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The Effects of Various Antihypertensive Agents on Cardiovascular Risk Factors in Patients With Renal Failure
The Effects of Various Antihypertensive Agents on Cardiovascular Risk Factors in Patients With Renal Failure Mario Zarama, MD, and Leopoldo Raij, MD • Systemic cardiovascular diseases are the most important cause of morbidity and mortality among patients with chronic renal failure. Hypertension, lipid-profile abnormalities, glucose intolerance, and left ventricular hypertrophy are found in most patients with chronic renal failure and are responsible for the increased incidence of atherosclerosis. Hypertension is the risk factor most susceptible to treatment, but consideration must be given in selecting an antihypertensive agent not only to its effect on blood pressure but to its effects on the other risk factors. Improper selection could impair the long-term benefit of good blood pressure control by increasing the severity of the other cardiovascular risk factors and eventually worsening the prognosis of the chronic renal failure. The remaining renal function in patients not yet in end-stage renal failure deserves special consideration; an adequate antihypertensive regimen could potentially delay the need for dialysis. © 1993 by the National Kidney Foundation, Inc. INDEX WORDS: Cardiovascular risk factors; chronic renal failure; dyslipidemia; glucose intolerance; hypertension, left ventricular hypertrophy.
Toss OF kidney function is accompanied by .L many cardiovascular alterations that promote disease in other end organs and at the same time accelerate progression of renal disease. According to Framingham study data, the main risk factors for cardiovascular disease are hypertension (HTN), lipid disturbances, glucose intolerance, and left ventricular hypertrophy (L VH), 1 these factors being synergistic. Many of these risk factors complicate the course of chronic renal failure. Hypertension is a major risk factor for cardiovascular disease (CVD), disability, and premature death in the general population,2.3 and mortality increases with increasing blood pressure levels. 2,4 Hypertension typically complicates the course of chronic renal failure (CRF),5 and is an important factor in the progression of renal injury;6 HTN control can delay the progression of CRF. 7 Hypertension in CRF is multifactorial and is related to positive sodium balance and the increased activity of both the renin-angiotensin-aldosterone system and the sympathetic nervous system. Concomitant reduction in vasodilator substances may also contribute. 8 In fully established HTN, cardiac output is decreased by as From the Department o/Medicine. Veterans Affairs Medical Center and University olMinnesota. Minneapolis, MN. Address reprint requests to Leopoldo Raij, MD. Chief, Nephrology/Hypertension. Veterans Affairs Medical CenterRenal Section 11 JJ. One Veterans Dr. Minneapolis, MN 55417. © 1993 by the National Kidney Foundation. Inc. 0272-6386/93/2105-2019$3.00/0
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much as 25%, systemic vascular resistance (SVR) is increased by 25% to 30%,9-12 and intravascular volume is variable. 12 In patients with CRF, poorly treated HTN fosters cerebrovascular accidents (CVA), congestive heart failure, and coronary artery disease (CAD)2,4 and accelerates renal insufficiency. Some of these complications are closely related to development of atherosclerotic changes in the different target organs. 13 Control of HTN reduces cardiovascular morbidity and mortality, particularly that related to CVA. 14 Evidence supporting the notion that treatment of HTN reduces CAD has been elusive;15 however, the Systolic Hypertension in the Elderly Patient (SHEP) Cooperative Research Group has recently shown that morbility and mortality associated with CAD and CVD were significantly reduced with antihypertensive therapy (27% and 32%, respectively) and total mortality was lowered by 13%.14,16 In dialysis patients, strict control of both blood pressure and dry body weight has been associated with a lower incidence of deaths attributable to CV A or myocardial infarction. 15,16 Lipid abnormalities are well-known cardiovascular risk factors in CRF patients. 3 Hypertriglyceridemia is the most common lipid abnormality and may occur in patients with mild to moderate renal insufficiency. 17-19 The prevalence of hypertriglyceridemia increases as the glomerular filtration rate (GFR) declines. 19 The mechanism of hypertriglyceridemia is not fully understood; however, most data suggest that
American Journal of Kidney Diseases, Vol 21, No 5, Suppl 2 (May). 1993: pp 100-107
EFFECTS OF ANTIHYPERTENSIVE AGENTS ON CARDIOVASCULAR RISK FACTORS
reduced lipolysis of triglyceride (TG)-rich lipoproteins is due to deficient lipoprotein lipase activity.20- 25 Evidence suggests that alteration in endothelial lipoprotein lipase plays a more important role in the pathogenesis of hypertriglyceridemia in dialysis patients than alterations in the hepatic TG lipase. 26 Factors that may explain the decrease in lipoprotein lipase activity in CRF and end-stage renal failure (ESRF) include the presence of an inhibitor of lipolytic enzymes in uremic serum,27-30 insulin resistance,31 and diminished hepatic protein synthesis in uremia. 32 The contribution of hypertriglyceridemia to CAD is uncertain. The Framingham study initially rejected a relationship between CAD and hypertriglyceridemia, but now data from the same study indicate treatment of hypertriglyceridemia. 33 .34 The role of TG in atherosclerosis is unclear,35-37 although it is possible that they contribute somewhat to the lipid component of the atherosclerotic plaque: The abnormal metabolism of TG raises the concentration of very-low density lipoprotein (VLDL) and low-density lipoprotein (LDL) and reduces the level of highdensity liproprotein (HDL)-metabolic changes that are known to promote atherogenesis. 25 ,38-43 Low levels ofHDL are present in 50% to 75% of CRF patients,44-48 which has been attributed to a faster-than-normal catabolic rate49 ,50 as well as to a low synthetic rate ofHDL,51-53 Recent studies have shown an increase in lipoprotein(a) in CRF patients, Lipoprotein(a) is atherogenic;54 hence, the increased Lipoprotein(a) and decreased HDL may favor accelerated atherogenesis in this population,55,56 Experimental evidence suggests close interaction between dyslipidemia and HTN in vascular injury.57,58 This may explain the increased incidence of CAD and CVD in ESRF patients; in addition, coexistence of HTN and dyslipidemia may contribute to progression of renal failure, 59 Factors other than those already described may also be responsible for the increased cardiovascular morbidity and mortality observed in CRF patients. These include smoking, electrolyte abnormalities (eg, diuretic-induced hypokalemia), hemostasis abnormalities, circulating arterial toxins,41 carnitine deficiency,60 and perhaps use
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of certain drugs, such as androgens, tJ-blockers, and diuretics. 61 -64 It has been proposed that abnormal glucose tolerance is associated with increased risk for CVD. 34,65-67 Mild glucose intolerance has been documented in 50% of CRF patients 68,70 and attributed to both peripheral resistance to the action of insulin and impaired insulin secretion associated with secondary hyperparathyroidism.71 As long as diabetes mellitus is not the cause of the glucose intolerance, this metabolic abnormality improves upon initiation of dialysis. 72 There is a high incidence of LVH (60% to 90%) among patients with CRF, most of them aquiring it before starting dialysis. 68 ,73 Factors associated with LVH are HTN, anemia, age, and aluminum accumulation. Some evidence suggests that LVH may be due in part to "uremia.,,74 Regression of L VH has been reported after blood pressure control,15 erythropoietin administration,76 and renal transplantation. 77 Left ventricular hypertrophy is associated with increased ventricular ectopic activity (a possible cause of sudden death),78 with diastolic dysfunction of the left ventricle/ 9 and with angina. 8o ANTIHYPERTENSIVE THERAPY IN RENAL FAILURE PATIENTS
The main goal of antihypertensive therapy is to obtain hemodynamic and metabolic stability. There are many drugs available to treat HTN, but their secondary effects at times limit their use in CRF patients. Antihypertensive drug selection in CRF patients must take into account the effects of the medication on lipids, glucose tolerance, hemodynamic status, and remaining renal function (Table I). We will briefly review the most important antihypertensive drugs currently in use, describing their basic mechanism of action and their effects on cardiac output, SVR, renal vasculature, and cardiovascular risk factors.
Diuretics These agents have been widely used to control HTN. 81 Initially they decrease intravascular volume, cardiac output, GFR, and renal blood flow and increase heart rate; however, after 8 to 10
ZARAMA AND RAIJ
102 Table 1. Interaction Between Antihypertensive Medications and Cardiovascular Risk Factors in Chronic Renal Failure
Medication
Calcium channel blockers ACE inhibitors Central £1'2 adrenergic agonist Peripheral £1'1 adrenergic antagonist (3-blockers-ISA (3-blockers-non-ISA Vasodilators Thiazides
Lipid Levels
Glucose Tolerance
LVH
N
+
+ +/N
+ +
N
N
+
+
N
N N
+ N/-
N
-IN
Variable
N/-
Abbreviations: LVH, left ventricular hypertrophy; ACE inhibitors, angiotensin-converting enzyme inhibitors; ISA, intrinsic sympathomimetic activity; (+), benefit; (N), no effect; (-), negative.
weeks of treatment, SVR, cardiac output, and intravascular volume return to normal. 82 ,83 Diuretic-induced hypokalemia or hypomagnesemia increases the probability of ventricular fibrillation in patients with abnormal myocardial function. 84.85 Diuretic-induced hypokalemia may impair endothelium-dependent vascular relaxation 81 ,86.88 and worsen endothelial dysfunction due to long-standing HTN and/or atherosclerosis. 89 ,90 Thiazides tend to induce lipid abnormalities. 91 In fact, diuretics and /3-blockers may have adverse effects on lipoprotein metabolism, which may partially offset the antiatherosclerotic benefits of blood pressure lowering. They increase TG, total cholesterol, and LDL-cholesterol levels but apparently bring no change in HDL-cholesterol levels. 63 .64 ,92 Thiazides may induce hyperglycemia and abnormal glucose tolerance 93 and increase hemoglobin A lc . 63 ,85 Loop diuretics appear to be relatively safer in relation to hyperglycemia. 63 .93 /3-Adrenergic Blockers
These agents act both by competitive inhibition of catecholamine /3-receptors in juxtaglomerular cells and in the presynaptic sympathetic nervous system, and by inhibition of sympathetic outflow at the central nervous system
level. 94 The agents decrease heart rate, cardiac output, and SVR.95 The effect of /3-blockers on lipid profile is related to whether they have intrinsic sympathomimetic activity (ISA). Those without ISA increase TG, LDL, and VLDL levels and decrease HDL levels,95.97 probably by impairing lipoprotein lipase activity.5I ,97.98 Those with ISA do not show any significant unfavorable effect on lipids. The lipid changes induced by different /3-blockers has been reviewed recently by Houston. 84 /3-blockers without ISA may induce carbohydrate intolerance or exacerbate diabetes mellitus;99.100 this is probably secondary to inhibition of insulin secretion, glucose utilization, decreased peripheral sensitivity to insulin, increased hepatic glucogenolysis, and elevation of growth hormone. IOI These effects on glucose metabolism appear less pronounced with the use of agents with ISA. 84,99.100 There is no consistent information regarding the action of /3-blockers on L VH;84 however, recent studies have shown that atenolol reduces LVH.102 Central a2 Adrenergic Agonists
These drugs act on presynaptic and postsynaptic a2 receptors at midbrain and medulla. 103 Methyldopa, clonidine, guanabenz, and guanfacine are included in this group. The drugs decrease heart rate, SVR, and probably cardiac output. I04 With the exception of methyldopa, they have a neutral effect on serum lipids. 84 They do not induce hyperglycemia,84,105.106 and they reduce L VH. I07 They have no significant effect on GFR, the ratio of effective renal plasma flow to renal blood flow (ERPF/ RBF); renal vascular resistance (RVR) is reduced, probably in response to reduced levels of circulating catecholamines. 108 Peripheral arAdrenergic Antagonists
These agents inhibit postjunctional ai-receptors.109 They have a favorable effect on lipids, decreasing total cholesterol, TG, LDL, and VLDL and increasing HDL cholesterol levels. 84 ai-Antagonists may increase lipoprotein lipase activity.51.98 They do not induce hyperglycemia I10 and may decrease L VH.84, III Prazosin, terazosin, and indoramin are included in this group.
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EFFECTS OF ANTIHYPERTENSIVE AGENTS ON CARDIOVASCULAR RISK FACTORS
Table 2. Hazards of Antihypertensive Therapy in Renal Insufficiency
Problem
Origin
Causal Agents
Rapid decline in renal function Hyperkalemia Overdose
Too rapid or extreme decrease in pressure Bilateral renal artery stenosis Decreased K+ secretion Accumulation of drugs excreted by kidney
Any ACE-Inhibitors, calcium channel blockers K+ -sparing diuretics; ACE-inhibitors Atenolol, nadolol
Abbreviations: ACE-Inhibitors, angiotensin-converting enzyme inhibitors; K, potassium.
Calcium Channel Blockers This class of drugs block calcium entry into cells at the level of voltage-dependent channels in the smooth muscle cells of resistance arteri01es. 112 Included in the group are nifedipine, diltiazem, verapamil, amilodipine, and others. Calcium channel blockers have no negative effect on glucose I13 or lipid metabolism,84,114 and may have an antiatherogenic effect. 84,93 The agents decrease L VH, 84 and may help control certain arrhythmias in patients with L VH.114 Direct Arterial Vasodilators These drugs have no effect on lipids or glucose metabolism, but they may not decrease L VH. 84 They have a variable effect on GFR and ERPF/ RBF, and they decrease RVR.llS Angiotensin-Converting Enzyme Inhibitors Agents in this class inhibit the renin-angiotensin-aldosterone system. I15 Captopril, lisinopril, and enalapril are examples of agents in this group. The angiotensin-converting enzyme (ACE) inhibitors do not modify lipid profile84 or glucose tolerance. 84,116 However, captopril has been shown to decrease insulin resistance. It is currently unclear whether this effect is a class effect or is specific to this ACE inhibitor. 117 Angiotensin-converting enzyme inhibitors decrease L VH 102, 118 and mortality after myocardial infarction. 119 They improve GFR and ERPF/ RBF and decrease R VR. lIS Serum potassium may be increased during therapy with ACE inhibitors (Table 2). ' Experimentally, ACE inhibitors are associated with normalization of glomerular capillary pressure and subsequent prevention of glomerular injury. 120 CONCLUSION
Selection of an antihypertensive regimen should take into account the interaction among
drugs and the presence of cardiovascular risk factors. Antihypertensive drugs such as {j-blockers without ISA, diuretics, and postganglionic inhibitors should, whenever possible, be second choices because of their potential deleterious effects in serum lipid profile, glucose tolerance, and L VH. Agents such as ACE inhibitors and calcium channel blockers do not modify either lipid or glucose metabolism; they have a favorable effect on L VH, and they have a potentially renoprotective effect in many cases when CRF has not reached ESRF. The ACE inhibitors, calcium channel blockers, and peripheral £xI-adrenergic antagonists should be among the first-line medications to use in treating HTN in patients with CRF. REFERENCES 1. Kannel WB: Coronary heart disease risk factors: A Framingham study update. Hosp Pract 25:93-104, 1990 2, Kannel WB: Some lessons in cardiovascular epidemiology from Framingham. Am J Cardiol 37:269-282, 1976 3, Feher MD: Doxazosin therapy in the treatment of diabetic hypertension, Am Heart J 121:1294-1301, 1991 4, Kannel WB, WolfPA, Verter J, McNamara P: Epidemiologic assessment of the role of blood pressure in stroke, The Framingham study. JAMA 214:301-310,1970 5. Layarve J, Hampers CL, Merril JP: Hypertension in chronic renal failure. Arch Intern Med 133: 1059-1066, 1974 6. Moyer JH, Heiden C, Pevey K, Ford RV: The effect of treatment on the vascular deterioration associated with hypertension, with particular emphasis on renal function. Am J Med 24:177-192,1958 7. Friedlander MM, Rubinger D, Poputzer MM: Improved renal function in patients with primary renal disease after control of severe hypertension. Am J NephroI2:12-14, 1982 8. Smith MC, Dunn MJ: Hypertension in renal parenchimal disease. In Laragh JH, Brenner BM (eds): Hypertension: Pathophysiology, Diagnosis and Management. New York, NY, Raven, 1990, pp 1583-1599 9. Mehta SK, Walsh JT, Goldberg AD, Topham WS: Increasing daytime vascular resistance with progresive hypertension in ambulant patients. Am Heart J 113: 156-162, 1987
104 10. Strauer BE: Ventricular function and coronary hemodynamics in hypertensive heart disease. Am J Cardiol 44: 999- 1006, 1979 II. Neill W A, Fluir-Lundeen JH: Myocardial oxygen supply in left ventricular hypertrophy and coronary heart disease. Am J CardioI44:746-53, 1979 12. Bauer JH, Broooks CS. Body-fluid composition in normal and hypertensive man. Clin Sci 62:43-49, 1982 13. Hypertension Detection and Follow-up Program Cooperative Group. Five year findings of the Hypertension Detection and Follow-up Program. I. Reduction in mortality of persons with high blood pressure including mild hypertension JAMA 242:2562-2571, 1979 14. Petrovitch H, Vogt TM, Berge KG: Isolated systolic hypertension. Lowering the risk of stroke in older patients. SHEP Cooperative Research Group. Geriatrics 47:30-32,3538, 1992 15. Stamler J, Stamer R: Intervention for the prevention and control of hypertension and atherosclerotic diseases: United States and international experience. Am J Med 76: 13-36, 1984 16. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effect of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 213:1143-1152, 1970 17. Grutzmacher P, Marz W, Peschke B, Gross W, Schoeppe W: Lipoproteins and apolipoproteins during the progression of chronic renal disease. Nephron 50: 103-111, 1988 18. Attman P, Alauporic P: Lipid and apolipoprotein profiles of uremic dyslipoproteinemia: Relation to renal function and dialysis. Nephron 57:401-410, 1991 19. Frank WM, Rao TK, Manis T, Delano BG, Avram M, Saxena I, Carter AC, Friedman EA: Relationship of plasma lipids to renal function and length of time on maintenance hemodialysis. Am J Clin Nutr 31: 1886-1892, 1978 20. Champ DG: Plasma lipid alterations in patients with chronic renal diseases. Crit Rev Clin Lab Sci 17:77-101, 1982 21. Sanfelippo M, Grundy S, Henderson L: Transport of very low density lipoprotein TG (VLDL-TG): Comparison of hemodialysis and hemofiltration. Kidney Int 16:868-872, 1979 22. Nestel PJ, Fidge NH, Tan MH: Increased lipoproteinremnant formation in chronic renal failure. N Engl J Med 307:239-333, 1982 23. Chan MK, Persaud J, Varghese Z, Moorhead JF: Pathogenic roles of postheparin lipases in lipid abnormalities in hemodialysis patients. Kidney Int 25:812-818, 1984 24. Mordasini R, Frey F, Flurry W, Kose G, Greten H: Selective deficiency of hepatic triglyceride lipase in uremic patients. N Engl J Med 297: 1362- 1366, 1977 25. Nikkila EA, Takinen M-R, Kekki M: Relation of plasma high-density lipoprotein cholesterol to lipoprotein-lipase activity in adipose tissue and skeletal muscle of man. Atherosclerosis 29:497-501, 1978 26. LaRosa JC, Levy RI, Windmuller HG, Fredrickson OS: Comparison of the triglyceride lipase of liver, adipose tissue and postheparin plasma. J Lipid Res 13:356-363, 1972
ZARAMA AND RAIJ 27. Murase T, Cattran DC, Rubenstein B, Steinder G: Inhibition of lipoprotein lipase by uremic plasma, a possible cause for hypertriglyceridemia. Metabolism 24: 1279-1286, 1975 28. Roullet JB, Lacour B, Yvert JP, Prat JJ, Drueke T: Correction by insulin of disturbed triglyceride-rich LP metabolism in rats with chronic renal failure. Am J Physiol 250: 373-376, 1986 29. Murase T, Cattran DC, Rubenstein B: Inhibition of lipoprotein lipase by uremic plasma, a possible cause of hypertriglyceridemia. Metabolism 24:1279-1286, 1975 30. Crawford GA, Mahony JF, Stewart JH: Impaired lipoprotein lipase activation by uremic and post-transplant sera. Clin Sci 60:73-80, 1981 31. Attman P, Alaupovic P: Lipid abnormalities in chronic renal failure. Kidney Int 39:SI6-S23, 1991 32. Grossman SB, Yap SH, Shafritz DA: Influence of chronic renal failure on protein synthesis and albumin metabolism in rat liver. J Clin Invest 59:869-878, 1977 33. Weussek M: Hypertrig!yceridemia: An independent risk factor for cardiovascular diseases? Acta Med Austriaca 16:4246, 1989 34. Fontbonne A, Eschewege E, Cambien F, Richard JL, Ducimitiere P, Thilbut N, Warnet JM, Claude JR: Hypertriglyceridaemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes: Results from the II-year follow-up of the Paris Prospective Study. Diabetologia 32:300-304, 1989 35. Hully SB, Rosenman RH, Bawol RD, Brand R: Epidemiology as a guide to clinical decisions: The association between triglycerides and coronary heart disease. N Engl J Med 302:1383-1389,1980 36. Carlson LA, Bottiger LE: Ischaemic heart disease in relation to fasting values of plasma trig!ycerides and cholesterol. Lancet 1:865-868, 1972 37. Rosenman RH, Brand RJ, Jenkins CD, Friedman EA, Straus R, Worn M: Coronary heart disease in the Western Collaborative Group study: JAMA 233:872-877, 1975 38. Brunzel JD, Albers JJ, Haas LB, Goldberg AP, Agadoa L, Sherrard 0: Prevalence of serum lipid abnormalities in chronic hemodialysis. Metabolism 26:903-910, 1977 39. Bagdade JD, Albers JJ: Plasma high density lipoprotein concentration in chronic hemodialysis and renal transplant patients. N Engl J Med 296:1436-1439, 1977 40. Editorial Review: Lipid abnormalities in uremia, dialysis and transplantation. Kidney Int 19:625-637, 1981 41. Management of hyperlipidemia of kidney disease. Kidney Int 37:847-853, 1990 (editorial review) 42. Grundy SM, Vega GL: Two different views of the relationship of hypertriglyceridemia to coronary heart disease: Implications for treatment. Arch Intern Med 152:28-34, 1992 43. Patsch JR, Muhlberger V, Drexel H, et al: Risk factors for coronary artery disease: A study comparing hypercholesterolaemia and hypertriglyceridaemia in angiographically characterized patients. Eur J Clin Invest 19:419-423, 1989 44. Lewis LA, Zuehike V, Nakamoto S, Kolff WJ, Page IH: Renal regulation of serum alpha-lipoproteins: Decrease of alpha-lipoproteins in the absence of renal function. N Eng! J Med 275:1097-1110,1966
EFFECTS OF ANTIHYPERTENSIVE AGENTS ON CARDIOVASCULAR RISK FACTORS
45. Goldberg AP, Harter HR, Patsch W, Schechtman KB, Province M, Weerts C, Kuisk I, McCrate M, Schonfeld G: Racial differences in plasma high-density lipoproteins in patients receiving hemodialysis: A possible mechanism for accelerated atherosclerosis in white men. N Engl J Med 308: 1245-1252, 1983 46. Attman P-O, Alaupovic P, Gustafson A: Serum apolipoprotein profile of patients with chronic renal failure. Kidney Int 32:368-375, 1987 47. Heuck CC, Ritz E: Hyperlipoproteinemia in renal insufficiency. Nephron 25: 1-7, 1980 48. Grutzmacher P, Marz W, Peschke B, et al: Lipoproteins and apolipoproteins during the progression of chronic renal disease. Nephron 50: 103-111 , 1988 49. Fidge N, Nestel P, Toshitsug I, Reardon M, Billington T: Turnover of apoproteins A-I and A-II of high density lipoprotein and the relationship to other lipoproteins in normal and hyperlipidemic individuals. Metabolism 29:643-653, 1980 50. Golay A, Zech L, Shi M-Z, Chiou Y-AM, Reaven GM, Chen YD: High density lipoprotein (HDL) metabolism in noninsulin-dependent diabetes mellitus: Measurement of HDL turnover using tritiated HDL. J Clin Endocrinol Metab 65:512-518, 1987 51. Dzau VJ: Mechanism of the interaction of hypertension and hypercholesterolemia in atherogenesis: The effect of antihypertensive agents. Am Heart J 116: 1725-1728, 1988 52. Fuh MMT, Lee CoM, Jeng C-Y, Sheng DC, Shieh SM, Reaven GM: Effect of chronic renal failure on high-density lipoprotein kinetics. Kidney Int 37 : 1295-1300, 1990 53. Nikkila EA, Takinen MR, Kekki M: Relation of plasma high-density lipoprotein cholesterol to lipoprotein-lipase activity in adipose tissue and skeletal muscle of man. Atherosclerosis 29:497-501 , 1978 54. Murai A, Miyahara T, Fujimoto N, Matsuda M, Kameyama M: Lipoprotein(a) lipoprotein as a risk factor for coronary artery disease and cerebral infarction. Atherosclerosis 59: 199-204, 1986 55. Hsia SL, Perez GO, Mendez AJ, Schiffman J, F1etcher S, Stoudemire J: Defect in cholesterol transport in patients receiving maintenance hemodialysis. J Lab Clin Med 106:5361 , 1985 56. Dieplinger H, Schoenfeld PY, Fielding CJ: Plasma cholesterol metabolism in end-stage renal disease. J Clin Invest 77:1071-1083,1986 57 . Tolins JP, Stone BG, Raij L: Interactions of hypercholesterolemia and HTA in initiation of glomerular injury. Kidney Int 41: 1254-1261 , 1992 58. Verbeuren TJ, Jordaens FH, Zonnekeyn LL, Van Hove CE, Coene MC, Herman, AG: Effect of hypercholesterolemia on vascular reactivity in the rabbit. I. Endothelium-dependent and endothelium-independent contractions and relaxations in isolated arteries of control and hypercholesterolemic rabbits. Circ Res 58:552-564, 1986 59. Chobanian AV, Lichtenstein AH, Nilakhe V, Handerschild CC, Drago R, Nickerson C: Influence of hypertension on aortic atherosclerosis in the Watanabe rabbit. Hypertension 14:203-205, 1989 60. Bartel LL, Hussey JL, Shrago E: Effect of dialysis on serum carnitine, free fatty acids and triglyceride levels in man and the rat. Metabolism 31 :944-947, 1982
105
61 . Ames RP, Hill P: Elevation of serum lipid levels during diuretic therapy of hypertension. Am J Med 61:748-757, 1976 62. Antihypertensive drugs, plasma lipids and coronary disease. Lancet 2: 19-20, 1980 (editorial) 63. Bioomgarden ZT, Gingberg-Fellner F, Rayfield EJ, Bookman J, Brown WV: Elevated hemoglobin Ale and lowdensity lipoprotein cholesterol levels in thiazide-treated diabetic patients. Am J Med 77:823-827, 1984 64. Ames RP: The effects of antihypertensive drugs on serum lipid and lipoproteins. I. Diuretics. Drugs 32:260-267, 1986 65. Consensus statement: Role of cardiovascular risk factor in prevention and treatment of macrosvascular disease in diabetes. Diabetes Care 12:573-579, 1989 66. Fontobone A, Eschwege E: Insulin-resistance, hypertriglyceridaemia and cardiovascular risk: The Paris Prospective Study. Diabete Metab May 7:93-98, 1991 67. Hypertriglyceridemia as vascular risk factor: Findings of the international evaluation [new]. Clin Cardiol 7:11-12, 1991 68. Hartnett JD, Parfrey PS, Griffiths SM , et al: Left ventricular hypertrophy in end-stage renal disease. Nephron 48 : 107-115, 1988 69. DeFronzo RA, Andres R, Edgar P, Walker P, Weisz A, DeFronzo RA: Carbohydrate metabolism in uremia: A review. Medicine (Baltimore) 52:469-481 , 1973 70. Spitz 1M, Rubenstein AH, Bersohn I, Abrahams C, Lowy C: Carbohydrate metabolism in renal disease. Q J Med 39:201-226, 1970 71. Akmal M, Massry SG, Goldstein DA, Fanti P, Weisz A, DeFronzo RA: Role of parathyroid hormone in the glucose intolerance of chronic renal failure. J Clin Invest 75: 10371044, 1985 72. DeFronzo RA , Smith JD: Is glucose intolerance harmful for the uremic patient. Kidney Int 28:S88-S97, 1985 73. Kramer W, Wizemann V, Thormann J, Kidnler M, Mueller K, Schlepper M: Cardiac dysfunction in patients on maintenance hemodialysis. Contrib NephroI52:97-109, 1983 74. Mall G, Rambausek M, Neumeister A, Kollmar S, Vetterlein F, Ritz E: Myocardial interstitial fibrosis in experimental uremia: Implication for cardiac compliance. Kidney Int 28:775-782, 1985 75. Leenen FHH, Smith DL, Khanna R, Oreopoulos DG: Changes in left ventricular hypertrophy and function in hypertensive patients started on continuous ambulatory peritoneal dialysis. Am Heart J 110: 102-106, 1985 76. Macdougall IC, Lewis NP, Saunders MJ, Cochlin DC, Davies ME, Hutton RD, Fox KA, Coles GA, Williams JD: Long term cardiorespiratory effects of amelioration of renal anemia by erythropoietin. Lancet 335:489-493, 1990 77. Himelman DB, Landzberg JS, Simonson JS, Cassidy MM, Schiller NB: Cardiac consequences of renal transplantation: Change in left ventricular morphology and function. J Am Coli Cardiol 12:915-923, 1988 78. Messerli FH, Ventura HO, Elizardi DJ, Dunn FG, Frohlich ED: Hypertension and sudden death: Increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med 77: 18-22, 1984 79. Gaasch WH: Diastolic dysfunction of the left ventricle: Importance to the clinician. Adv Intern Med 35:311-340, 1990
106 80. Rostand SG, Kirk Ka, Rutsky EA: Dialysis-associated ischemic heart disease: Insights from coronary angiography. Kidney Int 25:653-659, 1984 81. Musso MN, Vasquez EC, Carvalhinho FB, Dissoli NS, Cabral AM: Chlorthalidone alters the vascular reactivity of DOC-salt hypertensive rats to norepinephrine. Braz J Med Bioi Res 23:999-1003, 1990 82. Leth A: Changes in plasma and extracellular fluid volumes in patients with essential hypertension during long term treatment with hydrochlorothiazide. Circulation 42:479-85, 1970 83. Conway J, Lauwers P: Hemodynamic and hypotensive effects of long-term therapy with chlorothiazide. Circulation 21:21-27,1960 84. Houston MC: New insights and new approaches for the treatment of essential hypertension: Selection of therapy based on coronary heart disease risk factor analysis, hemodynamic profiles, quality oflife, and subsets of hypertension. Am Heart J 117:911-951, 1989 85. Flamenbaum W: Metabolic consequences of antihypertensive therapy. Ann Intern Med 98:875-880, 1983 86. Raij L, Luscher TF, Vanhoutte PM: High potassium diet augments endothelium-dependent relaxation in the Dahl rat. Hypertension 12:562-567, 1988 87. Vanhoutte PM, Rubany GM, Miller VM, et al: Modulation of vascular smooth muscle contraction by endothelium. Ann Rev Physiol 48:307-320, 1986 88. Criqui MH, Langer RD, Reed DM: Dietary alcohol, calcium, and potassium: Independent and combined effects on blood pressure. Circulation 80:609-614, 1989 89. Handerchild CC, Chobanian AV: Aortic endothelial and subendothelial cells in experimental hypertension and aging. Hypertension 3:148-51, 1981 90. Dzau VJ: Mechanism of the interaction of hypertension and hypercholesterolemia in atherogenesis: The effects of antihypertensive agents. Am Heart 1 116: 1725-1728, 1988 91. Weinberger MH: Antihypertensive therapy and lipids: Evidence, mechanisms and implications. Arch Intern Med 145:1102-1105,1985 92. Meyer-Sabellek W, Gotzen R, Heitz J, Arntz HR, Schulte KL: Serum lipoprotein levels during long-term treatment of hypertension and indapamide. Hypertension 7 II: 170-174, 1985 93. Fruman BL: Impairment of glucose intolerance produced by diuretics and other drugs. Pharmacol Ther 12:613, 1981 94. Hollifield 1W, Sherman K, Zwagg RV, et al: Proposed mechanism of propranolol's antihypertensive effect in essential hypertension. N Engl J Med 295:68-73, 1976 95. Man in't Veld A1, Van Der Meiracker AH, Schalekamp MA. Do beta-blockers really increase peripheral vascular resistance? Am 1 Hypertens 1:91-96, 1988 96. Leren P, Foss PO, Helgeland A: Effect of propranolol and prazosin on blood lipids: The Oslo Study. Lancet 2:4-6, 19S0 97. Dall'Aglio E, Chang H, Reaven GM: Disparate effects of prazosin and propranolol on lipid metabolism in a rat model. Am 1 Med 76:85-88, 1984 98. Day 1L, Metcalfe 1, Simpson N, Loewenthal L: Adrenergic mechanism in the control of plasma lipids in the man. Am 1 Med 76:94-96, 1984
ZARAMA AND RAIJ 99. Vulpis V, Antonacci A, Prandi P, Borkor D, Pirrelli A: The effects ofbisoprolol and atenolol on glucose metabolism in hypertensive patients with noninsulin-dependent diabetes mellitus. Minerva Med 82: 189-193, 1991 100. Ivashkin VT, Grigorev I, Sinopalnikov AL, Korneev NV, Levistkii DN, Kazakova IG, Virs EA: Prolonged cardioselective blockade of beta-I adrenoreceptor in combination with increased diuresis as a method of choice in the treatment of hypertension. Kardiologiia 31 :59-61, 1991 10 1. Frishman WH: Beta-adrenergic receptor blockers: Adverse effects and drug interactions. Hypertension 11 :21-29, 1988 102. Gonza1ez-1uanatey 1R, Amaro Cendon A, Calvo Gomez C, Vega-Fernandez M, Garcia-Acuna JM, Virgos-Lamela A, Gil-de-Ia-Pena L: Regression ofleft ventricular mass in arterial hypertension: Efficacy of 3 different treatment protocols. Med Clin 98:401-404, 1992 103. Louis W1, 1arrott B, Conway EL: Sites of action of alpha-2 agonist in the brain and periphery. Am 1 Cardiol 61: 15D-19D, 1988 104. Houston MC: Clonidine hydrochloride: Review of pharmacologic and clinical aspects. Prog Cardiovasc Dis 23: 337-350, 1981 105. Monova D, Daskalova I, Belovezhdov N: Guanfacine in the treatment of arterial hypertension in diabetics. Vutr Boles 29:44-47, 1990 106. Ames RP: The effect of antihypertensive drugs on serum lipids and lipoproteins II. Non-diuretic drugs. Drugs 32:335-357, 1986 107. Fouad FM, Nakashima Y, Tarazi RC, Salcedo EE: Reversal of left ventricular hypertrophy in hypertensive patients treated with methyldopa:: Lack of association with blood pressure control. Am 1 CardioI49:795-801, 1982 lOS. Bauer 1H: Adrenergic blocking agents and the kidney. 1 Clin Hypertens 3:199-207,1985 109. Langer SZ, Cavero I. Massingham R: Recent development in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents. Hypertension 2:372-382, 1980 110. Maruyama H, Saruta T, Itoh H, Koyama K, Kido K, Itoh K: Effect of alpha-adrenergic blockade on blood pressure, glucose, and lipid metabolism in hypertensive patients with non-insulin-dependent diabetes mellitus. Am Heart 1 121: 1302-1306, 1991 Ill. Leenen FH, Smith DL, Farkas RM, Reeves RA, Marquez-1ulio A: Vasodilators and regression ofleft ventricular hypertrophy: Hydralazine versus prazosin in hypertensive humans. Am 1 Med 82:969-978, 1987 112. Vanhootte PM: Calcium-entry blockers, vascular smooth muscle and systemic hypertension. Am 1 Cardiol 55: 17B-23B, 1985 113. Giuntoli F, Galeone F, Gabbani S, Spagnolo G, Natali A, Saba P: Nitrendipine does not impair long-term glucose control in hypertensive noninsulin-dependent diabetic patients. Clin Ther 13:216-223, 1991 114. Galderisi M, Celentano A, Tammaro P, Mureddu GF, Garofalo M: Hypertension and arrhythmias: Effects of slowrelease nicardipine vs chlorthalidone: A double-blind crossover study. Int 1 Clin Pharmacol Ther Toxicol 28:410-415, 1990
EFFECTS OF ANTIHYPERTENSIVE AGENTS ON CARDIOVASCULAR RISK FACTORS
liS. Bauer JH, Reams GP: Antihypertensive medications. In Brenner BM, Rector FC (eds): The Kidney, vol 2. Philadelphia, PA, Saunders, 1991, pp 2148-2185 116. Utsunomiya K, Ikeda Y: Beneficial effect of alacepril, a new angiotensin-converting enzyme inhibitor on albuminuria and glycemic state: An open multicenter trial. Alacepril Study Group. J Diab Complic 5:165-166,1991 1l7. Dinneen S, Gerich J, Rizza R: Carbohydrate metabolism in non-insulin-dependent diabetes mellitus. N Engl J Med 327:707-713, 1992 118. Verza M, Cacciapuoti F, Spiezia R: Effects of the angiotensin-converting enzyme inhibitor enalapril compared
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with diuretic therapy in elderly hypertensive patients. J Hypertens 6:90-97, 1988 119. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman E, Goldman S, Raker GC, Klein M, Lamas GA, Packer M, Rouleau JR, Rouleau JL, Rutheford J, Wertheimer JH, Hankins M: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Eng! J Med 327:669-677, 1992 120. Tolins P, Raij L: Antihypertensive therapy and the progression of chronic renal disease. Are there renoprotective drugs. Semin Nephrol 11:538-548, 1991
Toss OF kidney function is accompanied by .L many cardiovascular alterations that promote disease in other end organs and at the same time accelerate progression of renal disease. According to Framingham study data, the main risk factors for cardiovascular disease are hypertension (HTN), lipid disturbances, glucose intolerance, and left ventricular hypertrophy (L VH), 1 these factors being synergistic. Many of these risk factors complicate the course of chronic renal failure. Hypertension is a major risk factor for cardiovascular disease (CVD), disability, and premature death in the general population,2.3 and mortality increases with increasing blood pressure levels. 2,4 Hypertension typically complicates the course of chronic renal failure (CRF),5 and is an important factor in the progression of renal injury;6 HTN control can delay the progression of CRF. 7 Hypertension in CRF is multifactorial and is related to positive sodium balance and the increased activity of both the renin-angiotensin-aldosterone system and the sympathetic nervous system. Concomitant reduction in vasodilator substances may also contribute. 8 In fully established HTN, cardiac output is decreased by as From the Department o/Medicine. Veterans Affairs Medical Center and University olMinnesota. Minneapolis, MN. Address reprint requests to Leopoldo Raij, MD. Chief, Nephrology/Hypertension. Veterans Affairs Medical CenterRenal Section 11 JJ. One Veterans Dr. Minneapolis, MN 55417. © 1993 by the National Kidney Foundation. Inc. 0272-6386/93/2105-2019$3.00/0
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much as 25%, systemic vascular resistance (SVR) is increased by 25% to 30%,9-12 and intravascular volume is variable. 12 In patients with CRF, poorly treated HTN fosters cerebrovascular accidents (CVA), congestive heart failure, and coronary artery disease (CAD)2,4 and accelerates renal insufficiency. Some of these complications are closely related to development of atherosclerotic changes in the different target organs. 13 Control of HTN reduces cardiovascular morbidity and mortality, particularly that related to CVA. 14 Evidence supporting the notion that treatment of HTN reduces CAD has been elusive;15 however, the Systolic Hypertension in the Elderly Patient (SHEP) Cooperative Research Group has recently shown that morbility and mortality associated with CAD and CVD were significantly reduced with antihypertensive therapy (27% and 32%, respectively) and total mortality was lowered by 13%.14,16 In dialysis patients, strict control of both blood pressure and dry body weight has been associated with a lower incidence of deaths attributable to CV A or myocardial infarction. 15,16 Lipid abnormalities are well-known cardiovascular risk factors in CRF patients. 3 Hypertriglyceridemia is the most common lipid abnormality and may occur in patients with mild to moderate renal insufficiency. 17-19 The prevalence of hypertriglyceridemia increases as the glomerular filtration rate (GFR) declines. 19 The mechanism of hypertriglyceridemia is not fully understood; however, most data suggest that
American Journal of Kidney Diseases, Vol 21, No 5, Suppl 2 (May). 1993: pp 100-107
EFFECTS OF ANTIHYPERTENSIVE AGENTS ON CARDIOVASCULAR RISK FACTORS
reduced lipolysis of triglyceride (TG)-rich lipoproteins is due to deficient lipoprotein lipase activity.20- 25 Evidence suggests that alteration in endothelial lipoprotein lipase plays a more important role in the pathogenesis of hypertriglyceridemia in dialysis patients than alterations in the hepatic TG lipase. 26 Factors that may explain the decrease in lipoprotein lipase activity in CRF and end-stage renal failure (ESRF) include the presence of an inhibitor of lipolytic enzymes in uremic serum,27-30 insulin resistance,31 and diminished hepatic protein synthesis in uremia. 32 The contribution of hypertriglyceridemia to CAD is uncertain. The Framingham study initially rejected a relationship between CAD and hypertriglyceridemia, but now data from the same study indicate treatment of hypertriglyceridemia. 33 .34 The role of TG in atherosclerosis is unclear,35-37 although it is possible that they contribute somewhat to the lipid component of the atherosclerotic plaque: The abnormal metabolism of TG raises the concentration of very-low density lipoprotein (VLDL) and low-density lipoprotein (LDL) and reduces the level of highdensity liproprotein (HDL)-metabolic changes that are known to promote atherogenesis. 25 ,38-43 Low levels ofHDL are present in 50% to 75% of CRF patients,44-48 which has been attributed to a faster-than-normal catabolic rate49 ,50 as well as to a low synthetic rate ofHDL,51-53 Recent studies have shown an increase in lipoprotein(a) in CRF patients, Lipoprotein(a) is atherogenic;54 hence, the increased Lipoprotein(a) and decreased HDL may favor accelerated atherogenesis in this population,55,56 Experimental evidence suggests close interaction between dyslipidemia and HTN in vascular injury.57,58 This may explain the increased incidence of CAD and CVD in ESRF patients; in addition, coexistence of HTN and dyslipidemia may contribute to progression of renal failure, 59 Factors other than those already described may also be responsible for the increased cardiovascular morbidity and mortality observed in CRF patients. These include smoking, electrolyte abnormalities (eg, diuretic-induced hypokalemia), hemostasis abnormalities, circulating arterial toxins,41 carnitine deficiency,60 and perhaps use
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of certain drugs, such as androgens, tJ-blockers, and diuretics. 61 -64 It has been proposed that abnormal glucose tolerance is associated with increased risk for CVD. 34,65-67 Mild glucose intolerance has been documented in 50% of CRF patients 68,70 and attributed to both peripheral resistance to the action of insulin and impaired insulin secretion associated with secondary hyperparathyroidism.71 As long as diabetes mellitus is not the cause of the glucose intolerance, this metabolic abnormality improves upon initiation of dialysis. 72 There is a high incidence of LVH (60% to 90%) among patients with CRF, most of them aquiring it before starting dialysis. 68 ,73 Factors associated with LVH are HTN, anemia, age, and aluminum accumulation. Some evidence suggests that LVH may be due in part to "uremia.,,74 Regression of L VH has been reported after blood pressure control,15 erythropoietin administration,76 and renal transplantation. 77 Left ventricular hypertrophy is associated with increased ventricular ectopic activity (a possible cause of sudden death),78 with diastolic dysfunction of the left ventricle/ 9 and with angina. 8o ANTIHYPERTENSIVE THERAPY IN RENAL FAILURE PATIENTS
The main goal of antihypertensive therapy is to obtain hemodynamic and metabolic stability. There are many drugs available to treat HTN, but their secondary effects at times limit their use in CRF patients. Antihypertensive drug selection in CRF patients must take into account the effects of the medication on lipids, glucose tolerance, hemodynamic status, and remaining renal function (Table I). We will briefly review the most important antihypertensive drugs currently in use, describing their basic mechanism of action and their effects on cardiac output, SVR, renal vasculature, and cardiovascular risk factors.
Diuretics These agents have been widely used to control HTN. 81 Initially they decrease intravascular volume, cardiac output, GFR, and renal blood flow and increase heart rate; however, after 8 to 10
ZARAMA AND RAIJ
102 Table 1. Interaction Between Antihypertensive Medications and Cardiovascular Risk Factors in Chronic Renal Failure
Medication
Calcium channel blockers ACE inhibitors Central £1'2 adrenergic agonist Peripheral £1'1 adrenergic antagonist (3-blockers-ISA (3-blockers-non-ISA Vasodilators Thiazides
Lipid Levels
Glucose Tolerance
LVH
N
+
+ +/N
+ +
N
N
+
+
N
N N
+ N/-
N
-IN
Variable
N/-
Abbreviations: LVH, left ventricular hypertrophy; ACE inhibitors, angiotensin-converting enzyme inhibitors; ISA, intrinsic sympathomimetic activity; (+), benefit; (N), no effect; (-), negative.
weeks of treatment, SVR, cardiac output, and intravascular volume return to normal. 82 ,83 Diuretic-induced hypokalemia or hypomagnesemia increases the probability of ventricular fibrillation in patients with abnormal myocardial function. 84.85 Diuretic-induced hypokalemia may impair endothelium-dependent vascular relaxation 81 ,86.88 and worsen endothelial dysfunction due to long-standing HTN and/or atherosclerosis. 89 ,90 Thiazides tend to induce lipid abnormalities. 91 In fact, diuretics and /3-blockers may have adverse effects on lipoprotein metabolism, which may partially offset the antiatherosclerotic benefits of blood pressure lowering. They increase TG, total cholesterol, and LDL-cholesterol levels but apparently bring no change in HDL-cholesterol levels. 63 .64 ,92 Thiazides may induce hyperglycemia and abnormal glucose tolerance 93 and increase hemoglobin A lc . 63 ,85 Loop diuretics appear to be relatively safer in relation to hyperglycemia. 63 .93 /3-Adrenergic Blockers
These agents act both by competitive inhibition of catecholamine /3-receptors in juxtaglomerular cells and in the presynaptic sympathetic nervous system, and by inhibition of sympathetic outflow at the central nervous system
level. 94 The agents decrease heart rate, cardiac output, and SVR.95 The effect of /3-blockers on lipid profile is related to whether they have intrinsic sympathomimetic activity (ISA). Those without ISA increase TG, LDL, and VLDL levels and decrease HDL levels,95.97 probably by impairing lipoprotein lipase activity.5I ,97.98 Those with ISA do not show any significant unfavorable effect on lipids. The lipid changes induced by different /3-blockers has been reviewed recently by Houston. 84 /3-blockers without ISA may induce carbohydrate intolerance or exacerbate diabetes mellitus;99.100 this is probably secondary to inhibition of insulin secretion, glucose utilization, decreased peripheral sensitivity to insulin, increased hepatic glucogenolysis, and elevation of growth hormone. IOI These effects on glucose metabolism appear less pronounced with the use of agents with ISA. 84,99.100 There is no consistent information regarding the action of /3-blockers on L VH;84 however, recent studies have shown that atenolol reduces LVH.102 Central a2 Adrenergic Agonists
These drugs act on presynaptic and postsynaptic a2 receptors at midbrain and medulla. 103 Methyldopa, clonidine, guanabenz, and guanfacine are included in this group. The drugs decrease heart rate, SVR, and probably cardiac output. I04 With the exception of methyldopa, they have a neutral effect on serum lipids. 84 They do not induce hyperglycemia,84,105.106 and they reduce L VH. I07 They have no significant effect on GFR, the ratio of effective renal plasma flow to renal blood flow (ERPF/ RBF); renal vascular resistance (RVR) is reduced, probably in response to reduced levels of circulating catecholamines. 108 Peripheral arAdrenergic Antagonists
These agents inhibit postjunctional ai-receptors.109 They have a favorable effect on lipids, decreasing total cholesterol, TG, LDL, and VLDL and increasing HDL cholesterol levels. 84 ai-Antagonists may increase lipoprotein lipase activity.51.98 They do not induce hyperglycemia I10 and may decrease L VH.84, III Prazosin, terazosin, and indoramin are included in this group.
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EFFECTS OF ANTIHYPERTENSIVE AGENTS ON CARDIOVASCULAR RISK FACTORS
Table 2. Hazards of Antihypertensive Therapy in Renal Insufficiency
Problem
Origin
Causal Agents
Rapid decline in renal function Hyperkalemia Overdose
Too rapid or extreme decrease in pressure Bilateral renal artery stenosis Decreased K+ secretion Accumulation of drugs excreted by kidney
Any ACE-Inhibitors, calcium channel blockers K+ -sparing diuretics; ACE-inhibitors Atenolol, nadolol
Abbreviations: ACE-Inhibitors, angiotensin-converting enzyme inhibitors; K, potassium.
Calcium Channel Blockers This class of drugs block calcium entry into cells at the level of voltage-dependent channels in the smooth muscle cells of resistance arteri01es. 112 Included in the group are nifedipine, diltiazem, verapamil, amilodipine, and others. Calcium channel blockers have no negative effect on glucose I13 or lipid metabolism,84,114 and may have an antiatherogenic effect. 84,93 The agents decrease L VH, 84 and may help control certain arrhythmias in patients with L VH.114 Direct Arterial Vasodilators These drugs have no effect on lipids or glucose metabolism, but they may not decrease L VH. 84 They have a variable effect on GFR and ERPF/ RBF, and they decrease RVR.llS Angiotensin-Converting Enzyme Inhibitors Agents in this class inhibit the renin-angiotensin-aldosterone system. I15 Captopril, lisinopril, and enalapril are examples of agents in this group. The angiotensin-converting enzyme (ACE) inhibitors do not modify lipid profile84 or glucose tolerance. 84,116 However, captopril has been shown to decrease insulin resistance. It is currently unclear whether this effect is a class effect or is specific to this ACE inhibitor. 117 Angiotensin-converting enzyme inhibitors decrease L VH 102, 118 and mortality after myocardial infarction. 119 They improve GFR and ERPF/ RBF and decrease R VR. lIS Serum potassium may be increased during therapy with ACE inhibitors (Table 2). ' Experimentally, ACE inhibitors are associated with normalization of glomerular capillary pressure and subsequent prevention of glomerular injury. 120 CONCLUSION
Selection of an antihypertensive regimen should take into account the interaction among
drugs and the presence of cardiovascular risk factors. Antihypertensive drugs such as {j-blockers without ISA, diuretics, and postganglionic inhibitors should, whenever possible, be second choices because of their potential deleterious effects in serum lipid profile, glucose tolerance, and L VH. Agents such as ACE inhibitors and calcium channel blockers do not modify either lipid or glucose metabolism; they have a favorable effect on L VH, and they have a potentially renoprotective effect in many cases when CRF has not reached ESRF. The ACE inhibitors, calcium channel blockers, and peripheral £xI-adrenergic antagonists should be among the first-line medications to use in treating HTN in patients with CRF. REFERENCES 1. Kannel WB: Coronary heart disease risk factors: A Framingham study update. Hosp Pract 25:93-104, 1990 2, Kannel WB: Some lessons in cardiovascular epidemiology from Framingham. Am J Cardiol 37:269-282, 1976 3, Feher MD: Doxazosin therapy in the treatment of diabetic hypertension, Am Heart J 121:1294-1301, 1991 4, Kannel WB, WolfPA, Verter J, McNamara P: Epidemiologic assessment of the role of blood pressure in stroke, The Framingham study. JAMA 214:301-310,1970 5. Layarve J, Hampers CL, Merril JP: Hypertension in chronic renal failure. Arch Intern Med 133: 1059-1066, 1974 6. Moyer JH, Heiden C, Pevey K, Ford RV: The effect of treatment on the vascular deterioration associated with hypertension, with particular emphasis on renal function. Am J Med 24:177-192,1958 7. Friedlander MM, Rubinger D, Poputzer MM: Improved renal function in patients with primary renal disease after control of severe hypertension. Am J NephroI2:12-14, 1982 8. Smith MC, Dunn MJ: Hypertension in renal parenchimal disease. In Laragh JH, Brenner BM (eds): Hypertension: Pathophysiology, Diagnosis and Management. New York, NY, Raven, 1990, pp 1583-1599 9. Mehta SK, Walsh JT, Goldberg AD, Topham WS: Increasing daytime vascular resistance with progresive hypertension in ambulant patients. Am Heart J 113: 156-162, 1987
104 10. Strauer BE: Ventricular function and coronary hemodynamics in hypertensive heart disease. Am J Cardiol 44: 999- 1006, 1979 II. Neill W A, Fluir-Lundeen JH: Myocardial oxygen supply in left ventricular hypertrophy and coronary heart disease. Am J CardioI44:746-53, 1979 12. Bauer JH, Broooks CS. Body-fluid composition in normal and hypertensive man. Clin Sci 62:43-49, 1982 13. Hypertension Detection and Follow-up Program Cooperative Group. Five year findings of the Hypertension Detection and Follow-up Program. I. Reduction in mortality of persons with high blood pressure including mild hypertension JAMA 242:2562-2571, 1979 14. Petrovitch H, Vogt TM, Berge KG: Isolated systolic hypertension. Lowering the risk of stroke in older patients. SHEP Cooperative Research Group. Geriatrics 47:30-32,3538, 1992 15. Stamler J, Stamer R: Intervention for the prevention and control of hypertension and atherosclerotic diseases: United States and international experience. Am J Med 76: 13-36, 1984 16. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effect of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 213:1143-1152, 1970 17. Grutzmacher P, Marz W, Peschke B, Gross W, Schoeppe W: Lipoproteins and apolipoproteins during the progression of chronic renal disease. Nephron 50: 103-111, 1988 18. Attman P, Alauporic P: Lipid and apolipoprotein profiles of uremic dyslipoproteinemia: Relation to renal function and dialysis. Nephron 57:401-410, 1991 19. Frank WM, Rao TK, Manis T, Delano BG, Avram M, Saxena I, Carter AC, Friedman EA: Relationship of plasma lipids to renal function and length of time on maintenance hemodialysis. Am J Clin Nutr 31: 1886-1892, 1978 20. Champ DG: Plasma lipid alterations in patients with chronic renal diseases. Crit Rev Clin Lab Sci 17:77-101, 1982 21. Sanfelippo M, Grundy S, Henderson L: Transport of very low density lipoprotein TG (VLDL-TG): Comparison of hemodialysis and hemofiltration. Kidney Int 16:868-872, 1979 22. Nestel PJ, Fidge NH, Tan MH: Increased lipoproteinremnant formation in chronic renal failure. N Engl J Med 307:239-333, 1982 23. Chan MK, Persaud J, Varghese Z, Moorhead JF: Pathogenic roles of postheparin lipases in lipid abnormalities in hemodialysis patients. Kidney Int 25:812-818, 1984 24. Mordasini R, Frey F, Flurry W, Kose G, Greten H: Selective deficiency of hepatic triglyceride lipase in uremic patients. N Engl J Med 297: 1362- 1366, 1977 25. Nikkila EA, Takinen M-R, Kekki M: Relation of plasma high-density lipoprotein cholesterol to lipoprotein-lipase activity in adipose tissue and skeletal muscle of man. Atherosclerosis 29:497-501, 1978 26. LaRosa JC, Levy RI, Windmuller HG, Fredrickson OS: Comparison of the triglyceride lipase of liver, adipose tissue and postheparin plasma. J Lipid Res 13:356-363, 1972
ZARAMA AND RAIJ 27. Murase T, Cattran DC, Rubenstein B, Steinder G: Inhibition of lipoprotein lipase by uremic plasma, a possible cause for hypertriglyceridemia. Metabolism 24: 1279-1286, 1975 28. Roullet JB, Lacour B, Yvert JP, Prat JJ, Drueke T: Correction by insulin of disturbed triglyceride-rich LP metabolism in rats with chronic renal failure. Am J Physiol 250: 373-376, 1986 29. Murase T, Cattran DC, Rubenstein B: Inhibition of lipoprotein lipase by uremic plasma, a possible cause of hypertriglyceridemia. Metabolism 24:1279-1286, 1975 30. Crawford GA, Mahony JF, Stewart JH: Impaired lipoprotein lipase activation by uremic and post-transplant sera. Clin Sci 60:73-80, 1981 31. Attman P, Alaupovic P: Lipid abnormalities in chronic renal failure. Kidney Int 39:SI6-S23, 1991 32. Grossman SB, Yap SH, Shafritz DA: Influence of chronic renal failure on protein synthesis and albumin metabolism in rat liver. J Clin Invest 59:869-878, 1977 33. Weussek M: Hypertrig!yceridemia: An independent risk factor for cardiovascular diseases? Acta Med Austriaca 16:4246, 1989 34. Fontbonne A, Eschewege E, Cambien F, Richard JL, Ducimitiere P, Thilbut N, Warnet JM, Claude JR: Hypertriglyceridaemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes: Results from the II-year follow-up of the Paris Prospective Study. Diabetologia 32:300-304, 1989 35. Hully SB, Rosenman RH, Bawol RD, Brand R: Epidemiology as a guide to clinical decisions: The association between triglycerides and coronary heart disease. N Engl J Med 302:1383-1389,1980 36. Carlson LA, Bottiger LE: Ischaemic heart disease in relation to fasting values of plasma trig!ycerides and cholesterol. Lancet 1:865-868, 1972 37. Rosenman RH, Brand RJ, Jenkins CD, Friedman EA, Straus R, Worn M: Coronary heart disease in the Western Collaborative Group study: JAMA 233:872-877, 1975 38. Brunzel JD, Albers JJ, Haas LB, Goldberg AP, Agadoa L, Sherrard 0: Prevalence of serum lipid abnormalities in chronic hemodialysis. Metabolism 26:903-910, 1977 39. Bagdade JD, Albers JJ: Plasma high density lipoprotein concentration in chronic hemodialysis and renal transplant patients. N Engl J Med 296:1436-1439, 1977 40. Editorial Review: Lipid abnormalities in uremia, dialysis and transplantation. Kidney Int 19:625-637, 1981 41. Management of hyperlipidemia of kidney disease. Kidney Int 37:847-853, 1990 (editorial review) 42. Grundy SM, Vega GL: Two different views of the relationship of hypertriglyceridemia to coronary heart disease: Implications for treatment. Arch Intern Med 152:28-34, 1992 43. Patsch JR, Muhlberger V, Drexel H, et al: Risk factors for coronary artery disease: A study comparing hypercholesterolaemia and hypertriglyceridaemia in angiographically characterized patients. Eur J Clin Invest 19:419-423, 1989 44. Lewis LA, Zuehike V, Nakamoto S, Kolff WJ, Page IH: Renal regulation of serum alpha-lipoproteins: Decrease of alpha-lipoproteins in the absence of renal function. N Eng! J Med 275:1097-1110,1966
EFFECTS OF ANTIHYPERTENSIVE AGENTS ON CARDIOVASCULAR RISK FACTORS
45. Goldberg AP, Harter HR, Patsch W, Schechtman KB, Province M, Weerts C, Kuisk I, McCrate M, Schonfeld G: Racial differences in plasma high-density lipoproteins in patients receiving hemodialysis: A possible mechanism for accelerated atherosclerosis in white men. N Engl J Med 308: 1245-1252, 1983 46. Attman P-O, Alaupovic P, Gustafson A: Serum apolipoprotein profile of patients with chronic renal failure. Kidney Int 32:368-375, 1987 47. Heuck CC, Ritz E: Hyperlipoproteinemia in renal insufficiency. Nephron 25: 1-7, 1980 48. Grutzmacher P, Marz W, Peschke B, et al: Lipoproteins and apolipoproteins during the progression of chronic renal disease. Nephron 50: 103-111 , 1988 49. Fidge N, Nestel P, Toshitsug I, Reardon M, Billington T: Turnover of apoproteins A-I and A-II of high density lipoprotein and the relationship to other lipoproteins in normal and hyperlipidemic individuals. Metabolism 29:643-653, 1980 50. Golay A, Zech L, Shi M-Z, Chiou Y-AM, Reaven GM, Chen YD: High density lipoprotein (HDL) metabolism in noninsulin-dependent diabetes mellitus: Measurement of HDL turnover using tritiated HDL. J Clin Endocrinol Metab 65:512-518, 1987 51. Dzau VJ: Mechanism of the interaction of hypertension and hypercholesterolemia in atherogenesis: The effect of antihypertensive agents. Am Heart J 116: 1725-1728, 1988 52. Fuh MMT, Lee CoM, Jeng C-Y, Sheng DC, Shieh SM, Reaven GM: Effect of chronic renal failure on high-density lipoprotein kinetics. Kidney Int 37 : 1295-1300, 1990 53. Nikkila EA, Takinen MR, Kekki M: Relation of plasma high-density lipoprotein cholesterol to lipoprotein-lipase activity in adipose tissue and skeletal muscle of man. Atherosclerosis 29:497-501 , 1978 54. Murai A, Miyahara T, Fujimoto N, Matsuda M, Kameyama M: Lipoprotein(a) lipoprotein as a risk factor for coronary artery disease and cerebral infarction. Atherosclerosis 59: 199-204, 1986 55. Hsia SL, Perez GO, Mendez AJ, Schiffman J, F1etcher S, Stoudemire J: Defect in cholesterol transport in patients receiving maintenance hemodialysis. J Lab Clin Med 106:5361 , 1985 56. Dieplinger H, Schoenfeld PY, Fielding CJ: Plasma cholesterol metabolism in end-stage renal disease. J Clin Invest 77:1071-1083,1986 57 . Tolins JP, Stone BG, Raij L: Interactions of hypercholesterolemia and HTA in initiation of glomerular injury. Kidney Int 41: 1254-1261 , 1992 58. Verbeuren TJ, Jordaens FH, Zonnekeyn LL, Van Hove CE, Coene MC, Herman, AG: Effect of hypercholesterolemia on vascular reactivity in the rabbit. I. Endothelium-dependent and endothelium-independent contractions and relaxations in isolated arteries of control and hypercholesterolemic rabbits. Circ Res 58:552-564, 1986 59. Chobanian AV, Lichtenstein AH, Nilakhe V, Handerschild CC, Drago R, Nickerson C: Influence of hypertension on aortic atherosclerosis in the Watanabe rabbit. Hypertension 14:203-205, 1989 60. Bartel LL, Hussey JL, Shrago E: Effect of dialysis on serum carnitine, free fatty acids and triglyceride levels in man and the rat. Metabolism 31 :944-947, 1982
105
61 . Ames RP, Hill P: Elevation of serum lipid levels during diuretic therapy of hypertension. Am J Med 61:748-757, 1976 62. Antihypertensive drugs, plasma lipids and coronary disease. Lancet 2: 19-20, 1980 (editorial) 63. Bioomgarden ZT, Gingberg-Fellner F, Rayfield EJ, Bookman J, Brown WV: Elevated hemoglobin Ale and lowdensity lipoprotein cholesterol levels in thiazide-treated diabetic patients. Am J Med 77:823-827, 1984 64. Ames RP: The effects of antihypertensive drugs on serum lipid and lipoproteins. I. Diuretics. Drugs 32:260-267, 1986 65. Consensus statement: Role of cardiovascular risk factor in prevention and treatment of macrosvascular disease in diabetes. Diabetes Care 12:573-579, 1989 66. Fontobone A, Eschwege E: Insulin-resistance, hypertriglyceridaemia and cardiovascular risk: The Paris Prospective Study. Diabete Metab May 7:93-98, 1991 67. Hypertriglyceridemia as vascular risk factor: Findings of the international evaluation [new]. Clin Cardiol 7:11-12, 1991 68. Hartnett JD, Parfrey PS, Griffiths SM , et al: Left ventricular hypertrophy in end-stage renal disease. Nephron 48 : 107-115, 1988 69. DeFronzo RA, Andres R, Edgar P, Walker P, Weisz A, DeFronzo RA: Carbohydrate metabolism in uremia: A review. Medicine (Baltimore) 52:469-481 , 1973 70. Spitz 1M, Rubenstein AH, Bersohn I, Abrahams C, Lowy C: Carbohydrate metabolism in renal disease. Q J Med 39:201-226, 1970 71. Akmal M, Massry SG, Goldstein DA, Fanti P, Weisz A, DeFronzo RA: Role of parathyroid hormone in the glucose intolerance of chronic renal failure. J Clin Invest 75: 10371044, 1985 72. DeFronzo RA , Smith JD: Is glucose intolerance harmful for the uremic patient. Kidney Int 28:S88-S97, 1985 73. Kramer W, Wizemann V, Thormann J, Kidnler M, Mueller K, Schlepper M: Cardiac dysfunction in patients on maintenance hemodialysis. Contrib NephroI52:97-109, 1983 74. Mall G, Rambausek M, Neumeister A, Kollmar S, Vetterlein F, Ritz E: Myocardial interstitial fibrosis in experimental uremia: Implication for cardiac compliance. Kidney Int 28:775-782, 1985 75. Leenen FHH, Smith DL, Khanna R, Oreopoulos DG: Changes in left ventricular hypertrophy and function in hypertensive patients started on continuous ambulatory peritoneal dialysis. Am Heart J 110: 102-106, 1985 76. Macdougall IC, Lewis NP, Saunders MJ, Cochlin DC, Davies ME, Hutton RD, Fox KA, Coles GA, Williams JD: Long term cardiorespiratory effects of amelioration of renal anemia by erythropoietin. Lancet 335:489-493, 1990 77. Himelman DB, Landzberg JS, Simonson JS, Cassidy MM, Schiller NB: Cardiac consequences of renal transplantation: Change in left ventricular morphology and function. J Am Coli Cardiol 12:915-923, 1988 78. Messerli FH, Ventura HO, Elizardi DJ, Dunn FG, Frohlich ED: Hypertension and sudden death: Increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med 77: 18-22, 1984 79. Gaasch WH: Diastolic dysfunction of the left ventricle: Importance to the clinician. Adv Intern Med 35:311-340, 1990
106 80. Rostand SG, Kirk Ka, Rutsky EA: Dialysis-associated ischemic heart disease: Insights from coronary angiography. Kidney Int 25:653-659, 1984 81. Musso MN, Vasquez EC, Carvalhinho FB, Dissoli NS, Cabral AM: Chlorthalidone alters the vascular reactivity of DOC-salt hypertensive rats to norepinephrine. Braz J Med Bioi Res 23:999-1003, 1990 82. Leth A: Changes in plasma and extracellular fluid volumes in patients with essential hypertension during long term treatment with hydrochlorothiazide. Circulation 42:479-85, 1970 83. Conway J, Lauwers P: Hemodynamic and hypotensive effects of long-term therapy with chlorothiazide. Circulation 21:21-27,1960 84. Houston MC: New insights and new approaches for the treatment of essential hypertension: Selection of therapy based on coronary heart disease risk factor analysis, hemodynamic profiles, quality oflife, and subsets of hypertension. Am Heart J 117:911-951, 1989 85. Flamenbaum W: Metabolic consequences of antihypertensive therapy. Ann Intern Med 98:875-880, 1983 86. Raij L, Luscher TF, Vanhoutte PM: High potassium diet augments endothelium-dependent relaxation in the Dahl rat. Hypertension 12:562-567, 1988 87. Vanhoutte PM, Rubany GM, Miller VM, et al: Modulation of vascular smooth muscle contraction by endothelium. Ann Rev Physiol 48:307-320, 1986 88. Criqui MH, Langer RD, Reed DM: Dietary alcohol, calcium, and potassium: Independent and combined effects on blood pressure. Circulation 80:609-614, 1989 89. Handerchild CC, Chobanian AV: Aortic endothelial and subendothelial cells in experimental hypertension and aging. Hypertension 3:148-51, 1981 90. Dzau VJ: Mechanism of the interaction of hypertension and hypercholesterolemia in atherogenesis: The effects of antihypertensive agents. Am Heart 1 116: 1725-1728, 1988 91. Weinberger MH: Antihypertensive therapy and lipids: Evidence, mechanisms and implications. Arch Intern Med 145:1102-1105,1985 92. Meyer-Sabellek W, Gotzen R, Heitz J, Arntz HR, Schulte KL: Serum lipoprotein levels during long-term treatment of hypertension and indapamide. Hypertension 7 II: 170-174, 1985 93. Fruman BL: Impairment of glucose intolerance produced by diuretics and other drugs. Pharmacol Ther 12:613, 1981 94. Hollifield 1W, Sherman K, Zwagg RV, et al: Proposed mechanism of propranolol's antihypertensive effect in essential hypertension. N Engl J Med 295:68-73, 1976 95. Man in't Veld A1, Van Der Meiracker AH, Schalekamp MA. Do beta-blockers really increase peripheral vascular resistance? Am 1 Hypertens 1:91-96, 1988 96. Leren P, Foss PO, Helgeland A: Effect of propranolol and prazosin on blood lipids: The Oslo Study. Lancet 2:4-6, 19S0 97. Dall'Aglio E, Chang H, Reaven GM: Disparate effects of prazosin and propranolol on lipid metabolism in a rat model. Am 1 Med 76:85-88, 1984 98. Day 1L, Metcalfe 1, Simpson N, Loewenthal L: Adrenergic mechanism in the control of plasma lipids in the man. Am 1 Med 76:94-96, 1984
ZARAMA AND RAIJ 99. Vulpis V, Antonacci A, Prandi P, Borkor D, Pirrelli A: The effects ofbisoprolol and atenolol on glucose metabolism in hypertensive patients with noninsulin-dependent diabetes mellitus. Minerva Med 82: 189-193, 1991 100. Ivashkin VT, Grigorev I, Sinopalnikov AL, Korneev NV, Levistkii DN, Kazakova IG, Virs EA: Prolonged cardioselective blockade of beta-I adrenoreceptor in combination with increased diuresis as a method of choice in the treatment of hypertension. Kardiologiia 31 :59-61, 1991 10 1. Frishman WH: Beta-adrenergic receptor blockers: Adverse effects and drug interactions. Hypertension 11 :21-29, 1988 102. Gonza1ez-1uanatey 1R, Amaro Cendon A, Calvo Gomez C, Vega-Fernandez M, Garcia-Acuna JM, Virgos-Lamela A, Gil-de-Ia-Pena L: Regression ofleft ventricular mass in arterial hypertension: Efficacy of 3 different treatment protocols. Med Clin 98:401-404, 1992 103. Louis W1, 1arrott B, Conway EL: Sites of action of alpha-2 agonist in the brain and periphery. Am 1 Cardiol 61: 15D-19D, 1988 104. Houston MC: Clonidine hydrochloride: Review of pharmacologic and clinical aspects. Prog Cardiovasc Dis 23: 337-350, 1981 105. Monova D, Daskalova I, Belovezhdov N: Guanfacine in the treatment of arterial hypertension in diabetics. Vutr Boles 29:44-47, 1990 106. Ames RP: The effect of antihypertensive drugs on serum lipids and lipoproteins II. Non-diuretic drugs. Drugs 32:335-357, 1986 107. Fouad FM, Nakashima Y, Tarazi RC, Salcedo EE: Reversal of left ventricular hypertrophy in hypertensive patients treated with methyldopa:: Lack of association with blood pressure control. Am 1 CardioI49:795-801, 1982 lOS. Bauer 1H: Adrenergic blocking agents and the kidney. 1 Clin Hypertens 3:199-207,1985 109. Langer SZ, Cavero I. Massingham R: Recent development in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents. Hypertension 2:372-382, 1980 110. Maruyama H, Saruta T, Itoh H, Koyama K, Kido K, Itoh K: Effect of alpha-adrenergic blockade on blood pressure, glucose, and lipid metabolism in hypertensive patients with non-insulin-dependent diabetes mellitus. Am Heart 1 121: 1302-1306, 1991 Ill. Leenen FH, Smith DL, Farkas RM, Reeves RA, Marquez-1ulio A: Vasodilators and regression ofleft ventricular hypertrophy: Hydralazine versus prazosin in hypertensive humans. Am 1 Med 82:969-978, 1987 112. Vanhootte PM: Calcium-entry blockers, vascular smooth muscle and systemic hypertension. Am 1 Cardiol 55: 17B-23B, 1985 113. Giuntoli F, Galeone F, Gabbani S, Spagnolo G, Natali A, Saba P: Nitrendipine does not impair long-term glucose control in hypertensive noninsulin-dependent diabetic patients. Clin Ther 13:216-223, 1991 114. Galderisi M, Celentano A, Tammaro P, Mureddu GF, Garofalo M: Hypertension and arrhythmias: Effects of slowrelease nicardipine vs chlorthalidone: A double-blind crossover study. Int 1 Clin Pharmacol Ther Toxicol 28:410-415, 1990
EFFECTS OF ANTIHYPERTENSIVE AGENTS ON CARDIOVASCULAR RISK FACTORS
liS. Bauer JH, Reams GP: Antihypertensive medications. In Brenner BM, Rector FC (eds): The Kidney, vol 2. Philadelphia, PA, Saunders, 1991, pp 2148-2185 116. Utsunomiya K, Ikeda Y: Beneficial effect of alacepril, a new angiotensin-converting enzyme inhibitor on albuminuria and glycemic state: An open multicenter trial. Alacepril Study Group. J Diab Complic 5:165-166,1991 1l7. Dinneen S, Gerich J, Rizza R: Carbohydrate metabolism in non-insulin-dependent diabetes mellitus. N Engl J Med 327:707-713, 1992 118. Verza M, Cacciapuoti F, Spiezia R: Effects of the angiotensin-converting enzyme inhibitor enalapril compared
107
with diuretic therapy in elderly hypertensive patients. J Hypertens 6:90-97, 1988 119. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman E, Goldman S, Raker GC, Klein M, Lamas GA, Packer M, Rouleau JR, Rouleau JL, Rutheford J, Wertheimer JH, Hankins M: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Eng! J Med 327:669-677, 1992 120. Tolins P, Raij L: Antihypertensive therapy and the progression of chronic renal disease. Are there renoprotective drugs. Semin Nephrol 11:538-548, 1991