Summary
The effects of antianginal drugs, especially arylalkylamines and structurally related derivatives, on 3H-batrachotoxinin-A 20-α-benzoate (3H-BTX-B) binding and on 3H-tetracaine binding were studied on rat synaptosomal and heart membrane preparations. The effect of the same drugs on the Na+ influx induced by protoveratrine B was studied on the rat synaptosomal preparation.
Antianginal drugs tested inhibited 3H-BTX-B binding in rat synaptosomes, arylalkylamine derivatives being the most potent: IC50 values were 27 nM for flunarizine, 32 nM for prenylamine, 79 nM for cinnarizine. Similarly, these drugs were the most potent when tested in cardiac membrane preparations.
All the drugs tested were very weak inhibitors of 3H-tetracaine binding (IC50 ranging from 0.01 mM to more than 1 mM) except for guanabenz, which was more potent (IC50: 0.3 μM on the synaptosomal preparation).
The various drugs tested inhibited the 22 Na+ influx induced by protoveratrine B, with IC50 values ranging from 15 μM (prenylamine) to 110 μM (verapamil), with the exception of nifedipine which had an IC50 of more than 0.1 mM. The inhibition of 22Na+ influx correlated well with the inhibition of 3H-BTX-B binding.
These findings suggest that some antianginal drugs, especially the arylalkylamines may have, in addition to their calcium antagonist activity, direct effects on sodium channels.
Similar content being viewed by others
References
Catterall WA (1980) Neurotoxins that act on voltage-sensitive sodium channels in excitable tissue. Ann Rev Pharmacol Toxicol 20:14–43
Creveling CR, McNeal ET, Daly JW, Brown GB (1983) Batrachotoxin induced depolarization and 3H-batrachotoxi-nin-A 20-alpha-benzoate binding in a vesicular preparation from guinea pig cerebral cortex. Inhibition by local anesthetics. Mol Pharmacol 23:350–358
Ehlert FJ, Roeske WR, Itoga E, Yamamura HI (1982) The binding of 3H-nitrendipine to receptors for calcium channel antagonists in the heart, cerebral cortex and ileum of rats. Life Sci 30:2191–2202
Grima M, Schwartz J, Spach MO, Velly J (1985) 3H-tetracaine binding on rat synaptosomes and sodium channels. Br J Pharmacol 86:125–129
Grima M, Schwartz T, Spach MO, Velly J (1986) Antianginal arylalkylamines and sodium channels: [3H]-batrachotoxinin-A 20-alpha-benzoate and [3H]-tetracaine binding. Br J Pharmacol (in press)
Hellenbrecht D, Lemmer B, Wiethold G, Grobecker H (1973) Measurement of hydrophobicity, surface activity, local anesthesia and myocardial conduction velocity as quantitative parameters of the non-specific membrane affinity of nine beta-adrenergic blocking agents. Naunyn-Schmiedeberg's Arch Pharmacol 277:211–226
Hille B (1971) The permeability of the sodium channel to organic cations in myelinated nerve. J Gen Physiol 58:599–619
Leclerc G, Decker N, Schwartz J (1982) Synthesis and cardiovascular activity of a new series of cyclohexylaralkylamine derivatives related to perhexiline. J Med Chem 25:709–714
Lowry OH, Rosebrough NH, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Mason JW, Hondeghem LM, Katzung BG (1983) Amiodarone blocks inactivated cardiac sodium channels. Pflügers Arch 396:79–81
McNeal ET, Lewandowski GA, Daly JW, Creveling CR (1985) 3H-batrachotoxinin A 20-alpha-benzoate binding to voltage sensitive Sodium channels: a rapid and quantitative assay for local anesthetic activity in a variety of drugs. J Med Chem 28:381–388
Nokin P, Clinet M, Chatelain P, Devos C, Meysmans L, Zinebioui (1984) Inhibition by amiodarone of 3H-nitrendipine binding to cerebral cortex membranes. J Mol Cell Cardiol 16:(suppl 3) 13
Postma SW, Catterall WA (1984) Inhibition of binding of 3H-batrachotoxinin-A 20-alpha-benzoate to sodium channels by local anaesthetics. Mol Pharmacol 25:219–227
Reynolds IJ, Gould RJ, Snyder SH (1983) 3H-verapamil binding sites in brain and skeletal muscle: regulation by calcium. Eur J Pharmacol 95:319–321
Sada H (1978) Effect of phentolamine, alprenolol and prenylamine on maximum rate of rise of action potential in guinea pig papillary muscles. Naunyn-Schmiedeberg's Arch Pharmacol 304:191–201
Spedding M (1985) Calcium antagonist subgroups. Trends Pharmacol Sci 6:109–114
Tamkun MM, Catterall WA (1980) Ion flux studies of voltage sensitive sodium channels in synaptic nerve-ending particles. Mol Pharmacol 19:78–86
Weidmann S (1955) The effect of the cardiac membrane potential on the rapid availability of the sodium carrying system. J Physiol (Loud) 127:213–224
Author information
Authors and Affiliations
Additional information
Send offprint requests to J. Velly at the above address
Rights and permissions
About this article
Cite this article
Velly, J., Grima, M., Marciniak, G. et al. Effects of some antianginal and vasodilating drugs on sodium influx and on the binding of 3H-batrachotoxinin-A 20-α-benzoate and 3H-tetracaine. Naunyn-Schmiedeberg's Arch Pharmacol 335, 176–182 (1987). https://doi.org/10.1007/BF00177720
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00177720