: Stereoselective secretion of atenolol from PC12 cells.
abstract: Stereoselective storage and release of the cardioselective beta adrenergic receptor antagonist atenolol was studied using cultured PC12 cells as a neural model. [3H]Atenolol efflux from preloaded PC12 cells was increased 4-fold in response to membrane depolarization by elevated extracellular potassium (50 mM). [3H]Norepinephrine release was enhanced 4.5-fold under the same conditions. Potassium-induced release of both [3H] atenolol and [3H]norepinephrine was inhibited completely in the absence of extracellular calcium. [3H]Atenolol release from PC12 cells was also reduced by the calcium channel antagonist nifedipine (IC50 = 1.6 +/- 0.5 nM). In addition, the calcium channel agonist BAY K8644 (1 microM) significantly enhanced potassium-induced [3H]atenolol efflux. After loading overnight, accumulation and storage of the (-)-enantiomer of atenolol by PC12 cells was found to be approximately 3-fold greater than that of the (+)-enantiomer. The (-)-enantiomer of atenolol was also preferentially released by 50 mM potassium with a (-)/(+)-enantiomer ratio of 3.6 to 1. The results support the existence within neurosecretory cells of storage and calcium-dependent release mechanisms which result in stereoselective secretion of the (-)-or active enantiomer of atenolol in response to membrane depolarization.
authors.affiliation: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston.
authors.forename: J G
authors.initials: JG
authors.lastname: Webb
authors.forename: J A
authors.initials: JA
authors.lastname: Street
authors.forename: E E
authors.initials: EE
authors.lastname: Bagwell
authors.forename: T
authors.initials: T
authors.lastname: Walle
authors.forename: T E
authors.initials: TE
authors.lastname: Gaffney
mesh_terms: D000818:Animals; D001262:Atenolol / Q000378:metabolism*; D002118:Calcium / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism; D010673:Pheochromocytoma / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
chemical_list: D001262:Atenolol; D002118:Calcium; D009638:Norepinephrine