Summary
Increased peripheral vascular resistance is the cause of elevated systemic blood pressure in most patients with long standing hypertension. The desired haemodynamic effect in antihypertensive therapy is dilation of the constricted arterioles by a drug that acts directly on the vascular smooth muscle while not affecting the heart or the venous return.
Hydralazine, diazoxide and minoxidil act directly on vascular smooth muscle to produce vasodilatation and have been used with variable degrees of success in the long term treatment of hypertension. Their cellular mechanism of dilation is not understood fully, but the ability to chelate certain trace metals required for smooth muscle contraction has been proposed as a possible mechanism of action for these drugs.
The calcium antagonists (calcium entry blocking drugs) are a distinct group of compounds that interfere with the normal transmembrane flux of extracellular calcium ions on which vascular tissue depends for contraction or impulse generation. Thus, calcium antagonists can reduce the contractile activity of the heart, and promote coronary and systemic vasodilatation. These effects provide the clinical rationale for the use of calcium antagonists in the management of ischaemic heart disease and hypertrophic cardiomyopathy. Since systemic vasodilatation can be expected to reduce elevated arterial blood pressure, interest has focused recently on calcium antagonists in the medical management of systemic hypertension.
All the calcium antagonists are able, in low concentrations, to relax the smooth muscle vasculature from coronary, cerebral, mesenteric, and renal arteries. The effects on the myocardium, cardiac impulse tissue, and vascular smooth muscle are different in magnitude, however, depending on the individual agent that is used. Clinical experience in the treatment of hypertension with this class of agents is confined to verapamil, nifedipine, and diltiazem. In this article, the scientific rationale for using calcium antagonists in the treatment of arterial hypertension is explored and the clinical experiences with the different calcium antagonists used in hypertension are reviewed.
Similar content being viewed by others
References
Andreasen, F.; Boye, E.; Christoffersen, E.; Dalsgaard, P.; Henneberg, E.; Kallenbach, A.; Ladefogel, S.; Lillquist, K.; Mikkelsen, E.; Nordero, E.; Olsen, J.; Pedersen, J.K.; Pedersen, V.; Petersen, G.; Schroll, J.; Schultz, H. and Seidelin, J.: Assessment of verapamil in the treatment of angina pectoris. European Journal of Cardiology 2: 443–452 (1975).
Aoki, K.; Yoshida, T.; Kato, S.; Tazume, K.; Soto, I.; Takikawa, K. and Hotta, K.: Hypotensive action and increased plasma renin activity by calcium antagonist (nifedipine) in hypertensive patients. Japanese Heart Journal 17: 479–484 (1976).
Aoki, K.; Kondo, S.; Mochizaki, A.; Yoshida, T.; Kato, S.; Kato, K. and Takikawa, K.: Antihypertensive effect of cardiovascular Ca2+-antagonist in hypertensive patients in the absence and presence of beta-adrenergic blockade. American Heart Journal 96: 218–226 (1978)
Atterhög, J.H. and Ekelund, L.G.: Haemodynamic effects of intravenous verapamil at rest and during exercise in subjectively healthy middle-aged men. European Journal of Clinical Pharmacology 8: 317–322 (1975).
Avioli, L.V.: Stones, bones, abdominal groans, psychic moans and hypertones. Cardiovascular Medicine 3: 835–837 (1978).
Bartorelli, C.; Magrini, F.; Moruzzi, P.; Olivari, M.T.; Polese, A.; Fiorentini, C. and Guazzi, M.: Haemodynamic effects of a calcium antagonist agent (nifedipine) in hypertension: Therapeutic implications. Clinical Science and Molecular Medicine 55(Suppl.4): 291S–292S (1978).
Beer, N.; Gallegos, I.; Cohen, A.; Klein, N.; Sonnenblick, E. and Frishman, W.: Efficacy of sublingual nifedipine in the acute treatment of systemic hypertension. Chest 79: 571–574 (1981).
Blaustein, M.P.; Lang, S. and James-Kracke, M.: Cellular basis of sodium-induced hypertension; in Laragh et al. (Eds) Frontiers in Hypertension Research, pp.87–90 (Springer-Verlag, New York 1981).
Blaustein, M.P.: Sodium ions, calcium ions, blood pressure regulation and hypertension: A reassessment and a hypothesis. American Journal of Physiology 232(3): C165–C173 (1977).
Brennan, F.N. and Blake, S.: Use of nifedipine as a third step agent in the treatment of refractory hypertension. Irish Medical Journal 75: 29–30 (1982).
Brittinger, W.D.; Schwarzbeck, A.; Wittenmeier, K.W.; Tutkenhoff, W.D.; Stegaru, B.; Huber, W.; Ewald, R.W.; Henning, G.E.V.; Fabricius, M. and Strauch, M.: Klinish-experimentelle Untersuchungen über die Blutdruckenkende Wirkung von Verapamil. Deutsche Medizinische Wochenschrift 95: 1871–1877 (1970).
Chomdy, B.; Bell, P.D. and Navari L.G.: Renal hemodynamic and autoregulatory responses to acute hypercalcemia. American Journal of Physiology 232: G–13 (1977).
Christensson, T.; Hellstrom, K. and Wengle, B.: Blood pressure in subjects with hypercalcaemia and primary hyperparathyroidism detected in a health screening programme. European Journal of Clinical Investigation 7: 109–114 (1977).
Chrysant, S.G.; Dunn, F.G.; de Carvalbo, J.G.R.; Adamopoulos, P.N. and Frohlich, E.D.: Action of nitroglycerin and amyl nitrate in labile and essential hypertension. Archives of Internal Medicine 137: 1702–1705 (1977).
Corea, L; Miele, N.; Bentivoglio, M.; Boschetti, E.; Agabiti-Rosei, E. and Muiesan, G.: Acute and chronic effects of nifedipine on plasma renin activity and plasma adrenaline and noradrenaline in controls and hypertensive patients. Clinical Science and Molecular Medicine 57: 115S–117S (1979).
DeLeeuw, P.W.; Smout, A.J.P.M.; Willemse, P.J. and Birkenhager, W.H.: Effects of verapamil in hypertensive patients; in Zanchetti and Krikler (Eds) Calcium Antagonism in Cardiovascular Therapy: Experience with Verapamil, pp.233–237 (Excerpta Medica, Amsterdam-Oxford-Princeton 1981).
Deth, R. and van Breemen, C.: Agonist induced release of intracellular Ca2+ in the rabbit aorta. Journal of Membrane Biology 30: 363–380 (1977).
Doyle, A.E.; Anavekar, S.N. and Oliver, L.E.: A clinical trial of verapamil in the treatment of hypertension; in Zanchetti and Krikler (Eds) Calcium Antagonism in Cardiovascular Therapy: Experience with Verapamil, pp.252–258 (Excerpta Medica, Amsterdam-Oxford-Princeton 1981).
Ferlinz, J.: Effects of verapamil on normal and abnormal ventricular functions in patients with ischemic heart disease; in Zanchetti and Krikler (Eds) Calcium Antagonism in Cardiovascular Therapy: Experience with Verapamil, pp.92–105 (Excerpta Medica, Amsterdam-Oxford-Princeton 1981).
Flaim, S.F.; Irwin, J.M.; Ratz, P.H. and Swigart, S.: Differential effects of calcium channel blocking agents on oxygen consumption rate in vascular smooth muscle. American Journal of Cardiology 49: 511–518 (1982).
Frishman, W.H.; Klein, N.A.; Strom, J.A.; Willens, H.; LeJemtel, T.H.; Jentzer, J.; Siegel, L.; Klein, P.; Kirschen, N.; Silverman, R.; Pollack, S.; Doyle, R.; Kirsten, E. and Sonnenblick, EH.: Superiority of verapamil to propranolol in stable angina: A double-blind randomised placebo-controlled crossover comparison. Circulation 65(Suppl.1): 152–159 (1982a).
Frishman, W.H.; Klein, N.A.; Klein, P.; Strom, J.A.; Tawil, R.; Strair, R.; Wong, B.; Roth, S.; LeJemtel, T.; Pollack, S. and Sonnenblick, E.: A comparison of oral propranolol and verapamil in patients with hypertension and angina pectoris: A placebo-controlled double-blind randomised crossover trial. American Journal of Cardiology 50: 1164–1172 (1982b).
Gould, B.A.; Mann, S.; Kieso, H.; Subramanian, V.B. and Raftery, E.B.: The 24-hour ambulatory blood pressure profile with verapamil. Circulation 65(1): 22–27 (1982).
Guazzi, M.D.: The role of calcium antagonists in the management of hypertension. Practical Cardiology 8: 39–55 (1982).
Guazzi, M.D.; Fiorentini, C.; Olivari, M.T.; Bartorelli, A.; Necchi, G. and Polese, A.: Short and long-term efficacy of a calcium antagonistic agent (nifedipine) combined with methyldopa in the treatment of severe hypertension. Circulation 61: 913–919 (1980).
Guazzi, M.; Oliveri, M.T.; Polese, A.; Fiorentini, G; Magrini, F. and Moruzzi, P.: Nifedipine, a new anti-hypertensive with rapid action. Clinical Pharmacology and Therapeutics 22: 528–532 (1977).
Gutche, H.Y.; Muller-Suur, R. and Schurek, H.J.: Ca++-antagonist prevents feedback induced SN-GFR decrease in rat kidney. Kidney International 8: 477 (1978).
Haddy, F.J.; Scott, J.B. and Navari, L.G.: Renal hemodynamic and autoregulatory responses to acute hypercalcemia. American Journal of Physiology 232: 6–13 (1977).
Hecht, H.; Christopher, Y.C.; Burnam, M.H.; Hopkins, J.; Schnugg, S. and Singh, B.N.: Verapamil in chronic stable angina: Amelioration of pacing-induced abnormalities of left ventricular ejection fraction, regional wall motion, lactate metabolism and hemodyriamics. American Journal of Cardiology 48: 536–544 (1981).
Henry, P.D.: Comparative pharmacology of calcium antagonists: Nifedipine, verapamil and diltiazem. American Journal of Cardiology 46: 1047–1058 (1980).
Hinke, J.A.M.: Effect of Ca++ upon contractility of small arteries from DCA-hypertensive rats. Circulation Research 18-19 (Suppl. I): 23–24 (1966).
Hiwatari, M. and Taira, N.: Antihypertensive effect of niludipine (Bay a 7168) on conscious renal-hypertensive dogs. Arzneimittel-Forschung 29: 1373–1376 (1979).
Imai, Y.; Abe, K.; Otsuka, Y.; Irokawa, N.; Yasujima, M.; Saito, K.; Sakurai, Y.; Chiba, S.; Ito, T.; Sato, M.; Haruyama, T.; Miura, Y. and Yoshinaga, K.: Management of severe hypertension with nifedipine in combination with clonidine or propranolol. Arzneimittel-Forschung 30: 674–678 (1980).
Iriuchijima, J.: Effect of calcium antagonist, nifedipine, on blood pressure of various hypertensive rats. Hiroshima Journal of Medical Sciences 29: 15–19 (1980).
Jones, A.W.: Altered ion transport in large and small arteries from spontaneously hypertensive rats and the influence of calcium. Circulation Research 34-35 (Suppl. I): 117–122 (1974).
Kuwajima, I.; Ueda, K.; Kamata, C.; Matsushita, S.; Kuramoto, K.; Murakami, M. and Hada, Y.: A study of the effects of nifedipine in hypertensive crises and severe hypertension. Japanese Heart Journal 19: 455–467 (1978).
Kinoshita, M.; Motomura, M.; Kusukawa, R. and Kawakita, S.: Comparison of hemodynamic effects between β-blocking agents and a new antianginal agent, diltiazem hydrochloride. Japan Circulation Journal 43: 587–598 (1979).
Kubo, T.; Fujie, K.; Yamashita, M. and Misu, Y.: Antihypertensive effects of nifedipine on conscious normotensive and hypertensive rats. Journal of Pharmacobiodynamics 4: 294–300 (1981).
Kusukawa, R.; Kinoshita, M.; Shimono, Y.; Tomonaga, G. and Hosino, T.: Haemodynamic effects of a new anti-anginal drug, diltiazem hydrochloride. Arzneimittel-Forschung 27: 878–887 (1977).
Laaser, U.; Meurer, K.A. and Kaufmann, W.: On the clinical evaluation of therapy with nifedipine in association with various antihypertensive drugs. Arzneimittel-Forschung 27: 676–681 (1977).
Leary, W.P.; Phil, D. and Asmal, A.C.: Treatment of hypertension with verapamil. Current Therapeutic Research 25(5): 747–752 (1979).
Leonetti, G.; Sala, C.; Bianchini, C.; Terzoli, L. and Zanchetti, A.: Antihypertensive and renal effects of orally administered verapamil. European Journal of Clinical Pharmacology 18: 375–382 (1980).
Leonetti, G.; Pasotti, C.; Ferrari, G.P. and Zanchetti, A.: Double-blind comparison of the antihypertensive effects of verapamil and propranolol; in Zanchetti and Krikler (Eds) Calcium Antagonism in Cardiovascular Therapy: Experience with Verapamil, pp.260–267 (Excerpta Medica, Amsterdam-Oxford-Princeton 1981).
Lewis, G.R.; Morley, K.D.; Lewis, B.M. and Bones, P.J.: The treatment of hypertension with verapamil. New Zealand Medical Journal 87: 351–354 (1978).
Lewis, G.R.J.; Morley, K.D.; Maslowski, A.H. and Bones, P.J.: Verapamil in the management of hypertensive patients. Australian and New Zealand Journal of Medicine 9: 62–64 (1979).
Lewis, G.R.J.: Verapamil in the management of chronic hypertension. Clinical and Investigative Medicine 3: 175–177 (1980).
Lewis, G.R.J.; Stewart, D.J.; Lewis, B.M.; Bones, P.J.; Morley, K.D. and Janus, E.D.: The antihypertensive effect of oral verapamil — acute and long-term administration and its effects on the high-density lipoprotein values in plasma; in Zanchetti and Krikler (Eds) Calcium Antagonism in Cardiovascular Therapy: Experience with Verapamil, pp.270–277 (Excerpta Medica, Amsterdam-Oxford-Princeton 1981).
Lewis, G.R.J.: In discussion; in Zanchetti and Krikler (Eds) Calcium Antagonism in Cardiovascular Therapy: Experience with Verapamil, p.279 (Excerpta Medica, Amsterdam-Oxford-Princeton 1981).
Livesley, B.; Catley, P.F.; Campbell, R.C. and Oram, S.: Double-blind evaluation of verapamil, propranolol, and isosorbide dinitrate against a placebo in the treatment of angina pectoris. British Medical Journal 1: 375–378 (1973).
Maeda, K.; Takasugi, T.; Tsukano, Y.; Tanaka, Y. and Shiota, K.: Clinical study on the hypotensive effect of diltiazem hydrochloride. International Journal of Clinical Pharmacology, Therapy and Toxicology 19(2): 47–55 (1981).
Mangiardi, L.M.; Hartman, R.J.; McAllister Jr, R.G.; Bhargava, V.; Surawicz, B. and Shabetai, R.: Electrophysiologic and hemodynamic effects of verapamil. Correlation with plasma drug concentrations. Circulation 57: 366–372 (1978).
Marone, C.; Beretta-Piccoli, C. and Weidman, P.: Role of haemodynamics, catecholamines and renin in acute hypercalcaemic hypertension in man. Clinical Sciences 59: 369S–371S (1980).
Midtbo, D. and Hals, O.: Verapamil in the treatment of hypertension. Current Therapeutic Research 27(6): 830–838 (1980).
Mikkelsen, K.; Andersson, K.E. and Bengstsson, B.: Effects of verapamil and nitroglycerin on contractile responses to potassium and noradrenaline in isolated human peripheral veins. Acta Pharmacologica et Toxicologica 42: 14–22 (1978a).
Mikkelsen, E.; Andersson, K.E. and Pedersen, O.L.: The effect of nifedipine on isolated human peripheral vessels. Acta Pharmacologica et Toxicologica 43: 291–298 (1978b).
Mostbeck, A.; Partsch, H. and Peschl, L.: Investigations on peripheral blood distribution. Third International Adalat Symposium, pp.91–97 (Excerpta Medica, Amsterdam 1976).
Muiesan, G.; Agabiti-Rosei, E.; Alicandri, C.; Beschi, M.; Castellano, M.; Corea, L.; Fariello, R.; Romanelli, G.; Pasini, C. and Platto, L: Influence of verapamil on catecholamines, renin and aldosterone in essential hypertensive patients; in Zanchetti and Krikler (Eds) Calcium Antagonism in Cardiovascular Therapy: Experience with Verapamil, pp.238–249 (Excerpta Medica, Amsterdam-Oxford-Princeton 1981).
Murakami, M.; Murakami, E.; Takekoshi, N.; Tsuchiga, M.; Kin, T.; Onoe, T.; Takeuchi, N.; Funatsu, T.; Hara, S.; Ishise, S.; Mifune, J. and Maeda, M.: Antihypertensive effect of 4 (-2-nitrophenyl)-2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarbonic acid dimethylester (nifedipine, Bay-a 1040), a new coronary vasodilator. Japanese Heart Journal 13: 128–135 (1972).
Olivari, M.T.; Bartorelli, C.; Polese, A.; Fiorentini, C.; Moruzzi, P.; and Guazzi, M.D.: Treatment of hypertension with nifedipine, a calcium antagonistic agent. Circulation 59: 1056–1062 (1979).
Opie, L.H.: Drugs and the heart. III: Calcium antagonists. Lancet 1: 806–810 (1980).
Osada, T.; Kajiwara, N.; Kobayashi, Y.; Murakami, A.; Hashida, J.; Uchiyama, T.; Ono, M.; Kita, T.; Tei, T.; Fujiboyashi, Y.; Yamamoto, Y.; Shimoda, K.; Hatano, M. and Satoh, Y.: The inhibition of hypertension and the histological changes in SHR treated with diltiazem. Japanese Heart Journal 20: 745 (1979).
Overbeck, H.W. and Conrad, L.L.: Intracellular distribution of calcium-45 in arteries of normal and hypertensive dogs. Proceedings of the Society for Experimental Biology and Medicine 127: 565–570 (1968).
Pedersen, O.L.: Does verapamil have a clinically significant antihypertensive effect? European Journal of Clinical Pharmacology 13: 21–24 (1978).
Pedersen, O.L.; Mikkelsen, E.; Kornerup, H.J. and Christensen, N.J.: Effects of nifedipine on blood pressure, regional hemodynamics, plasma renin activity and plasma catecholamines in patients with hypertension. Acta Medica Scandinavica 625 (Suppl.): 65–67 (1978a).
Pedersen, O.L.; Christensen, C.K.; Mikkelsen, E. and Ramsch, K.D.: Relationship between antihypertensive effect and steady-state plasma concentration of nifedipine given alone or in combination with a β-adrenoceptor blocking agent. European Journal of Clinical Pharmacology 18: 287–293 (1980).
Pedersen, O.L. and Mikkelsen, E.: Acute and chronic effects of nifedipine in arterial hypertension. European Journal of Clinical Pharmacology 14: 375–381 (1978).
Pedersen, O.L.; Mikkelsen, E. and Andersson, K-E.: Effects of extracellular calcium on potassium and noradrenaline induced contractions in the aorta of spontaneously hypertensive rats — increased sensitivity to nifedipine. Acta Pharmacologica et Toxicologica 43: 137–144 (1978b).
Pedersen, O.L.; Mikkelsen, E.; Christensen, N.J.; Kornerup, H.J. and Pedersen, E.B.: Effect of nifedipine on plasma renin, aldosterone and catecholamines in arterial hypertension. European Journal of Clinical Pharmacology 15: 235–240 (1979).
Polese, A.; Fiorentini, C.; Olivari, M.T. and Guazzi, M.D.: Clinical use of a calcium antagonistic agent (nifedipine) in acute pulmonary edema. American Journal of Medicine 66: 825–830 (1979).
Rosenthal, F.D. and Roy, S.: Hypertension and hyperparathyroidism. British Medical Journal 4: 391–399 (1972).
Ross, G. and Jorgenson, C.R.: Cardiovascular action of iproveratril. Journal of Pharmacology and Experimental Therapeutics 158: 504–509 (1967).
Ryden, L. and Saetre, H.: The haemodynamic effect of verapamil. European Journal of Clinical Pharmacology 3: 153–157 (1971).
Sakuri, T.; Kurita, T.; Nagano, S. et al.: Antihypertensive, vasodilating, and sodium diuretic actions of D-cis-isomer of benzothiazepine derivative (CRD-401). Acta Urologica Japonica 18: 695–707 (1972).
Sandier, G.; Clayton, G.A. and Thornicroft, S.G.: Clinical evaluation of verapamil in angina pectoris. British Medical Journal 3: 224–227 (1968).
Sato, M.; Murata, S.; Narita, H.; Tomita, M.; Yamashita, K. and Yamaguchi, I.: Hypotensive effects of diltiazem hydrochloride in the normotensive, spontaneously hypertensive and renal hypertensive rats (authors’ translation of abstract). Nippon Yakurigaku Zasshi 75(2): 99–106 (1979).
Scharer, K.; Alatas, H. and Bein, G.: The treatment of renal hypertension with verapamil in childhood (abstract). Monatsschrift für Kinderheilkunde 125(7): 706–12 (1977).
Seabra-Gomes, R.; Rickards, A. and Sutton, R.: Haemodynamic effects of verapamil and practolol in man. European Journal of Cardiology 4: 79–85 (1976).
Singh, B. and Roche, A.: Effects of intravenous verapamil on hemodynamics in patients with heart disease. American Heart Journal 94(5): 593–599 (1977).
Stone, P.H.; Antman, E.M.; Muller, J.E. and Braunwald, E.: Calcium channel blocking agents in the treatment of cardiovascular disorders. Part II: Hemodynamic effects and clinical applications. Annals of Internal Medicine 93: 886–904 (1980).
Takekoshi, N.; Murakami, E.; Murakami, H.; Matsui, S.; Masuya, K.; Nomura, M.; Fujita, S.; Tsuji, S.; Chatani, T.; Emoto, J.; Tsugawa, H. and Hashimoto, A.: Treatment of severe hypertension and hypertensive emergency with nifedipine, a calcium antagonistic agent. Japan Circulation Journal 45: 852–860 (1981).
Tarazi, R.C.; Dustan, H.P.; Bravo, E.L. and Niarchos, A.P.: Vasodilating drugs: Contrasting hemodynamic effects. Clinical Science and Molecular Medicine 51: 575S–578S (1976).
Thibonnier, M.; Bonnet, F. and Corvol, P.: Antihypertensive effect of fractionated sublingual administration of nifedipine in moderate essential hypertension. European Journal of Clinical Pharmacology 17: 161–164 (1980).
Tobian, L. and Chesley, G.: Calcium content of arteriolar walls in normotensive and hypertensive rats. Proceedings of the Society for Experimental Biology and Medicine 121: 340–343 (1966).
Vincenzi, M.; Allegri, P.; Gabaldo, S.; Maiolino, P. and Ometto, R.: Haemodynamic effects caused by intravenous administration of verapamil in healthy subjects. Arzneimittel-Forschung 26: 1221–1223 (1976).
Wei, J-W.; Janis, R.A. and Daniel, E.E.: Calcium accumulation and enzymatic activities of subcellular fractions from aortas and ventricles of genetically hypertensive rats. Circulation Research 39: 133–140 (1976).
Weidmann, P.; Massry, S.R.; Coburn, J.W.; Maxwell, M.H.; Atleson, J. and Kleeman, C.R.: Acute hypercalcemic hypertension. Annals of Internal Medicine 76: 741–746 (1972).
Yamaguchi, I.; Ikezawa, K.; Takada, T. and Kiyomoto, A.: Studies on a new 1,5-benzothiazepine derivative (CRD-401). VI. Effects on renal blood flow and renal function. Japanese Journal of Pharmacology 24: 511–522 (1974).
Zsotér, T.T.; Nolchinsky, C.; Henein, N.F. and Ho, L.C.: Calcium kinetics in the aorta of spontaneously hypertensive rats. Cardiovascular Research 11: 353–357 (1977).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Spivack, C., Ocken, S. & Frishman, W.H. Calcium Antagonists. Drugs 25, 154–177 (1983). https://doi.org/10.2165/00003495-198325020-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003495-198325020-00004