The quantal secretion of catecholamines is impaired by the accumulation of β‐adrenoceptor antagonists into chromaffin cell vesicles

• Published in: British journal of pharmacology Vol. 159; no. 7; pp. 1548 - 1556
• Main Authors: Montesinos, Mónica S, Camacho, Marcial, Machado, J David, Viveros, O Humberto, Beltrán, Beatriz, Borges, Ricardo
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2010; Nature Publishing Group
• Subjects: Adrenergic beta-Antagonists - metabolism; amperometry; Animals; atenolol; Biological and medical sciences; catecholamines; Catecholamines - secretion; Cattle; chromaffin cells; Chromaffin Cells - metabolism; Chromatography, High Pressure Liquid; Electrochemistry; labetalol; Medical sciences; patch amperometry; Pharmacology. Drug treatments; propranolol; Rats; Research Papers; secretion; β‐adrenoceptor; catecholamines; Endocrine gland; Secretion; Adrenal medulla; β-adrenoceptor; patch amperometry; α1-Adrenergic receptor; Labetalol; Antiarrhythmic agent; Atenolol; Catecholamine; Chromaffin cell; β-Adrenergic receptor; amperometry; Alpha blocking agent; β1-Adrenergic receptor; chromaffin cells; Antihypertensive agent; Antagonist; Biological accumulation; Propranolol; Beta blocking agent
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2010.00650.x

Background and purpose:  The delayed onset of certain effects of antagonists of β‐adrenoceptors (β‐blockers), such as lowering arterial blood pressure (several days), cannot be explained solely by their effects on β‐adrenoceptors, an action that occurs within minutes. Although several mechanisms have been proposed, none of them explain this temporal delay. This work aimed at providing a new explanation based on the interference of these drugs with the functional accumulation of catecholamines within neurosecretory vesicles. Experimental approach:  We used the simultaneous on‐line monitoring of catecholamine and labetalol release from bovine isolated chromaffin cells and from rat perfused adrenal glands, as well as single cell amperometry, intracellular electrochemistry, patch amperometry and HPLC. Key results:  Using amperometry, three β‐blockers, labetalol, atenolol and propranolol, reduced the quantal size of secretory events in chromaffin cells, accompanied by a slowing down of exocytosis. By patch amperometry, we found that treatment with β‐blockers also increases the chromaffin vesicle volume, thereby creating a functional dilution of catecholamines. Experiments with intracellular electrochemistry show that vesicles cannot uptake new catecholamines. There was progressive accumulation of labetalol in secretory vesicles of bovine adrenal chromaffin cells, and this β‐blocker was co‐released with catecholamines from rat and bovine chromaffin tissues. Conclusions and implications:  We propose that β‐blockers are progressively concentrated into sympathetic secretory vesicles, and interfere with the storage of catecholamines and are co‐released with the natural transmitters, resulting in a decrease in the sympathetic tone. This could explain the delayed onset of the hypotensive effects of β‐blockers.