Hydralazine Reduces the Quantal Size of Secretory Events by Displacement of Catecholamines From Adrenomedullary Chromaffin Secretory Vesicles

• Published in: Circulation research Vol. 91; no. 9; pp. 830 - 836
• Main Authors: Machado, José D, Gómez, José F, Betancor, Gema, Camacho, Marcial, Brioso, Miguel A, Borges, Ricardo
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.11.2002; Lippincott; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Adrenal Medulla - cytology; Adrenal Medulla - drug effects; Adrenal Medulla - metabolism; Animals; Anti-Bacterial Agents - pharmacology; Antihypertensive Agents - pharmacokinetics; Antihypertensive Agents - pharmacology; Biological and medical sciences; Calcium - metabolism; Catecholamines - metabolism; Cattle; Cells, Cultured; Chromaffin Cells - cytology; Chromaffin Cells - drug effects; Chromaffin Cells - metabolism; Chromaffin Granules - drug effects; Chromaffin Granules - metabolism; Dose-Response Relationship, Drug; Drug toxicity and drugs side effects treatment; Electrochemistry; Enzyme Inhibitors - pharmacology; Exocytosis - drug effects; Exocytosis - physiology; Fluorescent Dyes; Hydralazine - pharmacokinetics; Hydralazine - pharmacology; Hydrogen-Ion Concentration - drug effects; Intracellular Fluid - metabolism; Kinetics; Macrolides; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Nucleotides - metabolism; Pharmacology. Drug treatments; Secretory Vesicles - drug effects; Secretory Vesicles - metabolism; intragranular pH; catecholamines; Endocrine gland; Vasodilator agent; Sympathoadrenal system; Toxicity; Adrenal medulla; Ox; Catecholamine; Chromaffin cell; Exocytosis; In vitro; chromaffin granules; amperometry; Vertebrata; Mammalia; Treatment; Chromaffin granule; Animal; Antihypertensive agent; Artiodactyla; Hydralazine; bafilomycin A1; Ungulata
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000039530.30495.6F

ABSTRACT—The effects of the antihypertensive agent hydralazine (1 to 100 nmol/L) on the exocytotic process of single adrenal chromaffin cells have been studied using amperometry. Hydralazine does not reduce the frequency of exocytotic spikes but rapidly slows the rate of catecholamine release from individual exocytotic events by reducing the quantal size of catecholamine exocytosis. Confocal and standard epifluorescence microscopy studies show that hydralazine rapidly accumulates within secretory vesicles. The blockade of the vesicular H pump with bafilomycin A1 inhibits hydralazine uptake. Experiments with permeabilized cells show that hydralazine displaces catecholamines from secretory vesicles. The drug also displaces vesicular Ca, as shown by fura-2 microfluorimetry. These data suggest that hydralazine acts, at least partially, by interfering with the storage of catecholamines. These effects of hydralazine occurred within seconds, and at the tissue concentrations presumably reached in antihypertensive therapy; these concentrations are a thousand times lower than those described for relaxing vascular tissues in vitro. We proposed that these novel effects could explain many of the therapeutic and side effects of this drug that are likely exerted in sympathetic nerve terminals.