oural of Candela Pharmacies TSunplAvSI2-SIS'6 1990 Raven res, Lut New York Calcium Channel Blockers and Atherosclerosis Philip D. Henry Department of Medicine, and Deparment of Molecular Physiology and Biophysics Baylor College of Medicine, Houston, Texas, U.S.A ‘Summary: There is evidence that calcium antagonists (cal- cium channel blockers) may suppress atheroma formation in animals fed high-fat diets. Studies on the antiatheroscle- roti effects of calcium blockers have suggested a variety of| possible mechanisms: (a) lowering of arterial pressure, (b) ecrease in atherogenic plasma lipoproteins, () suppres- sion of accumulation of intracellular lipids, (4) suppression ‘of atherogenic platelet dysfunction, (e) prevention of dys- lipidemic endothelial injury. (f) inhibition of chemotaxis ‘and cell migration, (g) inhibition of cell proliferation, (h) inhibition of deposition of matrix protein, (i) suppression ‘of tissue mineralization, and (j) retardation of cell ne- ferosis. Although it is tempting to ascribe the antiathe ‘There is considerable evidence that calcium chan- nel blockers may exert antiatherosclerotic effects in animals fed high-fat diets (1-3). In several studies, ‘drugs such as nifedipine (4), verapamil (5), or dilt ‘zem (6) have been reported to suppress the formation of atherosclerotic lesions developing within weeks after the onset of cholesterol feeding. In one study, however, nifedipine inhibited the progression of atl erosclerasis in Rhesus monkeys over a I-year period (7). Two controlled clinical trials using quantitative coronary arteriography to monitor the progression of coronary atherosclerosis in patients with symptom- atic ischemic heart disease have been recently completed (8,9). Preliminary reports indicate that treatment with nifedipine (8) or nicardipine (9) sup- pressed the development of new occlusive lesions. ‘These recent findings in subhuman primates and humans have generated new interest in the study of calcium channel blockers as antiatherogenic agents. In this article, we will briefly review possible mecha- nisms by which calcium channel blockers could influ- cence the progression of atherosclerosis (Table 1). LOWERING OF ARTERIAL PRESSURE In our initial study, we considered the possibility that calcium channel blockers exerted antiathero- sclerotic effects of calcium blockers to a blockade of cal cium channels, other possible common mechanisms of action involving low-affinity drug-binding sites must be considered. Recently, two randomized, prospective clinical ‘Wials designed to determine the effects of calcium channel blockers on the progression of coronary artery disease have ‘been completed. Results of the trials suggest that calcium channel blockers suppressed the progression of coronary atherosclerosis. The uilty of calcium channel blockers for ‘the treatment of atherosclerosis will equire further evalua- tion. Key Words: Calcium channel blockers—Atheroscle- rosis—Lipids. genic effects by reducing arterial pressure, an impor- tant determinant of atherogenesis (4). Although the cholesterol-fed rabbits received large doses of nifedi- pine, the treatment evoked only modest hypotensive effects. Therefore, it did not appear that the lowering of arterial pressure was a prominent effect of the treatment. Similarly, Blumlein et al. (10) concluded that the antiatherosclerotic effects of verapamil in cholesterol-fed rabbits were unrelated to a reduction in arterial pressure, More recently, we observed that isradipine in a low dose (<0.3 mg/kg of body weight/ day) suppressed atherogenesis in cholesterol-fed rab- bits without producing measurable decreases in arte- rial pressure (11), DECREASES IN ATHEROGENIC LIPOPROTEIN Calcium channel blockers have been used exten- sively since their introduction in the 1960s, but thus far consistent effects of these drugs on lipoprotein levels have not been demonstrated. Nevertheless, one must consider the possibility that calcium channel blockers could influence atherogenic lipoproteins [Lp(a), modified (oxidized) low-density lipoprotein (LDL), postprandial remnants} not measured in the usual clinical setting. In two recently completed pla- [Address correspondence and reprint requests to Dr. P.D. Henry at Baylor Collegeof Medicine, One Baylor Paza Suite S13E, Houston, TX 77030,USA.Ca BLOCKERS AND ATHEROSCLEROSIS S13 TABLE 1. Possible antiatheroscleraic mechanisms ‘of action of ealeium channel blockers ‘Lowering of arterial pressure Decrease in atherogenic plasma lipoproteins ‘Suppression of accumulation of intracellular iid Suppression of atherogenic placer dysfunction Prevention of dslipidemic endothelial injury Inhibition of chemotaxis and cell migration Inhibition of ell proliferation Inhibition of depesition of matrix proteins Suppression of tissue mineralization Retardation of ell necrosis cebo-controlled clinical trials, nifedipine and nicardi- pine did not appear to have appreciable effects on total cholesterol, LDL-cholesterol, or HDL-choles- terol (8,9). In the majority of studies with choles- terol-fed rabbits, calcium channel blockers were not found to exert hypolipidemic effects (1-3). In two reports, however, nicardipine (12) and diltiazem (13) reduced very-low-density lipoprotein (VLDL) levels. In one study, nicardipine reduced LDL and increased high-density lipoproteins (HDL) levels in fat-fed rats (14). SUPPRESSION OF ACCUMULATION OF INTRACELLULAR LIPIDS Stein et al. (15) have demonstrated that high con- centrations of verapamil (50 iM) can inhibit recep- tor-dependent uptake of LDL by fibroblasts in cul- ture. They theorized that increased uptake and metabolization of LDL could reduce the adverse ef- fects of LDL accumulating in the extracellular space. Corsini et al. (16) likewise have reported enhanced LDL uptake by fibroblasts exposed to verapamil Etingin and Hajar (17) have shown that submicro- molar concentrations of nifedipine promote the ef- flux of cholesterol from fat-laden rabbit vascular smooth muscle cells in culture. They ascribed the effect to a cyclic AMP-dependent activation of lyso- somal cholesterol ester hydrolase activity. In a subse- {quent study, these authors obtained aortic biopsies from patients undergoing open heart surgery and demonstrated that aortic cholesterol ester hydrolase activity was higher in patients treated preoperatively with calcium channel blockers compared to un- treated controls (18). Schmitz etal. (19) observed that fat-laden mouse macrophages in culture excreted lipid-rich lamellar bodies after addition of 2 uM ni- fedipine to the medium. SUPPRESSION OF ATHEROGENIC PLATELET DYSFUNCTION Studies of the effects of calcium channel blockers on platelet function in vitro and in vivo have yielded conflicting results (3). In vitro. dihydropyridine cal- ‘cium channel blockers have exerted inconsistent an- tiaggregatory effects (3). Verapamil in high concen- trations (>10 wif) has been repeatedly shown to inhibit aggregation, but this effect may be related to local anesthetic and az-adrenergic blocking effects of the drug. Rabbit platelet cyclic AMP phosphodiester- ase activity is inhibited by verapamil, diltiazem, and nifedipine, but substantial inhibition occurs only with very high drug concentrations (> 100 x87) (20). In vivo, nifedipine has been reported to suppress aggregability in patients with coronary disease (21) Such effects need not represent direct effects on plate- lets, as calcium channel blocker-induced vasodilation may decrease activation of platelets passing through the microcirculation of an ischemic organ. PREVENTION OF DYSLIPIDEMIC ENDOTHELIAL INJURY According to current concepts, endothelial injury plays a pivotal role in the pathogenesis of atheroscle- rosis, Betz et al. (22) have implanted electrodes on the carotid arteries of rabbits and showed that repeated electrical stimulation produced an endothelial hyper- permeability. Treatment of the rabbits with flunari- zine, anipamil, and nimodipine partly prevented the induced hyperpermeability. Tedgui et al. (23) mea- sured albumin flux across isolated, perfused rabbit aortas and were able to demonstrate decreased mac- romolecular permeation when nicardipine was added to the perfusate. In one study, we demonstrated that arteries from cholesterol-fed rabbits have an impaired endothelium-dependent relaxation that could be in part prevented by treating the rabbits with isradi- ine (11), INHIBITION OF CHEMOTAXIS AND CELL MIGRATION Calcium channel blockers have been shown to in- hibit the migration of cultured vascular smooth mus- cle cells in response to chemoattractants such as 12- HETE or zymosan-activated exudate (24,25). Of interest are the very low concentrations (<10~" M) of calcium channel blockers (nilvadipine, nicardi- pine) required to inhibit migration, INHIBITION OF CELL PROLIFERATION An essential process in the formation of atheroma- tous lesions is cell proliferation. Calcium channel blockers have been shown to inhibit smooth muscle proliferation in vitro and in vivo, Stein et al. (26) have shown that high concentrations (>10 uM) of verapamil may inhibit the proliferation of vascular smooth muscle in culture as assessed by ("H]thymi dine incorporation into DNA. Jackson et al. (27) demonstrated that the proliferation response of rabbit aortas evoked by injuring the artery with a balloon catheter can be suppressed by treatment with nifedi- pine. Similarly. the proliferation response developed J Cardona Pharmac Fo. 16 Sah, 1660sit by rabbit carotid arteries surrounded by a plastic cuf? is inhibited by calcium channel blockers (28) INHIBITION OF THE DEPOSITION OF MATRIX PROTEINS Weinstein and Heider (29) found that SO uM is- radipine inhibited the synthesis of glycosaminogly- ns and collagen in monkey aortic smooth muscle cells in culture. Decreased production of matrix pro- teins by cells (fibroblasts) not thought to possess volt- age-dependent (dihydropyridine-sensitive) calcium channels were interpreted to indicate a calcium- channel-independent pharmacological mechanism of action. SUPPRESSION OF TISSUE MINERALIZATION Fleckenstein et al. (30) were the first to report that vascular calcinosis induced in rats by injection of vi- tamin D, (500,000 IU/kg of body weight) was partly prevented by treating the rats with verapamil. Other calcium channel blockers, in particular nilvadipine, appear to exert similar protective effects (31). Hyper- calcemia and diffuse metastatic calcification evoked by vitamin D poisoning, however, is not a pathophys- iological feature of atherosclerosis in humans. RETARDATION OF CELL NECROSIS It has been proposed that necrosis of foam cells in fatty streaks plays a role in initiating the formation of proliferative lesions (32). Because calcium channel blockers may exert antinecrotic effects in a variety of syndromes (33), calcium channel blockers could re- tard foam cell necrosis and reactive proliferation (34), This hypothesis would explain the efficacy of calcium, channel blockers in treating foam cell lesions as seen in cholesterol-fed rabbits, However, experimental ev- idence for an antinecrotic effect of calcium channel blockers in atherosclerotic arteries has to our knowl- edge not been obtained. CONCLUSION ‘Over the past decade, evidence has accumulated that calcium channel blockers may suppress the de- velopment of atherosclerotic lesions. This action does not appear to depend on hypolipidemic effects. Cur- rent evidence suggests that calcium channel blockers may alter the uptake and release of lipid from fat- laden cells. The precise mechanism(s) of action of the drugs and their potential clinical utility for the treat- ment of atherosclerosis will require further evalua- tion. 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