This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mahata, M. Articles by O'Connor, D. T. Search for Related Content PubMed PubMed Citation Articles by Mahata, M. Articles by O'Connor, D. T. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB RESERPINE

(Hypertension. 1996;28:414-420.)
© 1996 American Heart Association, Inc.

Articles

Vesicular Monoamine Transport Inhibitors

Novel Action at Calcium Channels to Prevent Catecholamine Secretion

Manjula Mahata; Sushil K. Mahata; Robert J. Parmer; Daniel T. O'Connor

the Department of Medicine and Center for Molecular Genetics, University of California, and Department of Veterans Affairs Medical Center, San Diego, Calif.

Correspondence to Daniel T. O'Connor, MD, Department of Medicine (9111H), University of California, San Diego, 3350 La Jolla Village Dr, San Diego, CA 92161. E-mail doconnor@ucsd.edu.

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.

Key Words: reserpine • tetrabenazine • catecholamines • calcium channels • calcium antagonists • dihydropyridines • PC12 cells

This article has been cited by other articles:

				N. Biswas, J. L. Rodriguez-Flores, M. Courel, J. R. Gayen, S. M. Vaingankar, M. Mahata, J. W. Torpey, L. Taupenot, D. T. O'Connor, and S. K. Mahata Cathepsin L Colocalizes with Chromogranin A in Chromaffin Vesicles to Generate Active Peptides Endocrinology, August 1, 2009; 150(8): 3547 - 3557. [Abstract] [Full Text] [PDF]

				N. Biswas, S. M. Vaingankar, M. Mahata, M. Das, J. R. Gayen, L. Taupenot, J. W. Torpey, D. T. O'Connor, and S. K. Mahata Proteolytic Cleavage of Human Chromogranin A Containing Naturally Occurring Catestatin Variants: Differential Processing at Catestatin Region by Plasmin Endocrinology, February 1, 2008; 149(2): 749 - 757. [Abstract] [Full Text] [PDF]

				S. K. Mahata, M. Mahata, G. Wen, W. B. Wong, N. R. Mahapatra, B. A. Hamilton, and D. T. O'Connor The Catecholamine Release-Inhibitory "Catestatin" Fragment of Chromogranin A: Naturally Occurring Human Variants with Different Potencies for Multiple Chromaffin Cell Nicotinic Cholinergic Responses Mol. Pharmacol., November 1, 2004; 66(5): 1180 - 1191. [Abstract] [Full Text] [PDF]

				S. K. Mahata, N. R. Mahapatra, M. Mahata, T. C. Wang, B. P. Kennedy, M. G. Ziegler, and D. T. O'Connor Catecholamine Secretory Vesicle Stimulus-Transcription Coupling in Vivo: DEMONSTRATION BY A NOVEL TRANSGENIC PROMOTER/PHOTOPROTEIN REPORTER AND INHIBITION OF SECRETION AND TRANSCRIPTION BY THE CHROMOGRANIN A FRAGMENT CATESTATIN J. Biol. Chem., August 22, 2003; 278(34): 32058 - 32067. [Abstract] [Full Text] [PDF]

				T. D. Ardizzone, X.-H. Lu, and D. S. Dwyer Calcium-independent inhibition of glucose transport in PC-12 and L6 cells by calcium channel antagonists Am J Physiol Cell Physiol, August 1, 2002; 283(2): C579 - C586. [Abstract] [Full Text] [PDF]

				M. Mahata, N. R. Mahapatra, D. T. O'Connor, and S. K. Mahata Chromaffin Cell Catecholamine Secretion: Bisindolylmaleimide Compounds Exhibit Novel and Potent Antagonist Effects at the Nicotinic Cholinergic Receptor in Pheochromocytoma Cells Mol. Pharmacol., June 1, 2002; 61(6): 1340 - 1347. [Abstract] [Full Text] [PDF]

				S. K. Mahata, M. Mahata, A. R. Wakade, and D. T. O’Connor Primary Structure and Function of the Catecholamine Release Inhibitory Peptide Catestatin (Chromogranin A344-364): Identification of Amino Acid Residues Crucial for Activity Mol. Endocrinol., October 1, 2000; 14(10): 1525 - 1535. [Abstract] [Full Text]

				M. L. Mundorf, K. P. Troyer, S. E. Hochstetler, J. A. Near, and R. M. Wightman Vesicular Ca2+ Participates in the Catalysis of Exocytosis J. Biol. Chem., March 24, 2000; 275(13): 9136 - 9142. [Abstract] [Full Text] [PDF]

				L. Taupenot, M. Mahata, S. K. Mahata, and D. T. O’Connor Time-Dependent Effects of the Neuropeptide PACAP on Catecholamine Secretion : Stimulation and Desensitization Hypertension, November 1, 1999; 34(5): 1152 - 1162. [Abstract] [Full Text] [PDF]

				M. Mahata, S. K. Mahata, R. J. Parmer, and D. T. O'Connor Proadrenomedullin N-Terminal 20 Peptide : Minimal Active Region to Regulate Nicotinic Receptors Hypertension, November 1, 1998; 32(5): 907 - 916. [Abstract] [Full Text] [PDF]

				C. V. Taylor, L. Taupenot, S. K. Mahata, M. Mahata, H. Wu, S. Yasothornsrikul, T. Toneff, C. Caporale, Q. Jiang, R. J. Parmer, et al. Formation of the Catecholamine Release-inhibitory Peptide Catestatin from Chromogranin A. DETERMINATION OF PROTEOLYTIC CLEAVAGE SITES IN HORMONE STORAGE GRANULES J. Biol. Chem., July 21, 2000; 275(30): 22905 - 22915. [Abstract] [Full Text] [PDF]