The quantal secretion of catecholamines is impaired by the accumulation of beta-adrenoceptor antagonists into chromaffin cell vesicles.
OBJECTIVE
The delayed onset of certain effects of antagonists of beta-adrenoceptors (beta-blockers), such as lowering arterial blood pressure (several days), cannot be explained solely by their effects on beta-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.


METHODS
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.


RESULTS
Using amperometry, three beta-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 beta-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 beta-blocker was co-released with catecholamines from rat and bovine chromaffin tissues.


CONCLUSIONS
We propose that beta-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 beta-blockers.
Montesinos
Mónica S
MS
Unidad de Farmacología, Facultad de Medicina, Universidad de La Laguna, Tenerife, Spain.
Camacho
Marcial
M
Machado
J David
JD
Viveros
O Humberto
OH
Beltrán
Beatriz
B
Borges
Ricardo
R
D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D019439:Chromaffin Cells / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004563:Electrochemistry; D051381:Rats
D000319:Adrenergic beta-Antagonists; D002395:Catecholamines