Abstract
We compared the effects of representative members of three major classes of cardiac L-type channel antagonists, i.e. dihydropyridines (DHPs), phenylalkylamines (PAAs) and benzothiazepines (BTZs) on high-voltage-activated (HVA) Ca2+ channel currents recorded from a holding potential of −100 mV in rat ventricular cells, mouse sensory neurons and rat motoneurons. Nimodipine (DHP), verapamil (PAA) and diltiazem (BTZ) block the cardiac L-type Ca2+ channel current (EC50: 1 μM, 4 μM and 40 μM, respectively). At these concentrations, the drugs could also inhibit HVA Ca2+ channel currents in both sensory and motor neurons. Large blocking effects (> 50%) could be observed at 2–10 times these concentrations. The ω-conotoxin-GVIA-sensitive (ω-CTx-GVIA, N-type), ω-agatoxin-IVA-sensitive (ω-Aga-IVA, P- and Q-types) and non-L-type ω-CTx-GVIA-, ω-Aga-IVA-insensitive (R-types) currents accounted for more than 90% of the global current. Furthermore, our data showed that ωCTx-GVIA and ω-Aga-IVA spare L-type currents and have only additive blocking effects on neuronal HVA currents. We conclude that DHPs, PAAs and BTZs have substantial inhibitory effects on neuronal non-L-type Ca2+ channels. Inhibitions occur at concentrations that are not maximally active on cardiac L-type Ca2+ channels.
Similar content being viewed by others
References
Akaike N, Kostyuk PG, Osipchuk YV (1989) Dihydropyridinesensitive low-threshold calcium channels in isolated rat hypothalamic neurones. J Physiol (Lond) 412:181–195
Alvarez JL, Vassort G (1992) Properties of the low threshold Ca current in single frog atrial cardiomyocytes. A comparison with the high threshold Ca current. J Gen Physiol 100:519–545
Birnbaumer L, Campbell KP, Catterall WA, Harpold MM, Hofmann F, Home WA, Mori Y, Schwartz A, Snutch TP, Tanabe T, Tsien RW (1994) The naming of voltage-gated calcium channels. Neuron 13:505–506
Catterall WA, Striessnig J (1992) Receptor sites for Ca2+ channel antagonists. Trends Pharmacol Sci 13:256–262 5. Reference deleted
Docherty RJ, Brown DA (1986) Interaction of 1,4-dihydropyridines with somatic Ca currents in hippocampal CA1 neurones of the guinea pig in vitro. Neurosci Lett 70:110–115
Gurney AM, Nerbonne JM, Lester HA (1985) Photoinduced removal of nifedipine reveals mechanisms of calcium antagonist action on single heart cells. J Gen Physiol 86:353–379
Henderson CE, Camu W, Mettling C, Gouin A, Poulsen K, Karihaloo M, Rullamas J, Evans T, McMahon SB, Armanini MP, Berkemeier L, Phillips HS, Rosenthal A (1993) Neurotrophins promote motor neuron survival and are present in embryonic limb bud. Nature 363:266–270
Hivert B, Bouhanna S, Diochot S, Camu W, Dayanithi G, Henderson CE, Valmier J (1995) Embryonic rat motoneurons express a functional P-type voltage-dependent calcium channel. Int J Dev 13:429–436
Hockberger PE, Nam SC (1993) High voltage-activated calcium current in developing neurons is insensitive to nifedipine. Pflügers Arch 426:402–411
Jones SW, Jacobs LS (1990) Dihydropyridine actions on calcium currents of frog sympathetic neurons. J Neurosci 10:2261–2267
Jones SW, Marks TN (1989) Calcium currents in bullfrog sympathetic neurons. J Gen Physiol 94:169–182
Lee KS, Tsien RW (1984) Mechanism of calcium channel blockade by verapamil, D600, diltiazem and nitrendipine in single dialysed heart cells. Nature 302:790–794
McCarthy RT, TanPiengco PE (1992) Multiple types of hightreshold calcium channels in rabbit sensory neurons: highaffinity block of neuronal L-type by nimodipine. J Neurosci 12:2225–2234
McDonald TF, Pelzer S, Trautwein W, Pelzer DJ (1994) Regulation and modulation of calcium channels in cardiac, skeletal and smooth muscle cells. Physiol Rev 74:365–507
Mintz IM, Adams ME, Bean BP (1992) P-Type calcium channels in rat central and peripheral neurons. Neuron 9:85–95
Mintz IM, Venema VJ, Swiderek KM, Lee TD, Bean BP, Adams ME (1992) P-Type calcium channels blocked by the spider toxin ω-Aga-IVA. Nature 355:827–829
Nerbonne JM, Gurney AM (1987) Blockade of Ca2+ and K+ currents in bag cell neurons of Aplysia californica by dihydropyridine Ca2+ antagonists. J Neurosci 7:883–893
Neveu D, Nargeot J, Richard S (1993) Two high-voltage-activated, dihydropyridine-sensitive Ca2+ channel currents with distinct electrophysiological and pharmacological properties in cultured rat aortic myocytes. Pflügers Arch 424:45–53
Nowycky MC, Fox AP, Tsien RW (1985) Three types of neu ronal calcium channel with different calcium agonist sensitivity. Nature 316:440–443
O'Neill SK, Triggle CR (1994) Competitive binding experiments reveal differential interactions for dihydropyridine calcium channel activators and antagonists at dihydropyridine receptors on mouse brain membranes. Can J Physiol Pharmacol 72:738–745
Plummer MR, Logothetis DE, Hess P (1989) Elementary properties and pharmacological sensitivities of calcium channels in mammalian peripheral neurons. Neuron 2:1453–1463
Richard S, Diochot S, Nargeot J, Baldy-Moulinier M, Valmier J (1991) Inhibition of T-type calcium currents by dihydropyridine in mouse embryonic dorsal root ganglion neurons. Neurosci Lett 132:229–234
Richard S, Charnet P, Nerbonne JM (1993) Interconversion between distinct gating pathways of the high threshold calcium channel in rat ventricular myocytes. J Physiol (Lond) 462:197–228
Romanin C, Seydl K, Glossmann H, Schindler H (1992) The dihydropyridine niguldipine inhibits T-type Ca2+ currents in atrial myocytes. Pflügers Arch 420:410–412
Sanguinetti MC, Kass RS (1984) Voltage-dependent block of calcium channel current in the calf cardiac Purkinje fiber by dihydropyridine calcium channel antagonists. Circ Res 55:336–348
Scott RH, Pearson HA, Dolphin AC (1991) Aspects of vertebrate neuronal voltage-activated calcium currents and their regulation. Prog Neurobiol 36:485–520
Snutch TP, Reiner PB (1992) Ca2+ channels: diversity of form and function. Curr Opin Neurobiol 2:247–253
Soong TW, Stea A, Hodson CD, Dubel SJ, Vincent SR, Snutch TP (1993) Structure and functional expression of a member of the low voltage-activated calcium channel family. Science 260:1133–1136
Spedding M, Paoletti R (1992) Classification of calcium channels and the sites of action of drugs modifying channel function. Pharmacol Rev 44:363–373
Tang S, Yatani A, Bahinski A, Mori Y, Schwartz A (1993) Molecular localization of regions in the L-type calcium channel critical for dilydropyridine action. Neuron 11:1013–1021
Tsien RW, Lipscombe D, Madison DV, Bley KR, Fox AP (1988) Multiple types of neuronal calcium channels and their selective modulation. Trends Neurosci 11:431–438
Valmier J, Richard S, Devic E, Nargeot J, Simonneau M, Baldy Moulinier M (1991) Dihydropyridines interact with calciumindependent potassium currents in embryonic mammalian sensory neurons. Plfügers Arch 419:281–287
Wheeler DB, Randall A, Tsien RW (1994) Roles of N-type and Q-type Ca2+ channels in supporting hippocampal synaptic transmission. Science 264:107–111
Zhang J-F, Randall AD, Ellinor PT, Horne WA, Sather WA, Tanabe T, Schwarz TL, Tsien RW (1993) Distinctive pharmacology and kinetics of cloned neuronal Ca2+ channels and their possible counterparts in mammalian CNS neurons. Neuropharmacology 32:1075–1088
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Diochot, S., Richard, S., Baldy-Moulinier, M. et al. Dihydropyridines, phenylalkylamines and benzothiazepines block N-, P/Q- and R-type calcium currents. Pflügers Arch. 431, 10–19 (1995). https://doi.org/10.1007/BF00374372
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00374372