Document Detail

Vesicular monoamine transport inhibitors. Novel action at calcium channels to prevent catecholamine secretion.
MedLine Citation:
PMID:  8794826     Owner:  NLM     Status:  MEDLINE    
Vesicular monoamine transport (VMAT) inhibitors, such as reserpine and tetrabenazine, impair vesicular catecholamine storage in chromaffin cells and sympathetic neurons, thereby lowering blood pressure. Here we describe a novel action of VMAT inhibitors-blockade of L-type voltage-gated calcium channels-that may also influence catecholamine release from both PC12 rat pheochromocytoma cells and bovine adrenal chromaffin cells. When given alone, VMAT inhibitors acutely release catecholamines from chromaffin cells in a dose-dependent fashion. However, VMAT inhibitors block catecholamine secretion stimulated by either nicotinic cholinergic agonists or cell membrane depolarization, each of which rely on the opening of L-type channels; the inhibition was more potent after long-term exposure to VMAT inhibitors (IC50 < 100 nmol/L). Reserpine blocked nicotinic-stimulated catecholamine release from neurite-bearing PC12 cells. Reserpine also antagonized catecholamine release triggered by combined membrane depolarization and the dihydropyridine L-type channel agonist Bay K8644, and reserpine blocked cellular uptake of extracellular 45Ca2+ in response to nicotine. Taken together, these results indicate that VMAT inhibitors are also antagonists at L-type voltage-gated calcium channels. Classic L-type channel antagonists (verapamil or nifedipine) also exhibited the reciprocal actions; acutely, they released norepinephrine from chromaffin cells, and chronically, they depleted cellular catecholamine stores, albeit with inferior molar potency to reserpine (IC50 < 1 nmol/L). We conclude that VMAT inhibitors and L-type calcium channel antagonists exert reciprocal inhibitory actions on each other's more classic pharmacological targets. Furthermore, these novel actions are seen at concentrations of these compounds frequently taken to be specific in vitro and likely to occur during antihypertensive treatment in vivo.
M Mahata; S K Mahata; R J Parmer; D T O'Connor
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Hypertension     Volume:  28     ISSN:  0194-911X     ISO Abbreviation:  Hypertension     Publication Date:  1996 Sep 
Date Detail:
Created Date:  1996-11-22     Completed Date:  1996-11-22     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  414-20     Citation Subset:  IM    
Department of Medicine, University of California, San Diego 92161, USA.
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MeSH Terms
Adrenal Glands / cytology,  drug effects,  metabolism
Biological Transport / drug effects
Calcium Channel Blockers / pharmacology
Calcium Channels / drug effects*
Chromaffin System / cytology,  metabolism
Membrane Glycoproteins / antagonists & inhibitors*
Membrane Transport Proteins*
Norepinephrine / antagonists & inhibitors*,  secretion
PC12 Cells
Reserpine / pharmacology*
Tetrabenazine / pharmacology*
Vesicular Biogenic Amine Transport Proteins
Grant Support
Reg. No./Substance:
0/Calcium Channel Blockers; 0/Calcium Channels; 0/Membrane Glycoproteins; 0/Membrane Transport Proteins; 0/Neuropeptides; 0/Vesicular Biogenic Amine Transport Proteins; 50-55-5/Reserpine; 51-41-2/Norepinephrine; 58-46-8/Tetrabenazine

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