Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Antiatherosclerotic effects of calcium channel blockers James R. Sowers MD To cite this article: James R. Sowers MD (1992) Antiatherosclerotic effects of calcium channel blockers, Postgraduate Medicine, 92:2, 265-268, DOI: 10.1080/00325481.1992.11701430 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701430
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [University of Technology Sydney]
Date: 23 July 2016, At: 01:09
Antiatherosclerotic effects of calcium channel blockers
Downloaded by [University of Technology Sydney] at 01:09 23 July 2016
James R. Sowers, MD
Preview
Risk factors for coronary
Conventional treatment of hypertension has done little to reduce mortality from coronary artery disease. In fact, some of the antihypertensive agents routinely prescribed appear to be atherogenic. In this article, Dr Sowers suggests that in addition to life-style changes and use of lipid-lowering agents, certain calcium channel blockers may inhibit the atherosclerotic process in hypertensive patients. Using the results of animal and human studies, he describes the antiatherogenic mechanisms of these agents.
artery disease
Hypenension is not just a hemodynamic disease. Rather, it involves a constellation of pathogenetically linked factors that contribute to the development of coronary anery disease. Despite the clear impact of antihypenensive treatment on monality from such noncoronary events as stroke, reduction of blood pressure has failed to appreciably lower the morbidity and monality associated with coronary artery disease. One proposed explanation for this failure is that some of the conventional antihypenensive agents may cause metabolic side effects-including lipid abnormalities, electrolyte disturbances, and glucose intolerance-that in some patients may offset the benefits of lowering high blood pressure. For example, some studies have shown that thiazide diuretics cause increases in low-density
lipoprotein (LDL) cholesterol, while others have indicated that beta blockers produce a reduction in high-density lipoprotein (HDL) cholesterol and an elevation in triglycerides. 1 Although these alterations are not quantitatively dramatic, varying from less than 5% to 15% depending on the study, they may be imponant in hypenensive patients with preexisting borderline lipid abnormalities. Results of some studies have also suggested that hypenensive patients have increased insulin resistance or decreased insulin sensitivity and that some medications can funher increase resistance or decrease sensitivity. 2 There is concern that this hyperinsulinemic, insulin-resistant state may lead to enhanced atherosclerosis. Animal studies have indicated that insulin itself can be atherogenic.
VOL 92/NO 2/AUGUST 1992/POSTGRAOUATE MEDICINE • CALCIUM
~
Risk factors for coronary anery disease include early hypenension that later becomes sustained; metabolic abnormalities, including dyslipidemia (very common in the hypenensive population), hyperinsulinemia, and insulin resistance; and obesity. The Tecumseh Blood Pressure Studyl examined the association between borderline hypenension and the development of sustained hypenension as well as ischemic hean disease in four groups of young people. The investigators found that a normotensive child whose weight is normal for his or her age has a good probability of remaining normotensive. However, an obese normotensive child has an increased likelihood of having sustained hypenension later in life, and an obese child with borderline high blood pressure is at even greater risk for becoming a hypenensive adult. The investigators concluded that both borderline hypenension early in life and obesity are predictors of sustained hypenension. In the Tecumseh study, metabolic abnormalities found to be predictors of ischemic hean disease included dyslipidemia (increased levels of total cholesterol and triglycerides and reduced levcontinued
265
Downloaded by [University of Technology Sydney] at 01:09 23 July 2016
It is becoming increasingly clear that not only obesity itself but also the type of obesity is an important risk factor for coronary artery disease.
els ofHDL cholesterol) and increased insulin levels. This hyperinsulinemic state in the presence of relatively normal glucose levels suggests an insulin-resistant state in young people in whom sustained hypenension and coronary anery disease later develop. It is becoming increasingly clear that not only obesity itself but also the type of obesity is an imponant risk factor for coronary anery disease. Central, or android, obesity carries a much higher risk of ischemic hean disease than peripheral, or gynecoid, obesity. It is associated with insulin resistance, hyperinsulinemia, and the characteristic lipid abnormalities seen in hypenension, namely, an elevation in very-low-density lipoprotein cholesterol and a reduction in HDL cholesterol. Diabetes, whether type II (insulin resistance) or type I (decreased insulin sensitivity), is associated, at least in animal models, with accelerated atherogenesis. A number of early processes involved in atherosclerosis may be activated in states of glu-
James R. Sowers, MD Dr Sowers is professor of medicine and physiology and director, endocrinology and hypertension division, Wayne State University School of Medicine, Detroit.
266
cose intolerance. These include increased platelet aggregation, increased damage to the endothelium, increased migration of monocyres to form macrophages in the intima, and migration of smooth-muscle cells into the intima, with increased proliferation of these cells.
Regression of coronary lesions Study results have indicated that both use of lipid-lowering agents and adoption of cenain life-style changes lead to the regression of coronary lesions. UPID-IDWERING AGENTS--
Several large studies have shown that correcting lipid abnormalities with medications can produce regression of coronary lesions. For example, in the placebocontrolled Cholesterol-Lowering Atherosclerosis Study,4 the effect of combination treatment with the bile acid sequestrant colestipol and nicotinic acid was examined in 162 men with severe coronary artery disease who had undergone bypass surgery. After 2 years of treatment, coronary angiography demonstrated regression of coronary lesions in 13 (16.2%) of the 80 treated men, compared with only 2 (2.4%) of the 82 controls. In the treatment group, total cholesterol fell26%, LDL cholesterol de-
creased 43%, and HDL cholesterol increased 37%. Brown and associates 5 demonstrated that in men with coronary anery disease and at high risk for cardiovascular events, intensive lipid-lowering pharmacologic therapy increased the frequency of regression oflesions and reduced the incidence of cardiovascular events. UFE-SIYLE CHANGES--The Lifestyle Hean Trial6 focused on the effects of nonpharmacologic treatment on coronary lesions. In this randomized study of 48 patients with severe coronary anery disease, 28 were treated with a strict vegetarian diet, a rigorous exercise regimen, and a stress management program. The other 20 patients received usual care. Computed coronary angiography was performed at baseline and 1 year later. The investigators found that regression of coronary lesions was strongly related to changes in life-style. They concluded that apart from positive changes in lipoprotein profiles, life-style changes had a significant impact on the regression of coronary lesions.
Role of calcium channd blockers in lesion regression According to findings in animals and humans, calcium channel
CALCIUM BLOCKERS • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
Downloaded by [University of Technology Sydney] at 01:09 23 July 2016
Calcium channel blockers may inhibit the atherogenic process through two types of mechanisms: their effect on intracellular levels of calcium and their effect on the metabolism of LDL cholesterol.
blockers may alter the atherosclerotic process. ANIMAL sruniFS-Calcium channel blockers may have antiatherosclerotic properties, at least in animal models. Henry and Benclef demonstrated that nifedipine, in large doses, inhibits the progression of early arterial lesions in the cholesterol-fed rabbit. Similar results have been noted with diltiazem and several of the dihydropyridines. 8 In 1984, Blumlein and colleagues9 conducted an important study in normotensive rabbits. They compared the antiatherogenicity of verapamil with that of the beta blocker metoprolol (which reduced cardiac output) and with that of the peripheral vasodilator hydralazine, in doses that produced small but comparable reductions in blood pressure. While verapamil had an inhibitory effect on the progression of the lesions, metoprolol and hydralazine did not. The investigators concluded that the effects of calcium channel blockers in altering the atherogenic process in rabbits were independent of their hemodynamic effects. Exploration of the possible antiatherogenic mechanisms of calcium channel blockers requires a review of the early steps of the atherogenic process. In the rabbit
model, early atherosclerotic lesions are basically foam cell lesions. Initial steps in the process include loss of endothelial integrity, migration of smooth-muscle cells from the tunica media into the intima, and migration of monocytes into the intima, where they become macrophages. Once the migrating smooth-muscle cells reach the intima, they are no longer contractile cells. Instead, they behave like proliferative cells, undergoing mitosis and increasing in number. They also lay down connective tissue, which forms the matrix of the atherosclerotic plaque. LDL cholesterol then accumulates in both the migrated smooth-muscle cells and the macrophages. Once these cells become lipid-laden, they are called foam cells. Calcium itself is an important second messenger not only for contraction of smooth-muscle cells but also for platelet aggregation. Calcium is involved in migration and proliferation of smooth-muscle cells, secretion of connective tissue, calcification, and necrosis, which are part and parcel of the atherosclerotic process. Calcium channel blockers may inhibit the atherogenic process through two types of mechanisms: their effect on intracellular
levels of calcium and their effect on the metabolism ofLDL cholesterol.8 Diltiazem, verapamil, and nifedipine have been shown to inhibit smooth-muscle cell proliferation, reduce DNA synthesis, and protect against injuryinduced endothelial damage in rabbits. 10 Calcium channel blockers have also been shown to inhibit cholesteryl ester deposition in macrophages, an effect that appears to be independent of their calcium blockade properties. 8 In addition to inhibiting lipid accumulation in both macrophages and smooth-muscle cells, these agents restrict calcium entry into atherosclerotic lesions. HUMAN SIUDIFS--Several studies have addressed the issue of how these animal data relate to humans. In a randomized, double-blind, placebo-controlled trial,'' 282 patients were treated with nifedipine or placebo for 3 years. Some of these patients were treated concomitantly with other medications that could also affect the atherosclerotic process. After 3 years, no significant effect on the progression of existing lesions was noted, but fewer new lesions had formed in the patients treated with nifedipine versus controls. Similar findings were demonstrated in a Canadian
continued
VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE • CALCIUIIIILOCICaRS
267
Downloaded by [University of Technology Sydney] at 01:09 23 July 2016
The current approach to treatment of hypertension should not be dictated solely by measures to lower blood pressure.
study of nicardipine. 12 In a recent prospective study by Schroeder and associates, 13 134 cardiac allograft recipients were randomized immediately after surgery to receive diltiazem or no calcium channel blocker (usual care). After about 20 months, coronary angiography in a mean of 22 vessel segments revealed narrowing of lumen diameter in the usual-care group but no significant change in the diltiazem group.
• Platelet aggregation • Migration of monocytes and smooth-muscle cells into the intima • Incorporation of low-density lipoprotein cholesterol into these cells • Matrix formation • Calcium overload in atherosclerotic lesions However, additional studies
are needed to delineate the antiatherogenic effects of these and other antihypertensive agents. lUI Address for correspondence: James R. Sowers, MD, Endocrinology and Hypertension Division, Wayne State University School of Medicine, University Health Center, 4201 St Antoine, Detroit, MI 4820 I.
References
Summary
Hypertension is a constellation of abnormalities, including metabolic disorders. The current approach to treatment of hypertension should not be dictated solely by measures to lower blood pressure. It must also take into consideration the effect of antihypertensive drug treatment on the development of atherosclerosis and many other important factors. Evidence from rabbit models and cell cultures indicates that calcium channel blockers are antiatherogenic through a variety of mechanisms. In addition to preserving endothelial function, these agents inhibit the following:
268
I. Sowers JR. Metabolic effect of diuretic therapy in hypertension. Intern Med Specialist 1988;9: 133-45 2. Swisloki AL, Hoffman 88, Reaven GM. Insulin resistance, glucose intolerance and hyperinsulinemia in patients with hypertension. AmJ Hypertens 1989;2(6 Pt 1):419-23 3. Julius S, Jamerson K, Mejia A, et a!. The association of borderline hypertension with target organ changes and higher coronary risk. The Tecumseh Blood Pressure Study. JAMA 1990; 264:354-8 4. Blankenhorn DH, Nessim SA, Johnson RL, et a!. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA 1987;257:3233-40 [erratum, JAMA 1988:259:2698] 5. Brown G, Albers JJ, Fisher LD, eta!. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Eng! J Med 1990;323: 1289-98 6. Omish D, Brown SE, Sherwitt LW, et a!. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet 1990; 336:129-33 7. Henry PD, Bcndey KI. Suppression of atherosclerosis in cholesterol-fed rabbit treated
with nifedipine. J Clin Invest 1981;68:1366-9
8. Sowers J, Zcmd PC, Zcmd MD, eta!. Hypertension and atherosclerosis: calcium antagonists as antiatherogenic agents. J Vase Med Bioi 1990;2:1-6 9. Blwnlein SL, Sievers R, Kidd P, eta!. Mechanism of protection &om atherosclerosis by verapamil in the cholesterol-fed rabbit. Am J Cardiol 1984;54:884-9
I 0. Hal7ib J8, Bossaller C, Wells S, et a!. Preservation of endothelium-dependent vascular relaxation in cholesterol-fed rabbit by treatment with the calcium blocker PN 200110. Circ Res 1986;58(2):305-9
II. Lichden PR, Hugenholtt P, IWHenbcul W, et a!. Retardation of the progression of coronary artery disease with nifedipine: results of INTACT. (Abstr) Circulation 1989;80(Suppl 11):11382 12. Waters D, Lesperance], Francetich M, et a!. A controlled clinical trial ro assess the effect of a calcium antagonist upon progression of coronary atherosclerosis. (Abstr) Circulation 1989;80(Supplll):II266
13. Schroeder JS, Gao SZ, Alderman EL, et a!. Diltiazem inhibits development of early accelerated transplant coronary disease: an interim report. (Abstr) Circulation 1990;82(Suppl III):III257
CALCIUM BLOCIURS • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Antiatherosclerotic effects of calcium channel blockers James R. Sowers MD To cite this article: James R. Sowers MD (1992) Antiatherosclerotic effects of calcium channel blockers, Postgraduate Medicine, 92:2, 265-268, DOI: 10.1080/00325481.1992.11701430 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701430
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [University of Technology Sydney]
Date: 23 July 2016, At: 01:09
Antiatherosclerotic effects of calcium channel blockers
Downloaded by [University of Technology Sydney] at 01:09 23 July 2016
James R. Sowers, MD
Preview
Risk factors for coronary
Conventional treatment of hypertension has done little to reduce mortality from coronary artery disease. In fact, some of the antihypertensive agents routinely prescribed appear to be atherogenic. In this article, Dr Sowers suggests that in addition to life-style changes and use of lipid-lowering agents, certain calcium channel blockers may inhibit the atherosclerotic process in hypertensive patients. Using the results of animal and human studies, he describes the antiatherogenic mechanisms of these agents.
artery disease
Hypenension is not just a hemodynamic disease. Rather, it involves a constellation of pathogenetically linked factors that contribute to the development of coronary anery disease. Despite the clear impact of antihypenensive treatment on monality from such noncoronary events as stroke, reduction of blood pressure has failed to appreciably lower the morbidity and monality associated with coronary artery disease. One proposed explanation for this failure is that some of the conventional antihypenensive agents may cause metabolic side effects-including lipid abnormalities, electrolyte disturbances, and glucose intolerance-that in some patients may offset the benefits of lowering high blood pressure. For example, some studies have shown that thiazide diuretics cause increases in low-density
lipoprotein (LDL) cholesterol, while others have indicated that beta blockers produce a reduction in high-density lipoprotein (HDL) cholesterol and an elevation in triglycerides. 1 Although these alterations are not quantitatively dramatic, varying from less than 5% to 15% depending on the study, they may be imponant in hypenensive patients with preexisting borderline lipid abnormalities. Results of some studies have also suggested that hypenensive patients have increased insulin resistance or decreased insulin sensitivity and that some medications can funher increase resistance or decrease sensitivity. 2 There is concern that this hyperinsulinemic, insulin-resistant state may lead to enhanced atherosclerosis. Animal studies have indicated that insulin itself can be atherogenic.
VOL 92/NO 2/AUGUST 1992/POSTGRAOUATE MEDICINE • CALCIUM
~
Risk factors for coronary anery disease include early hypenension that later becomes sustained; metabolic abnormalities, including dyslipidemia (very common in the hypenensive population), hyperinsulinemia, and insulin resistance; and obesity. The Tecumseh Blood Pressure Studyl examined the association between borderline hypenension and the development of sustained hypenension as well as ischemic hean disease in four groups of young people. The investigators found that a normotensive child whose weight is normal for his or her age has a good probability of remaining normotensive. However, an obese normotensive child has an increased likelihood of having sustained hypenension later in life, and an obese child with borderline high blood pressure is at even greater risk for becoming a hypenensive adult. The investigators concluded that both borderline hypenension early in life and obesity are predictors of sustained hypenension. In the Tecumseh study, metabolic abnormalities found to be predictors of ischemic hean disease included dyslipidemia (increased levels of total cholesterol and triglycerides and reduced levcontinued
265
Downloaded by [University of Technology Sydney] at 01:09 23 July 2016
It is becoming increasingly clear that not only obesity itself but also the type of obesity is an important risk factor for coronary artery disease.
els ofHDL cholesterol) and increased insulin levels. This hyperinsulinemic state in the presence of relatively normal glucose levels suggests an insulin-resistant state in young people in whom sustained hypenension and coronary anery disease later develop. It is becoming increasingly clear that not only obesity itself but also the type of obesity is an imponant risk factor for coronary anery disease. Central, or android, obesity carries a much higher risk of ischemic hean disease than peripheral, or gynecoid, obesity. It is associated with insulin resistance, hyperinsulinemia, and the characteristic lipid abnormalities seen in hypenension, namely, an elevation in very-low-density lipoprotein cholesterol and a reduction in HDL cholesterol. Diabetes, whether type II (insulin resistance) or type I (decreased insulin sensitivity), is associated, at least in animal models, with accelerated atherogenesis. A number of early processes involved in atherosclerosis may be activated in states of glu-
James R. Sowers, MD Dr Sowers is professor of medicine and physiology and director, endocrinology and hypertension division, Wayne State University School of Medicine, Detroit.
266
cose intolerance. These include increased platelet aggregation, increased damage to the endothelium, increased migration of monocyres to form macrophages in the intima, and migration of smooth-muscle cells into the intima, with increased proliferation of these cells.
Regression of coronary lesions Study results have indicated that both use of lipid-lowering agents and adoption of cenain life-style changes lead to the regression of coronary lesions. UPID-IDWERING AGENTS--
Several large studies have shown that correcting lipid abnormalities with medications can produce regression of coronary lesions. For example, in the placebocontrolled Cholesterol-Lowering Atherosclerosis Study,4 the effect of combination treatment with the bile acid sequestrant colestipol and nicotinic acid was examined in 162 men with severe coronary artery disease who had undergone bypass surgery. After 2 years of treatment, coronary angiography demonstrated regression of coronary lesions in 13 (16.2%) of the 80 treated men, compared with only 2 (2.4%) of the 82 controls. In the treatment group, total cholesterol fell26%, LDL cholesterol de-
creased 43%, and HDL cholesterol increased 37%. Brown and associates 5 demonstrated that in men with coronary anery disease and at high risk for cardiovascular events, intensive lipid-lowering pharmacologic therapy increased the frequency of regression oflesions and reduced the incidence of cardiovascular events. UFE-SIYLE CHANGES--The Lifestyle Hean Trial6 focused on the effects of nonpharmacologic treatment on coronary lesions. In this randomized study of 48 patients with severe coronary anery disease, 28 were treated with a strict vegetarian diet, a rigorous exercise regimen, and a stress management program. The other 20 patients received usual care. Computed coronary angiography was performed at baseline and 1 year later. The investigators found that regression of coronary lesions was strongly related to changes in life-style. They concluded that apart from positive changes in lipoprotein profiles, life-style changes had a significant impact on the regression of coronary lesions.
Role of calcium channd blockers in lesion regression According to findings in animals and humans, calcium channel
CALCIUM BLOCKERS • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
Downloaded by [University of Technology Sydney] at 01:09 23 July 2016
Calcium channel blockers may inhibit the atherogenic process through two types of mechanisms: their effect on intracellular levels of calcium and their effect on the metabolism of LDL cholesterol.
blockers may alter the atherosclerotic process. ANIMAL sruniFS-Calcium channel blockers may have antiatherosclerotic properties, at least in animal models. Henry and Benclef demonstrated that nifedipine, in large doses, inhibits the progression of early arterial lesions in the cholesterol-fed rabbit. Similar results have been noted with diltiazem and several of the dihydropyridines. 8 In 1984, Blumlein and colleagues9 conducted an important study in normotensive rabbits. They compared the antiatherogenicity of verapamil with that of the beta blocker metoprolol (which reduced cardiac output) and with that of the peripheral vasodilator hydralazine, in doses that produced small but comparable reductions in blood pressure. While verapamil had an inhibitory effect on the progression of the lesions, metoprolol and hydralazine did not. The investigators concluded that the effects of calcium channel blockers in altering the atherogenic process in rabbits were independent of their hemodynamic effects. Exploration of the possible antiatherogenic mechanisms of calcium channel blockers requires a review of the early steps of the atherogenic process. In the rabbit
model, early atherosclerotic lesions are basically foam cell lesions. Initial steps in the process include loss of endothelial integrity, migration of smooth-muscle cells from the tunica media into the intima, and migration of monocytes into the intima, where they become macrophages. Once the migrating smooth-muscle cells reach the intima, they are no longer contractile cells. Instead, they behave like proliferative cells, undergoing mitosis and increasing in number. They also lay down connective tissue, which forms the matrix of the atherosclerotic plaque. LDL cholesterol then accumulates in both the migrated smooth-muscle cells and the macrophages. Once these cells become lipid-laden, they are called foam cells. Calcium itself is an important second messenger not only for contraction of smooth-muscle cells but also for platelet aggregation. Calcium is involved in migration and proliferation of smooth-muscle cells, secretion of connective tissue, calcification, and necrosis, which are part and parcel of the atherosclerotic process. Calcium channel blockers may inhibit the atherogenic process through two types of mechanisms: their effect on intracellular
levels of calcium and their effect on the metabolism ofLDL cholesterol.8 Diltiazem, verapamil, and nifedipine have been shown to inhibit smooth-muscle cell proliferation, reduce DNA synthesis, and protect against injuryinduced endothelial damage in rabbits. 10 Calcium channel blockers have also been shown to inhibit cholesteryl ester deposition in macrophages, an effect that appears to be independent of their calcium blockade properties. 8 In addition to inhibiting lipid accumulation in both macrophages and smooth-muscle cells, these agents restrict calcium entry into atherosclerotic lesions. HUMAN SIUDIFS--Several studies have addressed the issue of how these animal data relate to humans. In a randomized, double-blind, placebo-controlled trial,'' 282 patients were treated with nifedipine or placebo for 3 years. Some of these patients were treated concomitantly with other medications that could also affect the atherosclerotic process. After 3 years, no significant effect on the progression of existing lesions was noted, but fewer new lesions had formed in the patients treated with nifedipine versus controls. Similar findings were demonstrated in a Canadian
continued
VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE • CALCIUIIIILOCICaRS
267
Downloaded by [University of Technology Sydney] at 01:09 23 July 2016
The current approach to treatment of hypertension should not be dictated solely by measures to lower blood pressure.
study of nicardipine. 12 In a recent prospective study by Schroeder and associates, 13 134 cardiac allograft recipients were randomized immediately after surgery to receive diltiazem or no calcium channel blocker (usual care). After about 20 months, coronary angiography in a mean of 22 vessel segments revealed narrowing of lumen diameter in the usual-care group but no significant change in the diltiazem group.
• Platelet aggregation • Migration of monocytes and smooth-muscle cells into the intima • Incorporation of low-density lipoprotein cholesterol into these cells • Matrix formation • Calcium overload in atherosclerotic lesions However, additional studies
are needed to delineate the antiatherogenic effects of these and other antihypertensive agents. lUI Address for correspondence: James R. Sowers, MD, Endocrinology and Hypertension Division, Wayne State University School of Medicine, University Health Center, 4201 St Antoine, Detroit, MI 4820 I.
References
Summary
Hypertension is a constellation of abnormalities, including metabolic disorders. The current approach to treatment of hypertension should not be dictated solely by measures to lower blood pressure. It must also take into consideration the effect of antihypertensive drug treatment on the development of atherosclerosis and many other important factors. Evidence from rabbit models and cell cultures indicates that calcium channel blockers are antiatherogenic through a variety of mechanisms. In addition to preserving endothelial function, these agents inhibit the following:
268
I. Sowers JR. Metabolic effect of diuretic therapy in hypertension. Intern Med Specialist 1988;9: 133-45 2. Swisloki AL, Hoffman 88, Reaven GM. Insulin resistance, glucose intolerance and hyperinsulinemia in patients with hypertension. AmJ Hypertens 1989;2(6 Pt 1):419-23 3. Julius S, Jamerson K, Mejia A, et a!. The association of borderline hypertension with target organ changes and higher coronary risk. The Tecumseh Blood Pressure Study. JAMA 1990; 264:354-8 4. Blankenhorn DH, Nessim SA, Johnson RL, et a!. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA 1987;257:3233-40 [erratum, JAMA 1988:259:2698] 5. Brown G, Albers JJ, Fisher LD, eta!. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Eng! J Med 1990;323: 1289-98 6. Omish D, Brown SE, Sherwitt LW, et a!. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet 1990; 336:129-33 7. Henry PD, Bcndey KI. Suppression of atherosclerosis in cholesterol-fed rabbit treated
with nifedipine. J Clin Invest 1981;68:1366-9
8. Sowers J, Zcmd PC, Zcmd MD, eta!. Hypertension and atherosclerosis: calcium antagonists as antiatherogenic agents. J Vase Med Bioi 1990;2:1-6 9. Blwnlein SL, Sievers R, Kidd P, eta!. Mechanism of protection &om atherosclerosis by verapamil in the cholesterol-fed rabbit. Am J Cardiol 1984;54:884-9
I 0. Hal7ib J8, Bossaller C, Wells S, et a!. Preservation of endothelium-dependent vascular relaxation in cholesterol-fed rabbit by treatment with the calcium blocker PN 200110. Circ Res 1986;58(2):305-9
II. Lichden PR, Hugenholtt P, IWHenbcul W, et a!. Retardation of the progression of coronary artery disease with nifedipine: results of INTACT. (Abstr) Circulation 1989;80(Suppl 11):11382 12. Waters D, Lesperance], Francetich M, et a!. A controlled clinical trial ro assess the effect of a calcium antagonist upon progression of coronary atherosclerosis. (Abstr) Circulation 1989;80(Supplll):II266
13. Schroeder JS, Gao SZ, Alderman EL, et a!. Diltiazem inhibits development of early accelerated transplant coronary disease: an interim report. (Abstr) Circulation 1990;82(Suppl III):III257
CALCIUM BLOCIURS • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
