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Vesicular monoamine transport inhibitors. Novel action at calcium channels to prevent catecholamine secretion.
- Source :
-
Hypertension (Dallas, Tex. : 1979) [Hypertension] 1996 Sep; Vol. 28 (3), pp. 414-20. - Publication Year :
- 1996
-
Abstract
- 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.
- Subjects :
- Adrenal Glands cytology
Adrenal Glands drug effects
Adrenal Glands metabolism
Animals
Biological Transport drug effects
Calcium Channel Blockers pharmacology
Cattle
Chromaffin System cytology
Chromaffin System metabolism
Norepinephrine metabolism
PC12 Cells
Rats
Vesicular Biogenic Amine Transport Proteins
Calcium Channels drug effects
Membrane Glycoproteins antagonists & inhibitors
Membrane Transport Proteins
Neuropeptides
Norepinephrine antagonists & inhibitors
Reserpine pharmacology
Tetrabenazine pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0194-911X
- Volume :
- 28
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Hypertension (Dallas, Tex. : 1979)
- Publication Type :
- Academic Journal
- Accession number :
- 8794826
- Full Text :
- https://doi.org/10.1161/01.hyp.28.3.414