Atherogenesis, calcium and calcium antagonists

Hyperchotesterolemia and arterial hypertension are highly interrelated risk factors of atherosclerosis. Early lesions in nonhuman primates with dietary hyperchotesterolemia resemble atherosclerotic lesions demonstrable in the arteries of American children with comparably elevated plasma cholesterol levels. Lesion formation depends upon calcium-regulated cellular processes such as chemotaxis, adhesion, migration, proliferation, lipid uptake and necrosis. Interventions acting on cell calcium uptake including treatment with calcium chelating agents, lanthanum trichloride, and calcium antagonists may retard atherogenesis in fat-fed animals in the absence of hypolipidemic effects. Recent controlled coronary angiographic trials in patients with coronary artery disease suggest that calcium antagonists may retard the progression of coronary atherosclerosis in humans. Large-scale long-term studies are needed to determine the utility of these agents for the treatment of coronary artery disease.     

Use of calcium antagonists for cardiac arrhythmias

Calcium antagonists have emerged as a new class of antiarrhythmic agents for the control of certain supraventricular and ventricular arrhythmias. Electrophysiologically, these agents are heterogeneous but their main action is mediated through a depressant effect on the slow calcium channel in cardiac muscle, most readily demonstrated in isolated tissue preparations. In vivo, their actions are modulated by their reflex actions and by their interaction with the autonomic nervous system due to the noncompetitive adrenergic-blocking actions that some of the compounds exhibit. The major agents exerting antiarrhythmic actions are verapamil, diltiazem, gallopamil, tiapamil and bepridil; the dihydropyridines are devoid of electrophysiologic actions in vivo. Calcium antagonists prolong intranodal conduction time, lengthen the effective and functional refractory periods in the atrioventricular node but exert little or no effect on atrial, ventricular, His-Purkinje or bypass tract conduction or refractoriness (except in the case of bepridil, which has additional electrophysiologic properties). These effects form the basis of the clinical antiarrhythmic effects of this class of agents. The most striking action is the predictable and prompt termination of the reentrant supraventricular tachycardia by intravenous verapamil and diltiazem and the slowing of the ventricular response in atrial flutter and fibrillation. These agents may also be of value in the long-term control of ventricular response in atrial flutter and fibrillation; their role in multifocal atrial tachycardia and other ectopic tachycardias is less well defined. Calcium antagonists reverse ischemic ventricular arrhythmias caused by coronary artery spasm but exert little or no action in the usual forms of sustained ventricular tachyarrhythmias associated with severe structural heart disease. They are poor suppressants of ventricular premature complexes. Recent data have established their role in exercise-induced tachycardia occurring in the context of ischemic heart disease; they are also of value in ventricular tachycardia occurring in young patients who develop tachycardia with a right bundle branch block and left axis deviation morphology, an arrhythmia thought to be due to triggered automaticity.     

Classification of calcium antagonists

Drugs of several chemical families have been identified as calcium antagonists. This article examines some pharmacologic properties of these drugs to clarify their terminology and their classification and to provide a rationale for their clinical use. Studies with nifedipine show quantitatively that the therapeutic effect in angina is related to the interaction of this drug with membrane calcium channels in human coronary arteries. This gives support to a classification based on studies at the molecular, tissue and organ levels. Among calcium antagonists, calcium entry blockers are defined as agents able to block calcium inward fluxes evoked by various stimuli. They may be subdivided in 2 groups. Group I is the group of selective calcium entry blockers. Group IA consists of those agents selective for slow calcium channels in myocardium (slow channel blockers); the leading agents are verapamil, nifedipine and diltiazem. Group IB contains agents without action on slow calcium channels in myocardium but with selective action on arteries; the leading agents are cinnarizine and flunarizine. Group II is the group of nonselective calcium entry blockers. Group IIA contains agents acting at similar concentration on calcium and on fast sodium channels. Group IIB consists of agents interacting with calcium channels while having another primary site of action. Other agents modulate calcium movements by an action on sodium-calcium exchange and by an action within the cell. Their identification requires the use of cell biology. The actual clinical uses of these drugs are consistent with this pharmacologic classification.     

Myocardial ischaemia calcium antagonists

Myocardial ischaemia calcium antagonists     

Controversies concerning calcium antagonists

Summary The paper discusses the controversial attitude regarding the safety of calcium channel blockers (CCBs), especially of the dihydropyridine nifedipine, induced through several meta-analyses of studies with CCBs by Dr. Furberg et al.; as a result, a detrimental effect of CCBs, especially during acute myocardial infarction, has been claimed. Several independent re-analyses of the 16 studies, all performed in the 1980s and mainly using the short-acting nifedipine capsule, did not confirm Furberg's results and showed an insignificant mortality difference between patients on CCBs versus those on control. Nevertheless, new safety studies applying long-acting CCBs (half-lives of 1 or more days) combined with efficacy assessments are necessary, both in hypertension as well as coronary artery disease, to finally clear up this important question.     

Cardioselectivity of calcium antagonists

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 ₁ 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.     

Pharmacology of calcium antagonists

Although the calcium antagonists verapamil, nifedipine, diltiazem and bepridil are structurally diverse, they share, to a variable extent, several pharmacologic properties. These effects are presumably the result of dose-related inhibition of transmembrane calcium ion flux through the slow channel. In diseased tissue, other routes of calcium entry may also be inhibited, and intracellular sites of action also are now strongly suspected. The calcium antagonists tend to relax vascular smooth muscle in a dose-dependent and site-specific manner. Effective coronary vasodilation is found with each agent; peripheral vasodilation is most pronounced with nifedipine, followed, in descending order of potency, by verapamil, diltiazem and bepridil. Atrioventricular conduction is also inhibited by diltiazem, bepridil and verapamil, whereas nifedipine paradoxically has no effect at therapeutic doses. The calcium antagonists also reduce muscle contractile force, but again in variable degrees. Negative inotropy is significant with verapamil and minimal with diltiazem and bepridil. Nifedipine often causes a reflex increase in contractility and heart rate. At therapeutic doses, bepridil has additional properties: it appears to affect sodium and perhaps potassium channels, producing a quinidine-like effect, and it prolongs the refractory period. Experimentally, bepridil has also been found to extend the duration of the action potential, raise the ventricular fibrillation threshold and possess both class I and class IV antiarrhythmic activity at relatively small doses. If documented clinically, bepridil may prove to be an effective antiarrhythmic as well as antianginal agent.     

Nitrates and calcium antagonists for silent myocardial ischemia

Continuous Holter monitoring of patients with coronary heart disease can show transient ischemic episodes occurring spontaneously with or without angina throughout the day. A controlled double-blind trial was conducted comparing the effects of isosorbide-5-mononitrate (IS-5-MN) and nifedipine in patients with documented transient ischemic episodes. Seventy-five percent of the ischemic episodes were not accompanied by pain. Twenty patients with documented coronary heart disease were included; 15 finished the 4-week study (1 patient had headaches, 1 thyrotoxicosis, 1 hypertensive crisis and 2 unstable angina). On a dual-channel FM-recorded electrocardiogram, ischemic episodes were counted when ST deviation was greater than 1 mm for greater than 1 minute. Patients received IS-5-MN (20 mg 3 times a day or 50 mg in a sustained-release tablet) or nifedipine (20 mg in a sustained-release tablet 3 times a day) in random order over four 1-week periods. At the end of each week, Holter monitoring was repeated and showed reductions of episodes by 67% and 67% after weeks of IS-5-MN therapy and 56% and 58% after weeks of nifedipine therapy (all p less than 0.05). Painful and painless episodes were reduced to a similar extent. Individual responses showed great variability, and in all treatment periods not more than half of the patients were completely free of ischemic episodes. One of the 12 patients did not respond to either way of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Usefulness of calcium antagonists for congestive heart failure

In patients with congestive heart failure (CHF) due to dilated cardiomyopathy, nifedipine, diltiazem and several of the newer calcium antagonists including nicardipine, nitrendipine, felodipine and PN 200-110 (isradipine) improve left ventricular function. Because of its relatively more pronounced negative inotropic and chronotropic actions, verapamil is generally not tolerated by patients with left ventricular failure. In addition, even relatively vascular-selective agents such as nifedipine can occasionally cause significant left ventricular depression, particularly if combined with beta-adrenergic blocking agents. Comparative studies using nitroprusside to cause an equivalent decrease in arterial pressure indicate that nifedipine acts predominantly on the arterial vasculature, and that a small but significant decrease in contractility occurs, apparently due to a direct myocardial action. Although diltiazem causes a depression in myocardial contractility in dogs with volume overload heart failure, limited data show no significant negative inotropic action in patients with heart failure. The negative inotropic effects, if any, of newer and possibly more vascular-selective agents are not yet known. Calcium antagonists appear to act predominantly on the limb and coronary vasculature, with relatively less effect on renal and hepatic vessels. In patients with CHF, nifedipine causes an increase in coronary blood flow and a decrease in the aorto-coronary sinus oxygen difference indicating an improvement in myocardial energetics. Although nifedipine causes an increase in cardiac index and decreases in systemic vascular resistance and pulmonary capillary wedge pressure during exercise, the limited data available fail to show a short- or long-term increase in exercise capacity. Nifedipine causes an increase in plasma renin activity, possibly due to a direct action on the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antiatherogenic properties of calcium antagonists

A generalized accumulation of cholesterol, calcium and matrix materials (collagen, elastin and proteoglycans) occurs in an age-dependent manner in major arteries. Human atherogenesis is a disease of arteries characterized by a focal accumulation of fibrous matrix elements, lipids and calcium at lesion sites. Studies in cholesterol-fed animal models have indicated that calcium competitors and chelating agents can reduce calcium, lipid and matrix accumulation in arterial lesions and reduce the extent of lesion formation. These agents generally alter soft and hard tissue calcium pools or have deleterious side-effect profiles. Antiatherogenic studies with calcium antagonists (which have been shown to be safe in human clinical studies) have created confusion because of conflicting results. It is apparent, however, that high doses of calcium antagonists can significantly decrease atherogenic lesion development in cholesterol-fed rabbits. The antiatherogenic effects of calcium antagonists may be the result of changes in intracellular calcium pools within smooth muscle cells, which may lead to alterations in cellular metabolic activity or may be due to activities not related to calcium channel effects. Several mechanisms involving regulation of lipoprotein receptor synthesis, lipoprotein uptake or degradation, cholesterol ester hydrolytic activity and arterial matrix synthesis are discussed as potential sites of activity for calcium antagonists. A dihydropyridine channel antagonist, PN 200-110 (isradipine), has been shown to be a very potent antiatherogenic agent in the rabbit and also to be a potent inhibitor of smooth muscle cell matrix synthesis.     

The search for calcium receptor antagonists (calcilytics)

The Ca(2+) receptor on the surface of parathyroid cells is the primary molecular entity regulating secretion of parathyroid hormone (PTH). Because of this, it is a particularly appealing target for new drugs intended to increase or decrease circulating levels of PTH. Calcilytic compounds are Ca(2+) receptor antagonists which increase the secretion of PTH. The first reported calcilytic compound was NPS 2143, an orally active molecule which elicits rapid, 3- to 4-fold increases in circulating levels of PTH. These rapid changes in plasma PTH levels are sufficient to increase bone turnover in ovariectomized, osteopenic rats. When administered together with an antiresorptive agent (estradiol), NPS 2143 causes an increase in trabecular bone volume and bone mineral density in osteopenic rats. The magnitude of these changes are far in excess of those caused by estradiol alone and are comparable with those achieved by daily administration of PTH or a peptide analog. These anabolic effects of NPS 2143 on bone are not associated with hyperplasia of the parathyroid glands. Calcilytic compounds can increase endogenous levels of circulating PTH to an extent that stimulates new bone formation. Such compounds could replace the use of exogenous PTH or its peptide fragments in treating osteoporosis.     

Smoking, calcium, calcium antagonists, and aging

Aging is characterized, besides other changes, by a progressive increase in calcium content in the arterial wall, which is enhanced by diabetes mellitus, osteoporosis, arterial hypertension, and tabagism. As to tabagism, experiments in animals have shown that nicotine can increase calcium content of the arterial wall, and clinical studies have demonstrated that cigarette smoking induces peripheral vasoconstriction, with consequent increase in blood pressure levels. In order to study the role of calcium ions in the pathogenesis of the vasoconstrictive lesions caused by "acute" smoking, the author has studied the peripheral vascular effects of the calcium-channel antagonist nifedipine, a dihydropyridine derivative, and calcitonin, a hypocalcemizing hormone which possess vasoactive actions on 12 elderly regular smokers (mean age 65.8 years). The results demonstrated that both nifedipine (10 mg sublingually 20 min before smoking) and salmon calcitonin (100 MRC U/daily intramuscularly for three days) are able to prevent peripheral vasoconstriction evaluated by Doppler velocimetry, as well as the increase of blood pressure induced by smoking. On the basis of our results, the author proposes that cigarette smoking-induced vasoconstriction is a calcium-mediated process, which can be hindered by drugs with calcium antagonist action.     

Renal hemodynamic effects of calcium antagonists

Recently, attention has focused on the effects of calcium antagonists on renal function. When administered in vitro to the isolated perfused kidney, calcium antagonists exhibit predictable actions allowing for characterization of their renal effects. Calcium antagonists do not affect the vasodilated isolated perfused kidney; however, they do dramatically alter the response of the kidney to vasoconstrictor agents. In the presence of norepinephrine, calcium antagonists markedly augment the glomerular filtration rate but produce only a modest improvement in renal perfusion. A study using the postischemic hydronephrotic rat kidney model that permits direct visualization of afferent and efferent arterioles, this study demonstrated that this preferential augmentation of the glomerular filtration rate is primarily attributable to a selective vasodilation of pre-glomerular vessels. Although the clinical implications of such observations are not yet clear, preliminary studies in experimental animal models indicate that calcium antagonists might exert salutary effects on renal function in clinical settings characterized by impaired renal hemodynamics. The possible benefits of calcium antagonists in ameliorating the development of renal dysfunction in patients in whom there is increased risk of acute renal insufficiency remain to be evaluated.