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Calcium Channel Antagonists in Coronary Artery Spasm and Bronchial Spasm

1982; Elsevier BV; Volume: 82; Issue: 4 Linguagem: Inglês

10.1378/chest.82.4.401

1931-3543

Robert G. Townley,

Ion channel regulation and function

The mechanisms of variant angina and bronchial asthma are both unknown. However, it is intriguing to observe some of the similarities of coronary vasospasm and bronchial spasm observed more or less independently by cardiologists and clinical immunologists respectively. Clinically, coronary vasospasm (also known as variant or Prinzmetal’s angina) typically manifests itself as chest pain at rest. Attacks often occur during sleep and last longer than exertional angina. Spontaneous remissions of coronary vasospasm are common. Attacks occur spontaneously or can be elicited with methacholine, histamine or a serotonin agonist, ergonovine.1Ginsburg R Bristow MR Kantrowitz N Baim DS Harrison DS Histamine provocation of clinical coronary artery spasm. Implications concerning pathogenesis of variant angina.Am Heart J. 1981; 102: 819Abstract Full Text PDF PubMed Scopus (181) Google Scholar Twenty percent of all patients with angina have ergot-induced spasm, as demonstrated by coronary angiography; and 46 percent of those with pain only at rest and 95 percent of those with rest pain and ST segment elevation have demonstrable coronary artery spasm.2Resnekov L Calcium antagonist drugs.Chest. 1980; 78: 121Abstract Full Text Full Text PDF Google Scholar Spasm of variant angina has certain characteristic features reminiscent of bronchial asthma. Both conditions can be precipitated with methacholine, histamine or serotonin, and beta-adrenergic blocking agents. Both can occur at rest and tend to occur nocturnally. Both can be precipitated by exercise and exposure to cold air, and in the case of coronary artery spasm, by the cold pressor test. One postulated mechanism of bronchial asthma is an autonomic imbalance with heightened alpha-adrenergic and decreased beta-adrenergic response.3Henderson WR Shelhamer JH Reingold DB Smith LJ Evans R Kaliner M Alpha-adrenergic hyper-responsiveness in asthma: Analysis of vascular and pupillary response.N Engl J Med. 1979; 300: 642-647Crossref PubMed Scopus (119) Google Scholar, 4Townley RG Trapani IL Szentivanyi A Sensitization to anaphylaxis and to some of its pharmacological mediators by blockade of the beta adrenergic receptors.).Allergy. 1967; 39: 177-397Abstract Full Text PDF Scopus (49) Google Scholar, 5Szentivanyi A The radioligand binding approach in the study of lymphocytic adrenoceptors and the constitutional basis of atopy.J Allergy Clin Immunol 1980;. 1969; 65: 1Google Scholar A similar autonomic imbalance in coronary spasm is suggested by the favorable responses to alpha-adrenergic blocking agents such as phentolamine and phenoxybenzamine in some patients with coronary spasm. Contrariwise, an unfavorable response is elicited by beta-adrenergic blocking agents in both coronary and bronchial spasm. An alternate mechanism that has been postulated for both asthma and variant angina is a hyperactive cholinergic response. Both bronchial spasm in the patient with asthma, and coronary spasm in the patient with variant angina can be induced by administration of methacholine. Contrariwise, administration of atropine has been associated with symptomatic relief in both conditions. Thus, factors that can trigger attacks in patients with either asthma or variant angina are stimulation of cholinergic receptors with acetyl choline or methacholine, or serotonin receptors with serotonin or ergonovine, or histamine receptors with histamine.1Ginsburg R Bristow MR Kantrowitz N Baim DS Harrison DS Histamine provocation of clinical coronary artery spasm. Implications concerning pathogenesis of variant angina.Am Heart J. 1981; 102: 819Abstract Full Text PDF PubMed Scopus (181) Google Scholar, 2Resnekov L Calcium antagonist drugs.Chest. 1980; 78: 121Abstract Full Text Full Text PDF Google Scholar, 6Townley RG Mechanisms and management of bronchial asthma.in: Walber P Practice of medicine. Vol 1. Harper & Row, Hagerstown, Maryland1979Google Scholar Finally, an additional three factors known to induce episodes of asthma or variant angina include exercise, hyperventilation, and exposure to cold. In the case of asthma, it is now clear that exercise-induced asthma is a direct result of heat loss from the airway and can be elicited by hyperventilation while breathing cold air.7Deal EC Wasserman SI Soter NA Ingram RH McFadden ER Evaluation of the role played by the mediators of immediate hypersensitivity in exercise induced asthma.J Clin Invest. 1980; 65: 659Crossref PubMed Scopus (82) Google Scholar A primary mechanism common to all of the neurotransmitters and physical factors that elicit smooth muscle contraction in variant angina or asthma is an increased free calcium in the cytoplasm. Thus, all muscle contracts and relaxes according to increases and decreases of intracellular free calcium. In this regard, various neurotransmitters that can evoke coronary and bronchial spasm could do so through a common mechanism of activating receptor-operated (eg, serotonin-stimulated) calcium channels and eventuating an increased intracellular calcium which initiates the contractile response. The provocation of bronchospasm or coronary vasospasm with the neurotransmitters acetylcholine, serotonin or histamine may activate specific receptors that open calcium channels. The cytoplasmic concentration of free calcium appears to be the primary intracellular signal controlling smooth muscle tissue tonus. However, the cyclic nucleotides play a role in modulating the intracellular availability of calcium. An increase in cAMP, whether by stimulation of adenylate cyclase with beta-adrenergic agonists or inhibition of phosphodiesterase by theophylline, have been shown to relax smooth muscle. Many of the phosphodiesterase inhibitors such as theophylline are reported to be “calcium antagonists.”8Schultz G Possible interrelations between calcium and cyclic nucleotides in smooth muscle.in: Lichtenstein LM Austen KF Asthma, physiology, immunopharmacology, and treatment. Academic Press, New York1977Google Scholar Additionally, stimulation of alpha2 adrenergic receptors results in a decrease in adenyl cyclase and cAMP, and an influx of calcium, eg, in platelets with resultant platelet aggregation.8Schultz G Possible interrelations between calcium and cyclic nucleotides in smooth muscle.in: Lichtenstein LM Austen KF Asthma, physiology, immunopharmacology, and treatment. Academic Press, New York1977Google Scholar Increased removal of calcium from the cytoplasm (and an increase in membrane potential) may contribute to the relaxant effect of cAMP. Beta-adrenergic blocking agents alone or in combination with alpha adrenergic stimulation would result in decreased removal of calcium and/or an increase in calcium influx, respectively. The exacerbation of asthma or variant angina by beta-adrenergic blocking agents could be explained by the above mechanism. Furthermore, the resultant adrenergic imbalance by beta-adrenergic blockade alone or in combination with alpha adrenergic stimulation has been shown in animal models of asthma,4Townley RG Trapani IL Szentivanyi A Sensitization to anaphylaxis and to some of its pharmacological mediators by blockade of the beta adrenergic receptors.).Allergy. 1967; 39: 177-397Abstract Full Text PDF Scopus (49) Google Scholar as well as in patients with allergic rhinitis9Townley RG McGeady S Bewtra A The effect of beta adrenergic blockade on bronchial sensitivity to acetyl-beta-methacholine in normal and allergic rhinitis subjects.J Allergy Clin Immunol. 1976; 57: 358-366Abstract Full Text PDF PubMed Scopus (45) Google Scholar and asthma10Ryo UY Townley RG Comparison of respiratory and cardiovascular effects of isoproterenol, propranolol and practolol in asthmatic and normal subjects.J Allergy Clin Immunol. 1976; 57: 12-24Abstract Full Text PDF PubMed Scopus (36) Google Scholar to increase the sensitivity to serotonin, histamine and methacholine. The calcium channel blocking agents inhibit or diminish transmembrane penetration of calcium in various cells such as cardiac muscle cells, a variety of smooth muscle cells, and secretory cells. As a consequence, calcium channel blocking agents can inhibit or reduce calcium-dependent activities of these cells, eg, contractility of smooth muscle and/ or mast cell granule secretion. Both contraction of bronchial smooth muscle and secretion of mast cell granules are calcium-dependent and operative in asthma. Cobum11Coburn RF The airway smooth muscle cell.Fed Proc. 1977; 36: 2692-2697PubMed Google Scholar has shown that serotonin-induced contraction of canine tracheal muscle is inhibited by lanthanum and verapamil. These considerations led Cerrina et al12Cerrina J Denjean A Alexandre G Lockhard A Duroux P Inhibition of exercise-induced asthma by a calcium antagonist, nifedipine.Am Rev Respir Dis. 1981; 123: 156-160PubMed Google Scholar to investigate the effects of nifedipine, a calcium channel blocking agent, in exercise-induced asthma. Their results showed that exercise-induced asthma could be prevented by therapy with nifedipine without producing significant bronchodilation. Verapamil, by aerosol inhalation, has also been shown to be as potent as cromolyn sodium in exercise-induced asthma.13Patel KE Calcium antagonists in exercise induced asthma.Br Med J. 1981; 282: 932-933Crossref PubMed Scopus (130) Google Scholar The mechanism of exercise-induced or respiratory heat loss-induced asthma is unknown. It is conceivable that the protective effect of cromolyn sodium in exercise and in respiratory heat loss-induced asthma may be through a direct effect on calcium channels in the airway mucosa and smooth muscle which may be in addition to any effect on mast cell mediator release. Similarly, the beneficial effect of cromolyn sodium in allergic asthma may also be mediated through its action on calcium channels. Studies of calcium channel antagonists in bronchoprovocation and cold air-induced asthma should further elucidate the role of calcium and its relation to adrenergic and cholinergic mechanisms in asthma. The hyperreactivity of the airways to the various mediators such as acetylcholine, histamine, serotonin, and prostaglandin F2 alpha that occurs in asthma patients could have a common mechanism since they all require calcium for their smooth muscle stimulating activity. Thus, it is possible that airway hyperreactivity is due to a partial depolarization of the smooth muscle. Although the basic cause of the hypersensitivity is unknown, it suggests an increased permeability of smooth muscle cell membrane to calcium ions, which activate the contractile mechanism. If the critical pathogenetic pathways in asthma are ultimately related to free calcium-ion availability in smooth muscle, mast cells and mucous glands, it follows that effective therapy must reduce calcium availability to the essential contractile and secretory functions. Much of the information derived with respect to smooth muscle pharmacology may be relevant to calcium-ion involvement in mast-cell mediator release. Calcium ions play an important role in allergic reactions, mainly by relating to release mechanisms of chemical mediators from mast cells. The requirement for Ca2+ in the anaphylactic release of chemical mediators from target cells such as mast cells or basophils is well established. It has been suggested that antigen-antibody stimulus opens a calcium “gate” in the membrane, permitting an influx of Ca2+ ions.14Ishizaka T Foreman JC Sterk AR Ishizaka K Induction of calcium flux across the rat cell membrane by bridging IgE receptors.Proc Natl Acad Sci USA. 1979; 76: 5858-5862Crossref PubMed Scopus (71) Google Scholar Recently, Ishizaka et al14Ishizaka T Foreman JC Sterk AR Ishizaka K Induction of calcium flux across the rat cell membrane by bridging IgE receptors.Proc Natl Acad Sci USA. 1979; 76: 5858-5862Crossref PubMed Scopus (71) Google Scholar reported that increased phospholipid methylation of cell membrane induced by bridging of IgE receptors causes influx of Ca2+ into the cells and subsequent histamine release. A close relationship between the rate of histamine release and the amount of Ca2+ uptake has been observed in stimulated cells. When the entry of Ca2+ into target cells is inhibited by certain agents, histamine release from the cells is also inhibited. Theophylline also inhibits both the increase in calcium uptake and histamine release from mast cells. Thus, it seems possible that allergic reactions could be suppressed by inhibiting Ca2+ influx into target cells at the early stage of the release mechanism. The inhibitory effect of nifedipine, one of the calcium channel antagonists, has been observed on rat skin reactions, elicited by IgE antibody, and on the 45Ca uptake of rat peritoneal mast cells stimulated by IgE antibody, concanavalin A, compound 48/80 or Ca ionophore A23187. At the same time, the effect of nifedipine was compared to that of sodium cromolyn in rat skin reactions.15Tanizaki Y, Akagi K, Lee KN, Townley RG. Inhibitory effect of nifedipine on skin reactions and 45Ca uptake of mast cells induced by IgE antibody and various stimulating agents (in press)Google Scholar Nifedipine was 50 times as potent as cromolyn sodium in inhibiting the rat PCA reaction induced by IgE antibody. Skin reactions induced by histamine (1 mg) or methacholine (10 mg) were not inhibited by nifedipine or cromolyn sodium. Similarly, when mast cells from either actively or passively sensitized rats were stimulated with antigen, the 45Ca uptake and histamine release of the antigen-induced cells was significantly inhibited. The inhibitory effect of nifedipine was dose-dependent and biphasic.15Tanizaki Y, Akagi K, Lee KN, Townley RG. Inhibitory effect of nifedipine on skin reactions and 45Ca uptake of mast cells induced by IgE antibody and various stimulating agents (in press)Google Scholar Cromolyn sodium also similarly produces a dose-dependent and biphasic response. From these results, it seems reasonable to conclude that nifedipine inhibits allergic reactions mediated by IgE and certain mast cell stimulating agents by blocking the entry of Ca2+ into the target cells. In addition, these calcium channel blocking agents have a direct smooth muscle effect that provides an important investigative key to begin to unlock some of the intricate mechanisms of diseases like asthma and variant angina. To emphasize the molecular nature of these mechanisms in terms of channels in membranes, I would quote from Asher Rothstein:16Rothstein A Fashions in membranes.Ann NY Acad Sci. 1980; 358: 96-102Crossref Scopus (3) Google Scholar A channel’s a hole with a physiological role; A peptide chain in a lipid domain, with its helical coil twisted through oil, and its aqueous core an open pore. A path for flow where ions may go, if not too large with electrostatic charge.