Summary
Calcium antagonists comprise a diverse group of chemically unrelated agents that interact with voltage-operated calcium channels (L-type) and thereby inhibit smooth muscle and cardiac contractility. Although they interact with the α1 subunit of voltage-operated calcium channels, all calcium antagonists are not identical pharmacological agents. They are not only different from a chemical point of view, but also because some of them exhibit tissue selectivity, being more powerful blockers of the contraction of arteries than of cardiac muscle. The current view that their major therapeutic action is related to vasodilation is an oversimplification, as their action is more complex and may be related to factors other than hemodynamic ones.
Key words
calcium antagonists calcium channel modulators voltage-operated calcium channels left ventricular dysfunction cardiac hypertrophy cardiovascular remodeling classification of calcium antagonistsPreview
Unable to display preview. Download preview PDF.
References
- 1.Heilbrunn LV, Wiercinski FJ. The action of various cations on muscle protoplasm.J Cell Comp Physiol 1947;29:15–32.Google Scholar
- 2.Kamada T, Konosita H. Disturbances initiated from naked surface of muscle protoplasm.Jpn J Zool 1943;10:469–493.Google Scholar
- 3.Fleckenstein A. History of calcium antagonists.Circ Res 1983;52(Suppl 1):3–16.Google Scholar
- 4.Godfraind T, Miller RC, Wibo M. Calcium antagonism and calcium entry blockade.Pharmacol Rev 1986;38:321–416.Google Scholar
- 5.Spedding M, Paoletti, R. Classification of calcium channels and the sites of action of drugs modifying channel function.Pharmacol Rev 1992;44:363–376.Google Scholar
- 6.Nowycky MC, Rox AP, Tsien RW. Three types of neuronal calcium channel with different calcium agonist sensitivity.Nature 1985;316:440–443.Google Scholar
- 7.Hess P, Lansman JB, Tsien RW. Calcium channel selectivity for divalent and monovalent cations. Voltage and concentration dependence of single channel current in ventricular heart cells.J Gen Physiol 1986;88:293–319.Google Scholar
- 8.Fox AP, Nowycky MC, Tsien RW. Kinetic and pharmacological properties distinguishing three types of calcium currents in chick sensory neurons.J Physiol (Lond) 1987;394:149–172.Google Scholar
- 9.Tsien RW, Tsien RY. Calcium channels, stores, and oscillations.Annu Rev Cell Biol 1990;6:715–760.Google Scholar
- 10.Sher E, Biancardi E, Passafaro M, Clementi F. Physiopathology of neuronal voltage-operated calcium channels.FASEB J 1991;5:2677–2683.Google Scholar
- 11.Tytgat J, Pauwels PJ, Vereecke J, Carmeliet E. Flunarizine inhibits a high-threshold inactivating calcium channel (N-type) in isolated hippocampal neurons.Brain Res 1991;549:112–117.Google Scholar
- 12.Hagiwara N, Irisawa H, Kameyama M. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells.J Physiol (London) 1988;395:233–253.Google Scholar
- 13.Sher E, Biancardi E, Pollo A, et al. Omega-contoxin-sensitive, voltage-operated Ca2+ channels in insulinsecreting cells.Eur J Pharmacol 1992;216:407–414.Google Scholar
- 14.Llinas R, Sugimori M, Hillman DE, Cherksey B. Distribution and functional significance of the P-type, voltage-dependent Ca2+ channels in the mammalian central nervous system.Trends Neurosci 1992;15:351–355.Google Scholar
- 15.Triggle DJ. Calcium antagonists—History and perspective.Stroke 1990;21:IV.49-IV.58.Google Scholar
- 16.Godfraind T, Salomone S, Dessy C, Verhelst B, Dion R, Schoevaerts JC. Selectivity scale of calcium antagonists in the human cardiovascular system (based on in vitro studies).J Cardiovasc Pharmacol 1992;20(Suppl 5):S34-S41.Google Scholar
- 17.Bosse E, Bottlender R, Kleppisch T, et al. Stable and functional expression of the calcium channel α1 subunit from smooth muscle in somatic cell lines.EMBO J 1992;11:2033–2038.Google Scholar
- 18.Godfraind T, Kazda S, Wibo M. Effects of a chronic treatment by nisoldipine, a calcium antagonist dihydropyridine, on arteries of spontaneously hypertensive rats.Circ Res 1991;68:674–682.Google Scholar
- 19.Tsien RW, Ellinor PT, Horne WA. Molecular diversity of voltage-dependent Ca2+ channels.Trends Pharmacol Sci 1991;12:349–354.Google Scholar
- 20.Morel N, Godfraind T. Characterization in rat aorta of the binding sites responsible for blockade of nonradrenalineevoked calcium entry and contraction by nisoldipine.Br J Pharmacol 1991;102:467–477.Google Scholar
- 21.Godfraind T, Dessy C, Salomone S. A comparison of the potency of selective L-calcium channel inhibitors in human coronary and internal mammary arteries exposed to serotonin.J Pharmacol Exp Ther 1992;263:112–122.Google Scholar
- 22.Morel N, Godfraind T. Selective modulation by membrane potential of the interaction of some calcium entry blockers with calcium channels in rat mesenteric artery.Br J Pharmacol 1988;95:252–258.Google Scholar
- 23.Morel N, Godfraind T. Prolonged depolarization increases the pharmacological effect of dihydropyridines and their binding affinity for calcium channel of vascular smooth muscle.J Pharmacol Exp Ther 1987;243:711–715.Google Scholar
- 24.Striessnig J, Glossman H. Purification of L-type calcium channel drug receptors.Methods Neurosci 1991;4:210–229.Google Scholar
- 25.Wibo M, De Roth L, Godfraind T. Pharmacologic relevance of dihydropyridine binding sites in membrane from rat aorta: Kinetic and equilibrium studies.Circ Res 1988;62:91–96.Google Scholar
- 26.Salomone S, Godfraind T. Radioligand and functional estimates of the interaction of the 1,4-dihydropyridines, isradipine and lacidipine, with calcium channels in smooth muscle.Br J Pharmacol 1993;109:100–106.Google Scholar
- 27.Godfraind T. Analysis of factors involved in the tissue selectivity of calcium antagonists. In: Frank GB, Bianchi CP, TerKevrs H, eds.Excitation-Contraction Coupling in Skeletal, Cardiac and Smooth Muscle. New York: Plenum, 1992:103–120.Google Scholar
- 28.Godfraind T. Importance of kinetic parameters for the tissue selectivity of calcium antagonists.Biochem Pharmacol 1992;43:55–56.Google Scholar
- 29.Packer M. How should physicians view heart failure? The philosophical and physiological evolution of three conceptual models of the disease.Am J Cardiol 1993;71:3C-11C.Google Scholar
- 30.Kannel WB, Dannenberg AL, Levy D. Population implications of electro-cardiographic left ventricular hypertrophy.Am J Cardiol 1987;60:851–931.Google Scholar
- 31.Jalil JE, Doering CW, Janiscki JS, Pick R, Shroff SG, Weber KT. Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle.Circ Res 1989;64:1041–1050.Google Scholar
- 32.Nadal-Ginard B, Mahdavi V. Molecular basis of cardiac performance: Plasticity of the myocardium generated through protein isoform switches.J Clin Invest 1989;84:1693–1700.Google Scholar
- 33.Frohlich ED, Apstein C, Chobanian AV, et al. The heart in hypertension.N Engl J Med 1992;327:998–1008.Google Scholar
- 34.Godfraind T, Menning D, Morel N, Wibo M. Effect of endothelin-1 on calcium channel gating by agonists in vascular smooth muscle.J Cardiovasc Pharmacol 1989;13(Suppl 5):S112-S117.Google Scholar
- 35.Böhm M, Gierschik P, Knorr A, Larisch K, Weismann K, Erdmann E. Desensitization of adenylate cyclase and increase of Giα in cardiac hypertrophy due to acquired hypertension.Hypertension 1992;20:103–112.Google Scholar
- 36.Brodde OE. β1- and β2-adrenoceptors in the human heart: Properties, function, and alterations in chronic heart failure.Pharmacol Rev 1991;43:203–242.Google Scholar
- 37.Morgan JP. Abnormal intracellular modulation of calcium as a major cause of cardiac contractile dysfunction.N Engl J Med 1991;325:625–632.Google Scholar
- 38.Beuckelmann DJ, Näbauer M, Erdmann E. Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure.Circulation 1992;85:1046–1055.Google Scholar
- 39.Wagner JA, Sax FL, Weisman HF, et al. Calciumantagonist receptors in the atrial tissue of patients with hypertrophic cardiomyopathy.N Engl J Med 1989;320:755–761.Google Scholar
- 40.Takahasi T, Allen PD, Lacro RV, et al. Expression of dihydropyridine receptor (Ca2+ channel) and calsequestrin genes in the myocardium of patients with end-stage heart failure.J Clin Invest 1992;90:927–935.Google Scholar
- 41.Fleckenstein A.Calcium Antagonism in Heart and Smooth Muscle. Experimental Facts and Therapeutic Prospects. New York: John Wiley, 1983.Google Scholar
- 42.Fleckenstein A. Historical overview: The calcium channel of the heart. In: Vanhoutte PM, Paoletti R, Govoni S, eds.Calcium Antagonists, Pharmacology and Clinical Research. Ann NY Acad Sci 1988;522:1–15.Google Scholar
- 43.Tanaka H, Shigenobu K. Effect of ryanodine on neonatal and adult rat heart: Developmental increase in sarcoplasmic reticulum function.J Mol Cell Cardiol 1989;21:1305–1313.Google Scholar
- 44.Bers DM, Philipson KD, Langer GA. Cardiac contractility and sarcolemmal calcium binding in several cardiac muscle preparations.Am J Physiol 1981;240:H576-H583.Google Scholar
- 45.Wibo M, Bravo G, Godfraind T. Postnatal maturation of excitation-contraction coupling in rat ventricle in relation to the subcellular localization and surface density of 1,4-dihydropyridine and ryanodine receptors.Circ Res 1991;68:662–673.Google Scholar
- 46.Page E, Earley J, Power B. Normal growth of ultrastructures in rat left ventricular myocardial cells.Circ Res 1974;35(Suppl II):II12-II16.Google Scholar
- 47.Lai FA, Meissner G. The muscle ryanodine receptor and its intrinsic Ca2+ channel activity.J Bioenerg Biomembr 1989;21:227–246.Google Scholar
- 48.Fosset M, Jaimovich E, Delpont E, Lazdunski M. [3H]Nitrendipine receptors in skeletal muscle. Properties and preferential localization in transverse tubules.J Biol Chem 1983;258:6086–6092.Google Scholar
- 49.Page E, Surdyk-Drosk M. Distribution, surface density, and membrane area of diadic junctional contacts between plasma membrane and terminal cisterns in mammalian ventricle.Circ Res 1979;45:260–267.Google Scholar
- 50.Fabiato A. Appraisal of the physiological relevance of two hypotheses for the mechanism of calcium release from the mammalian cardiac sarcoplasmic reticulum: Calcium-induced release versus charge-coupled release.Mol Cell Biochem 1989;89:135–140.Google Scholar
- 51.Block BA, Imagawa T, Campbell KP, Franzini-Armstrong C. Structural evidence for direct interaction between the molecular components of the transverse tubule/sarcoplasmic reticulum junction in skeletal muscle.J Cell Biol 1988;107:2587–2600.Google Scholar
- 52.Diebold RJ, Koch WJ, Ellinor PT, et al. Mutually exclusive exon splicing of the cardiac calcium channel α1 subunit gene generates developmentally regulated isoforms in the rat heart.Proc Natl Acad Sci USA 1992;89:1497–1501.Google Scholar
- 53.Editorial. Calcium antagonist caution.Lancet 1991;337:885–888.Google Scholar
- 54.Opie LH.Clinical Use of Calcium Channel Antagonists Drugs, 2nd ed. Boston: Kluwer Academic, 1990, p. 326.Google Scholar
- 55.Opie LH. Calcium antagonists for congestive heart failure: Is it really one bridge too far to cross?Cardiovasc Drugs Ther 1993;7:93–94.Google Scholar
- 56.Packer M. Calcium antagonists for congestive heart failure: Evolving concepts in bridge building.Cardiovasc Drugs Ther 1993;7:95–96.Google Scholar
- 57.Dei Cas L, Metra M, Ferrari R, Visioli O. Acute and chronic effects of the dihydropyridine calcium antagonist nisoldipine on the resting and exercise hemodynamics, neurohumoral parameters and functional capacity of the patients with chronic heart failure.Cardiovasc Drugs Ther 1993;7:103–110.Google Scholar
- 58.Boyd RA, Giocomini JC, Giacomini KM. Species differences in the negative inotropic response of 1,4-dihydropyridine calcium channel blockers in myocardium.J Cardiovasc Pharmacol 1988;12:650–657.Google Scholar
- 59.Finet M, Godfraind T, Khoury G. The positive inotropic action of a nisoldipine analogue, Bay K 8644, in guinea-pig and rat isolated cardiac preparations.Br J Pharmacol 1985;86:27–32.Google Scholar
- 60.Kazda S, Garthoff B, Meyer H, et al. Pharmacology of a new calcium antagonistic compound, isobutyl methyl 1,4 dihydro-2,6-demethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylate (nisoldipine, Bay k 5552).Arzneim Forsch 1980;30:2144–2162.Google Scholar
- 61.Bristow MR, Ginsburg R, Laser JA, McAuley BJ, Minobe W. Tissue response selectivity of calcium antagonists is not due to heterogeneity of [3H]nitrendipine binding sites.Br J Pharmacol 1984;82:309–320.Google Scholar
- 62.Spedding M, Fraser S, Clarke B, Patmore L. Factors modifying the tissue selectivity of calcium antagonists.J Neural Transm 1990;Suppl 31:5–16.Google Scholar
- 63.Godfraind T, Eglème C, Finet M, Jaumin P. The actions of nifedipine and nisoldipine on the contractile activity of human coronary arteries and human cardiac tissue in vitro.Pharmacol Toxicol 1987;61:79–84.Google Scholar
- 64.Godfraind T, Menning D, Bravo G, Chalant C, Jaumin, P. Inhibition by amlodipine of activity evoked in isolated human coronary arteries by endothelin, prostaglandin F2α and depolarisation.Am J Cardiol 1989;64:I58-I64.Google Scholar
- 65.Böhm M, Schwinger RHG, Erdmann E. Different cardiode-pressant potency of various calcium antagonists in human myocardium.Am J Cardiol 1990;65:1039–1041.Google Scholar
- 66.Uehara A, Hume JR. Interactions of organic calcium channel antagonists with calcium channels in single frog atrial cells.J Gen Physiol 1985;85:621–647.Google Scholar
- 67.Bean BP, Sturek M, Puga A, Hersmeyer K. Calcium channels in muscle cells isolated from rat mesenteric arteries: Modulation by dihydropyridine drugs.Circ Res 1986;59:229–235.Google Scholar
- 68.Sanguinetti MC, Kass RS. Voltage-dependent block of calcium channel current in the calf cardiac Purkinje fiber by dihydropyridine calcium channel antagonists.Circ Res 1984;55:336–348.Google Scholar