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Differential effects of ACE-inhibition and angiotensin II antagonism on fibrinolysis and insulin sensitivity in hypertensive postmenopausal women
AJH
2001; 14:921–926
Differential Effects of ACE-Inhibition and Angiotensin II Antagonism on Fibrinolysis and Insulin Sensitivity in Hypertensive Postmenopausal Women Roberto Fogari, Annalisa Zoppi, Paola Preti, Elena Fogari, GianDomenico Malamani, and Amedeo Mugellini The aim of this study was to compare the effects of trandolapril and losartan on plasminogen activator inhibitor type 1 (PAI-1) levels and insulin sensitivity in hypertensive postmenopausal women. We studied 89 hypertensive (diastolic blood pressure ⬎90 and ⬍110 mm Hg) postmenopausal women, aged 51 to 60 years not taking any hormone replacement therapy. Diabetic, obese, and smoking patients were excluded. After a 4-week placebo period, they were randomized to receive 2 mg of oral trandolapril (n ⫽ 45) or 50 mg of oral losartan (n ⫽ 44) for 12 weeks according to a double-blind, parallel group design. At the end of the placebo and active treatment periods, blood pressure (BP) was measured, plasma samples were drawn to evaluate PAI-1 antigen levels, and insulin sensitivity was assessed. Both trandolapril and losartan reduced systolic BP (by a mean of 16.9 mm Hg and 15.2 mm Hg, respectively, P ⬍ .01 v placebo) and diastolic BP (by a mean of 13.1 mm Hg and 11.9 mm Hg, respectively, P ⬍ .01 v placebo) with no difference between the two treatments. The PAI-1 antigen levels were significantly decreased by trandolapril (from 36.9 ⫾ 21 ng/dL to 27.2 ⫾ 17 ng/dL, P ⬍ .05), but not by losartan
S
(from 35.3 ⫾ 22 ng/dL to 37.1 ⫾ 23 ng/dL, P ⫽ not significant). Glucose infusion rate was significantly increased by trandolapril (from 6.67 ⫾ 0.56 mg/min/kg to 7.9 ⫾ 0.65 mg/min/kg, P ⬍ .05), but was not significantly modified by losartan (from 6.7 ⫾ 0.47 mg/min/kg to 6.9 ⫾ 0.50 mg/min/kg, P ⫽ not significant). In the trandolapril group the PAI-1 decrease correlated with glucose infusion rate increase (r ⫽ 0. 36, P ⫽ .045) These results provide evidence of different effects of angiotensin converting enzyme inhibitors and AT1 antagonists on fibrinolysis and suggest that the PAI-1 decrease induced by angiotensin converting enzyme inhibitors is related to their action on insulin sensitivity and is not dependent on angiotensin II antagonism but rather on other mechanisms. It remains to be seen whether these findings apply to other patient populations than postmenopausal women. Am J Hypertens 2001;14:921–926 © 2001 American Journal of Hypertension, Ltd. Key Words: Angiotensin converting enzyme inhibitor, angiotensin II antagonist, fibrinolysis, insulin sensitivity, hypertension.
everal studies have demonstrated an association between increased plasma levels of plasminogen activator inhibitor type 1 (PAI-1) and risk of atherosclerosis and its ischemic manifestations.1– 4 Impaired fibrinolysis due to increased PAI-1 plasma levels has been described in hypertensive subjects,5–7 as well as in postmenopausal women8,9 and may account, in part, for the increased risk of atherosclerosis and its clinical complication in these subjects.6,8 –10 In addition, it has been demonstrated that insulin resistance with resulting
hyperinsulinemia is common in patients with hypertension11,12 and in postmenopausal women,13,14 and has been identified as increasing the risk of coronary heart disease (CHD).15–17 A significant correlation between PAI-1 and fasting plasma insulin has been demonstrated in hypertension,6 non-insulin-dependent diabetes,18 obesity,19 angina pectoris,20 and in normal subjects,21 which is supported by in vitro evidence that insulin increases the production of PAI-1 by hepatocytes and endothelial cells.22,23 The increase in PAI-1 associated with hyperinsulinemia may link
Received March 29, 2000. Accepted February 13, 2001.
Pavia, Italy. Address correspondence and reprint requests to Dr. Roberto Fogari, Department of Internal Medicine and Therapeutics, Via Parco Vecchio 27, 27100 Pavia, Italy.
From the Department of Internal Medicine and Therapeutics, University of Pavia, Clinica Medica I, IRCCS, Policlinico S. Matteo, © 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
0895-7061/01/$20.00 PII S0895-7061(01)02140-9
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insulin resistance to CHD by impaired fibrinolysis and increased thrombosis.24 Furthermore, recent in vitro and in vivo studies have suggested an interaction between the fibrinolytic system and the renin angiotensin system (RAS), and angiotensin II (Ang II) has been shown to stimulate PAI-1 expression in cultured endothelial cells and to produce a rapid and significant increase in circulating levels of PAI-1 antigen in humans.25–27 Beneficial effects of angiotensin converting enzyme (ACE) inhibitors on impaired fibrinolysis28 –30 and insulin resistance31–36 have been reported and some studies have suggested that the changes in fibrinolytic parameters seen with the ACE inhibitors may be mediated, at least in part, through their effect on insulin sensitivity.35 The effects of the specific Ang II type 1 (AT1) receptor antagonists, recently introduced into clinical practice, on fibrinolysis and insulin sensitivity has been less extensively studied in humans and contrasting results have been reported.35,36 – 41 The aim of this study was to assess the effects on PAI-1 antigen plasma levels and insulin sensitivity of the ACE inhibitor trandolapril42 as compared to the Ang II antagonist losartan43 in the treatment of postmenopausal women with essential hypertension.
Methods The study population included 89 postmenopausal women, aged 51 to 60 years (mean age, 55.5 years) with mild-tomoderate, uncomplicated essential hypertension (diastolic blood pressure [DBP] ⬎90 and ⬍110 mm Hg). Menopausal status was defined as the cessation of menses for at least 1 year and was confirmed by plasma follicle-stimulating hormone levels higher than 20 U/L, higher concentrations of follicle-stimulating hormone than luteinizing hormone and plasma 17--estradiol levels ⬍50 pmol/L. Women who had taken hormone replacement therapy during the 6 months preceding the study were excluded from the study as were those with diabetes mellitus, obesity, smoking habits, myocardial infarction, or stroke within the previous 6 months, history of breast cancer or thromboembolic diseases, major systemic diseases, and any condition that would require the use of concomitant medications. The study protocol was approved by the local ethics committee and informed consent was obtained from each participant at the time of enrollment. After an initial 4-week washout period with placebo, patients were randomly given 2 mg of trandolapril (n ⫽ 45) or 50 mg of losartan (n ⫽ 44) according to a double-blind, parallel group design. Both trial medications were given once daily in the morning between 8 and 9 AM, for 12 weeks. From the time of enrollment until the completion of the study, each participant maintained her diet, usual level of physical activity, and avoided a change in body weight. At the end of the placebo and active treatment period, BP, PAI-1 antigen levels, and insulin sensitivity were evalu-
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ated. The BP measurements were obtained from each patient (right arm) in the seated position by using a standard mercury sphygmomanometer (Korotkoff I and V) with a cuff of appropriate size. Measurements were taken in the morning before daily drug intake (ie, 24 h after dosing, at trough) and after the subject had rested 10 min in a quiet room. Three successive BP readings were obtained at 1-min intervals and averaged. After BP measurements, after the subjects had fasted 12 h overnight, an intravenous catheter was placed in an antecubital vein for blood sampling and a second catheter was inserted into a contralateral vein for infusion of insulin and 20% glucose. Blood was drawn during the morning because PAI-1 concentration peaks during this period.44 The PAI-1 antigen levels were determined by a commercially available sandwich enzyme-linked immunosorbent assay (TintElize PAI-1, Biopool, Inc., Ulmeå, Sweden), following a procedure described by Ranby et al.45 Insulin sensitivity was assessed by the euglycemic, hyperinsulinemic clamp, according to the technique of De Fronzo et al.46 It was calculated from the mean glucose uptake rate for the last 30 min of the clamp and expressed as the amount of glucose infused during that time (glucose infusion rate [GIR]) in milligrams per kilograms per minute. Blood glucose in the fasting state and during glucose clamp studies was measured by the glucose oxidase method (Beckman Auto-Analyzer, Fullerton, CA). Plasma insulin concentrations were determined by radioimmunoassay (RIA). Metabolic parameters including total cholesterol (TC), HDL-cholesterol (HDL-C), and triglycerides (TG), as well as body mass index (BMI) were measured at the end of the placebo and active treatment periods. The TC and TG were determined by the enzymatic method of the Chemetron Company (Frankfurt, Germany). The HDL-C was determined by the enzymatic method of Roschlau47 and LDL and very low density lipoprotein precipitation with polyethylene glycol 6000 by the method of Viikari.48 Body weight and height were measured in the fasting state with the subjects only wearing underclothes and BMI was computed as weight in kilograms divided by height in meters squared. Data are expressed as means ⫾ standard deviation. The statistical analysis of the results was performed by analysis of variance for repeated measures and Spearman’s rank correlation test. A P value ⬍ .05 was considered statistically significant.
Results All the 89 patients enrolled in the trial completed the study. Table 1 shows their demographic and clinical characteristics at the end of the placebo period; there were no significant differences in age, BMI, BP values, TC, HDL-C, TG, fasting glycemia, plasma PAI-1 antigen, and insulin levels between the two treatment groups. The main results of the study are reported in Table 2.
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Table 1. Baseline demographic and clinical characteristics of postmenopausal hypertensive women in the two treatment groups
Parameters Age (y) BMI (kg/m2) SBP (mm Hg) DBP (mm Hg) HR (beats/min) PAI-1 (ng/mL) TC (mg/dL) HDL-C (mg/dL) TG (mg/dL) Glycemia (mg/dL) Insulin (pmol/L)
Trandolapril Group (n ⴝ 45) 55.7 26.1 162.1 101.2 76.1 36.9 231 50 128 92 74
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
2 2.2 12 5 7 21 31 15 59 10 36
Losartan Group (n ⴝ 44) 56.1 25.9 160.6 100.5 75.9 35.3 227 49 120 93 77
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
2 2.1 12 5 7 22 33 16 51 9 39
BMI ⫽ body mass index; SBP ⫽ systolic blood pressure; DBP ⫽ diastolic blood pressure; HR ⫽ heart rate; PAI-1 ⫽ plasminogen activator inhibitor type 1; TC ⫽ total cholesterol; HDL-C ⫽ high density lipoprotein-cholesterol; TG ⫽ triglycerides. P ⫽ not significant.
Both trandolapril and losartan significantly decreased systolic BP (SBP) (by a mean of 17 mm Hg and 15 mm Hg, respectively, P ⬍ .01 v placebo) and DBP (by a mean of 13 mm Hg and 12 mm Hg, respectively, P ⬍ .01 v placebo) with no difference between the two treatments. The PAI-1 antigen levels were significantly reduced by trandolapril (by a mean of 9 ng/dL, P ⬍ .05), but were not affected by losartan; the difference between the two treatments being statistically significant (P ⬍ .05). The mean rate of glucose uptake for the last 30 min of the clamp (GIR), considered as an index of insulin sensitivity, was significantly increased by trandolapril (by a mean of 1.3 mg/min/kg), but not by losartan (⫹0. 2 mg/min/kg, P ⫽ not significant); the difference between the two active treatments being statistically significant. The trandoloapril-induced decrease in PAI-1 antigen levels showed a significant but rather weak correlation
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with the increase in GIR (r ⫽ 0.35 P ⫽ .045). Such a correlation became more significant when considering only women with reduced insulin sensitivity at baseline (r ⫽ 0.60, P ⫽ .0081) (Fig. 1). There was no significant change in body weight, BMI, fasting blood glucose, plasma insulin, TC, HDL-C, and TG during treatment with both trandolapril and losartan (Table 2).
Discussion In comparison to men, women appear to lose their relative protection from coronary heart disease on becoming postmenopausal.49 Increased levels of PAI-1 as well as insulin resistance with consequent hyperinsulinemia, which may promote PAI-1 synthesis by hepatocytes and endothelial cells, have been observed in postmenopausal women and can both contribute to their increased cardiovascular risk.8,9,13,14,24 In agreement with these observations, in the present study postmenopausal women presented with baseline mean levels of PAI-1 antigen greater than the upper limit of the normal range and insulin resistance was noted in about 50% of the subjects. The concomitant presence of hypertension might have contributed to such abnormalities in fibrinolysis and glucose metabolism,5,6 thus enhancing the risk of congestive heart disease. The results of this study indicated that the ACE inhibitor trandolapril and the Ang II antagonist losartan were both effective in significantly reducing BP values in hypertensive postmemopausal women, with no statistical difference between the two drugs. However, despite their similar BP-lowering effect, losartan did not significantly affect PAI-1 antigen concentrations and insulin sensitivity, whereas trandolapril produced a significant decrease in PAI-1 antigen levels and enhanced insulin sensitivity. The dissimilar effects of trandolapril and losartan on PAI-1 levels might result from their different effects on insulin sensitivity. Such a hypothesis, which is in agree-
Table 2. Mean values of SBP, DBP, PAI-1 antigen levels, GIR, TC, HDL-C, TG, fasting glycemia, and BMI during treatment with trandolapril and losartan Trandolapril Parameters SBP (mm Hg) DBP (mm Hg) PAI-1 (ng/mL) GIR (mg/min/kg) TC (mg/dL) HDL-C (mg/dL) TG (mg/dL) Glycemia (mg/dL) BMI (kg/m2)
Placebo 162.1 101.2 36.9 6.67 231 50 128 92 26.1
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
12 5 21 0.56 31 15 59 10 2.2
Losartan
Treatment 145.2 88.1 27.2 7.99 226 50 125 89 26.0
GIR ⫽ glucose infusion rate; other abbreviations as in Table 1. * P ⬍ .05; † P ⬍ .01 v placebo; ‡ P ⬍ .05 v placebo and v losartan.
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
10† 4† 17*‡ 0.65* 29 16 57 10 2.2
Placebo 160.6 100.5 35.3 6.74 227 49 120 93 25.9
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
12 5 22 0.47 33 16 51 9 2.1
Treatment 145.4 88.6 37.1 6.96 224 48 123 92 25.9
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
11† 5† 23 0.50 31 17 50 10 2.1
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FIG. 1. Relationship between glucose infusion rate (GIR) changes (last 30 min) and PAI-1 changes in the trandolapril-treated women.
ment with the results of intervention studies aimed at reducing insulin resistance that produced a parallel decrease in plasma insulin and PAI-1 levels,21,24,50 is supported by the observation that in the present study the trandolapril-induced decrease in PAI-1 levels was significantly correlated with the increase in GIR, considered as an index of insulin sensitivity. Such a correlation was particularly evident in women with baseline insulin resistance. The dissimilar effects of the ACE inhibitor and the Ang II antagonist on insulin sensitivity may depend on their different action on the RAS. Unlike AT1 antagonists, which do not alter the metabolism of bradykinin,51 ACE inhibitors prevent the degradation of bradykinin and increase bradykinin plasma levels.52 In the present study we did not measure bradykinin concentrations or muscle blood flow, but data from the literature suggest that bradykinin or other vasoactive mediators, which are released in response to bradykinin such as prostaglandins and nitric oxide, might improve the glucose metabolism by enhancing muscle blood flow and consequently the rate of insulin and glucose delivery to the target tissues.53,54 In addition, bradykinin has been shown to facilitate the translocation of the glucose transport proteins GLUT 1 and GLUT 4 across the cell membrane,55,56 and to accelerate oxidation of plasma glucose and attenuate increased rates of hepatic glucose production.57 However, mechanisms other than the effects on insulin sensitivity might explain the lowering effect on PAI-1 concentrations by the ACE inhibitors and not by the Ang II antagonist. Angiotensin II has been demonstrated to increase the synthesis of PAI-1 in the vascular endothelium25,26 and this response is mediated by its hexapeptide metabolite Ang IV, which acts through a pharmacologically and biochemically distinct form of the angiotensin receptor.58,59 The reduction of Ang II levels by an ACE inhibitor, limiting the conversion of Ang II to smaller peptides, prevents the endothelial expression of PAI-1.59
In contrast, AT1 receptor antagonists are associated with increased plasma levels of Ang II,60 which might lead to increased Ang IV production. If this was the case, one would expect to observe increased PAI-1 levels during AT1 antagonism, although downregulation of the AT4 receptor by its ligand could attenuate such an effect. In conclusion, the results of this study showed that monotherapy of hypertension with the ACE inhibitor trandolapril in postmenopausal hypertensive women improved the fibrinolytic balance and the insulin sensitivity, whereas the Ang II antagonist losartan did not. These findings indicate that trandolapril has some theoretic clinical advantages beyond BP lowering in the antihypertensive treatment of these subjects who are at greater risk of cardiovascular complications because of the presence of fibrinolytic and metabolic disorders in addition to high blood pressure values. It remains to be seen whether these findings apply to other patient populations.
References 1.
2.
3.
4.
5.
6.
Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH: Endogenous tissue-plasminogen activator and risk of myocardial infarction. Lancet 1993;341:1165–1168. Ridker PM, Hennekens CH, Stamper MJ, Manson JAE, Vaughan DE: Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994;343:940 –943. Thompson SG, Kienast J, Pyke SDM, Haverkate F, Van de Loo JCW: Haemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332:635– 641. Salomaa V, Stinson V, Kark JD, Folsom AR, Davis CE, Wu KK: Association of fibrinolytic parameters with early atherosclerosis: the ARIC study. Circulation 1995;91:284 –290. Jeng JR, Sheu WHH, Jeng CY, Huang SH, Shieh SH: Impaired fibrinolysis and insulin resistance in patients with hypertension. Am J Hypertens 1996;9:484 – 490. Landin K, Tengborn L, Smoth U: Elevated fibrinogen and plasminogen activator inhibitor (PAI-1) in hypertension are related to metabolic risk factors for cardiovascular disease. J Intern Med 1990; 227:273–278.
AJH–September 2001–VOL. 14, NO. 9, PART 1
7.
8.
9.
10.
11. 12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
Eliasson M, Jansson JH, Nilsson P, Asplund K: Increased levels of tissue plasminogen activator inhibitor antigen in essential hypertension: a population-based study in Sweden. J Hypertens 1997;15: 349 –356. Gebara OCE, Mittleman MA, Sutherland P, Lipinska I, Matheney T, Xu P, Welty FK, Wilson PW, Levy D, Muller JE: Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation 1995;91:1952– 1958. Kon Koh K, Horne MDK, Csako G, Waclawiw MA, Cannon RO: Relation of fibrinolytic potentiation by estrogen to coagulation pathway activation in postmenopausal women. Am J Cardiol 1999;83: 466 – 469. Winther K, Gleerup G, Hedner T: Enhanced risk of thromboembolic disease in hypertension from platelet hyperfunction and decreased fibrinolytic activity: has antihypertensive therapy any influence? J Cardiovasc Pharm Ther 1997;19(suppl 3):S1–S24. Ferrannini E, Buzzigoli G, Bonadonna R: Insulin resistance in essential hypertension. N Engl J Med 1987;317:350 –357. Pollare T, Lithell H, Berne C: Insulin resistance is a characteristic feature of primary hypertension independent of obesity. Metabolism 1990;39:167–174. Walton C, Godsland IF, Proudder AJ, Wynn W, Stevenson JC: The effects of menopause on insulin sensitivity, secretion and elimination in non-obese, healthy women. Eur J Clin Invest 1993:23:466 – 473. Lindheim SR, Buchanan TA, Duffy DM, Vijod MA, Kojima T, Stanczyk FZ, Lobo RA: Comparison of estimates of insulin sensitivity in pre and postmenopausal women using the insulin tolerance test and the frequently sampled intravenous glucose tolerance test. J Soc Gynecol Invest 1994;1:150 –154. Pyorala K: Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two population studies in Finland. Diabetes Care 1979;2:131–141. Welborn TA, Weame K: Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care 1979;2:154 –160. Ducimetiere P, Eschwege E, Papoz L, Richard JL, Claude JF, Rosselin G: Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia 1980;19:205–221. Juhan-Vague I, Roul C, Alessi MC, et al: Increased plasminogen activator inhibitor activity in non-insulin-dependent diabetic patients. Relationship with plasma insulin. Thromb Haemost 1989;61: 370 –373. Vague P, Juhan Vague I, Chabert V, Alessi MC, Atlan C: Fat distribution and plasminogen activator inhibitor activity in nondiabetic obese women. Metabolism 1989;38:913–915. Juhan Vague I, Alessi MC, Joly P, Thirion X, Vague P, Declerck PJ, Serradimiqni A, Collen D: Plasma plasminogen activator inhibitor in angina pectoris. Influence of plasma insulin and acute-phase response. Arteriosclerosis 1989;9:362–367. Vague P, Juhan Vague I, Aillaud MF, Badier C, Viard R, Alessi M, Collen D: Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level and relative body weight in normal and obese subjects. Metabolism 1986;35:250 – 253. Kooistra T, Bosma PJ, Tons HAM, Van de Berg P, Meyer P, Princen HMG: Plasminogen activator inhibitor 1: biosynthesis and mRNA level are increased by insulin in cultured human hepatocytes. Thromb Haemost 1989;62:723–728. Nordt TK, Schneider DJ, Sobel BE: Augmentation of the synthesis of plasminogen activator inhibitor type-1 by precursors of insulin. A potential risk factor for vascular disease. Circulation 1994;89:321– 330. Juhan Vague I, Alessi MC, Vague P: Increased plasma plasminogen activator inhibitor 1 levels. A possible limk between insulin resistance and atherothrombosis. Diabetologia 1991;34:457– 462.
TRANDOLAPRIL, LOSARTAN, AND FIBRINOLYSIS IN POSTMENOPAUSAL WOMEN
925
25. Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE: Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Circulation 1993;87:1969 –1973. 26. Vaughan DE, Lazos SA, Tong K: Angiotensin II regulates the expression of plasminogen activator inhibitor -1 in cultured endothelial cells. J Clin Invest 1995;95:995–1001. 27. Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE: Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. Hypertension 1998;32:965–971. 28. Wright RA, Flapan AD, Alberti KGMM, Ludlam CA, Fox KAA: Effects of captopril therapy on endogenous fibrinolysis in men with recent uncomplicated myocardial infarction. J Am Coll Cardiol 1994;24:67–73. 29. Vaughan DE, Rouleau JC, Ridker P, Arnold JMO, Menapace FJ, Pfeffer MA: Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. Circulation 1997; 96:442– 447. 30. Sakata K, Shirotani M, Yoshida H, Urano T, Takada Y, Takada A: Differential effects of enalapril and nitrendipine on the fibrinolytic system in essential hypertension. Am Heart J 1999;137:1094 –1099. 31. Lithel HOL: Effects of antihypertensive drugs on insulin, glucose and lipid metabolism. Diabetes Care 1991;14:203–209. 32. Paolisso G, Gamardella A, Verza M: ACE inhibition improves insulin sensitivity in aged insulin-resistant hypertensive patients. J Hum Hypertens 1992;6:175–179. 33. Tomiyama H, Kushiro T, Abeta H, Ishii T, Takahashi A, Furukawa L, Asagami T, Hino T, Saito F, Otsuka Y: Kinins contribute to the improvement of insulin sensitivity during treatment with angiotensin converting enzyme inhibitor. Hypertension 1994;23:450 – 455. 34. Carvalho CR, Thirone AC, Gontijo JA, Velloso LA, Saad MJ: Effect of captopril, losartan and bradykinin on early steps of insulin action. Diabetes 1997;46:1950 –1957. 35. Fogari R, Zoppi A, Lazzari P, Preti P, Mugellini A, Corradi L, Lusardi P: ACE inhibition but not angiotensin II antagonism reduces plasma fibrinogen and insulin resistance in overweight hypertensive patients. J Cardiovasc Pharmacol 1998;32:616 – 620. 36. Fogari R, Zoppi A, Corradi L, Lazzari P, Mugellini A, Lusardi P: Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive patients. Br J Clin Pharmacol 1998;46:467– 471. 37. Seljeflot I, Moan A, Kjeldsen S, Sandvik E, Arnesen H: Effect of angiotensin II receptor blockade on fibrinolysis during acute hyperinsulinemia in patients with essential hypertension. Hypertension 1996;27:1299 –1304. 38. Laakso M, Karjalaainen L, Lempiainen-Kuosa P: Effects of losartan on insulin sensitivity in hypertensive subjects. Hypertension 1996; 28:392–396. 39. Moan A, Hoieggen A, Seljeflot I, Risanger T, Arnesen H, Kjeldsen SE: The effect of angiotensin II receptor antagonism with losartan on glucose metabolism and insulin sensitivity. J Hypertens 1996; 14:1093–1097. 40. Brown NJ, Agirbasli M, Vaughan DE: Comparative effect of angiotensin-converting enzyme inhibition and angiotensin II type-1 receptor antagonism on plasma fibrinolytic balance in humans. Hypertension 1999;34:285–290. 41. Goodfield N, Newby DE, Ludlam CA, Flapan AD: Effects of acute angiotensin II type 1 receptor antagonism and angiotensin converting enzyme inhibition on plasma fibrinolytic parameters in patients with heart failure. Circulation 1999;99:2983–2985. 42. Brown N, Badel MY, Benzoni F, Zanirato J, Vincent JC, Fichelle J, Worcel M: Angiotensin converting enzyme inhibition, antihypertensive activity and haemodynamic profile of trandolapril (RU 44570). Eur J Pharmacol 1988;148:79 –91. 43. Goa KL, Nagstaff AJ: Losartan potassium. A review of its pharmacology, clinical efficacy and tolerability in the management of hypertension. Drugs 1996;51:820 – 845.
926
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44. Grimaudo V, Hauert J, Backmann F, Kruithof EKO: Diurnal variation of the fibrinolytic system. Thromb Haemost 1988;59:495– 499. 45. Ranby M, Bergsdorf N, Nilsson T, Mellbring G, Winblad B, Butch A: Age dependence of tissue plasminogen activator concentrations in plasma, as studied by an improved enzyme linked immunosorbent assay. Clin Chem 1986;32:2160 –2165. 46. De Fronzo RA, Tobin JA, Andres B: Glucose clamp technique, a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:214 –223. 47. Roschlau P: Enzymatische Bestimmung des Gesamtcholesterin in Serum. Z Clin Chem Klin Biochem 1974;12:403. 48. Viikari J: Precipitation of plasma lipoproteins by PEG-6000 and its evaluation with electrophoresis and ultracentrifugation. J Lab Invest 1976;36:265. 49. Gordon T, Kannel WB, Hjortland MC, McNamara PM: Menopause and coronary heart disease: The Framingham Study. Ann Intern Med 1978;89:157–161. 50. Vague P, Juhan-Vague I, Alessi MC, Badier C, Valadier J: Metformin decreases the high plasminogen activator inhibitor capacity, plasma insulin and triglycerides levels in non diabetic obese subjects. Thromb Haemost 1987;57:326 –328. 51. Cockcroft JR, Sciberras DG, Goldberg MR, Ritter JM: Comparison of angiotensin converting enzyme inhibition with angiotensin II receptor antagonism in the human forearm. J Cardiovasc Pharmacol 1993;22:579 –584. 52. Brown NJ, Ryder D, Gainer JV, Morrow JD, Nadeau J: Differential
AJH–September 2001–VOL. 14, NO. 9, PART 1
53.
54.
55.
56.
57.
58. 59.
60.
effects of ACE-inhibitors on the vasodepressor and prostacyclin responses to bradykinin. J Pharmacol Exp Ther 1996;279:703–712. Rett K, Wicklay R, Diewtze GJ: Metabolic effects of kinins: historical and recent developments. J Cardiovasc Pharmacol 1990;15: S57–S59. Dyer SM, Frewin DB, Head RJ: The influence of chronic captopril treatment and its withdrawal on endothelium dependent relaxation. Blood Pressure 1997;1:247–253. Henriksen EJ, Jacob S, Augustin HJ, Dietze GJ: Glucose transport activity in insulin-resistant rat muscle. Diabetes 1996;45(suppl 1): S125–S128. Kishi K, Muromoto N, Nakaya Y, Miyata I, Hagi A, Hayashi H, Ebina Y: Bradykinin directly triggers GLUT4 translocation via an insulin-independent pathway. Diabetes 1998;47:550 –558. Hartl WH, Jauch KW, Wolfe RF, Schildberg FW: Effects of kinins on glucose metabolism in vivo. Horm Metab Res Suppl Ser 1990; 22:79 – 84. Saksela O, Rifkin DB: Cell-associated plasminogen activation: regulation and physiologic functions. Annu Rev Cell Biol 1988;4:93–126. Kerins DM, Hao Q, Vaughan DE: Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV. J Clin Invest 1995;96:2515–2520. Goldberg MR, Bradstreet TE, McWilliams EJ, Tanaka WK, Lipert S, Bjornsson TD, Waldman SA, Osborne B, Pivadori L, Lewis G: Biochemical effects of losartan, a nonpeptide angiotensin II receptor antagonist, on the renin-angiotensin-system in hypertensive patients. Hypertension 1995;25:37– 46.
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Differential Effects of ACE-Inhibition and Angiotensin II Antagonism on Fibrinolysis and Insulin Sensitivity in Hypertensive Postmenopausal Women Roberto Fogari, Annalisa Zoppi, Paola Preti, Elena Fogari, GianDomenico Malamani, and Amedeo Mugellini The aim of this study was to compare the effects of trandolapril and losartan on plasminogen activator inhibitor type 1 (PAI-1) levels and insulin sensitivity in hypertensive postmenopausal women. We studied 89 hypertensive (diastolic blood pressure ⬎90 and ⬍110 mm Hg) postmenopausal women, aged 51 to 60 years not taking any hormone replacement therapy. Diabetic, obese, and smoking patients were excluded. After a 4-week placebo period, they were randomized to receive 2 mg of oral trandolapril (n ⫽ 45) or 50 mg of oral losartan (n ⫽ 44) for 12 weeks according to a double-blind, parallel group design. At the end of the placebo and active treatment periods, blood pressure (BP) was measured, plasma samples were drawn to evaluate PAI-1 antigen levels, and insulin sensitivity was assessed. Both trandolapril and losartan reduced systolic BP (by a mean of 16.9 mm Hg and 15.2 mm Hg, respectively, P ⬍ .01 v placebo) and diastolic BP (by a mean of 13.1 mm Hg and 11.9 mm Hg, respectively, P ⬍ .01 v placebo) with no difference between the two treatments. The PAI-1 antigen levels were significantly decreased by trandolapril (from 36.9 ⫾ 21 ng/dL to 27.2 ⫾ 17 ng/dL, P ⬍ .05), but not by losartan
S
(from 35.3 ⫾ 22 ng/dL to 37.1 ⫾ 23 ng/dL, P ⫽ not significant). Glucose infusion rate was significantly increased by trandolapril (from 6.67 ⫾ 0.56 mg/min/kg to 7.9 ⫾ 0.65 mg/min/kg, P ⬍ .05), but was not significantly modified by losartan (from 6.7 ⫾ 0.47 mg/min/kg to 6.9 ⫾ 0.50 mg/min/kg, P ⫽ not significant). In the trandolapril group the PAI-1 decrease correlated with glucose infusion rate increase (r ⫽ 0. 36, P ⫽ .045) These results provide evidence of different effects of angiotensin converting enzyme inhibitors and AT1 antagonists on fibrinolysis and suggest that the PAI-1 decrease induced by angiotensin converting enzyme inhibitors is related to their action on insulin sensitivity and is not dependent on angiotensin II antagonism but rather on other mechanisms. It remains to be seen whether these findings apply to other patient populations than postmenopausal women. Am J Hypertens 2001;14:921–926 © 2001 American Journal of Hypertension, Ltd. Key Words: Angiotensin converting enzyme inhibitor, angiotensin II antagonist, fibrinolysis, insulin sensitivity, hypertension.
everal studies have demonstrated an association between increased plasma levels of plasminogen activator inhibitor type 1 (PAI-1) and risk of atherosclerosis and its ischemic manifestations.1– 4 Impaired fibrinolysis due to increased PAI-1 plasma levels has been described in hypertensive subjects,5–7 as well as in postmenopausal women8,9 and may account, in part, for the increased risk of atherosclerosis and its clinical complication in these subjects.6,8 –10 In addition, it has been demonstrated that insulin resistance with resulting
hyperinsulinemia is common in patients with hypertension11,12 and in postmenopausal women,13,14 and has been identified as increasing the risk of coronary heart disease (CHD).15–17 A significant correlation between PAI-1 and fasting plasma insulin has been demonstrated in hypertension,6 non-insulin-dependent diabetes,18 obesity,19 angina pectoris,20 and in normal subjects,21 which is supported by in vitro evidence that insulin increases the production of PAI-1 by hepatocytes and endothelial cells.22,23 The increase in PAI-1 associated with hyperinsulinemia may link
Received March 29, 2000. Accepted February 13, 2001.
Pavia, Italy. Address correspondence and reprint requests to Dr. Roberto Fogari, Department of Internal Medicine and Therapeutics, Via Parco Vecchio 27, 27100 Pavia, Italy.
From the Department of Internal Medicine and Therapeutics, University of Pavia, Clinica Medica I, IRCCS, Policlinico S. Matteo, © 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
0895-7061/01/$20.00 PII S0895-7061(01)02140-9
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insulin resistance to CHD by impaired fibrinolysis and increased thrombosis.24 Furthermore, recent in vitro and in vivo studies have suggested an interaction between the fibrinolytic system and the renin angiotensin system (RAS), and angiotensin II (Ang II) has been shown to stimulate PAI-1 expression in cultured endothelial cells and to produce a rapid and significant increase in circulating levels of PAI-1 antigen in humans.25–27 Beneficial effects of angiotensin converting enzyme (ACE) inhibitors on impaired fibrinolysis28 –30 and insulin resistance31–36 have been reported and some studies have suggested that the changes in fibrinolytic parameters seen with the ACE inhibitors may be mediated, at least in part, through their effect on insulin sensitivity.35 The effects of the specific Ang II type 1 (AT1) receptor antagonists, recently introduced into clinical practice, on fibrinolysis and insulin sensitivity has been less extensively studied in humans and contrasting results have been reported.35,36 – 41 The aim of this study was to assess the effects on PAI-1 antigen plasma levels and insulin sensitivity of the ACE inhibitor trandolapril42 as compared to the Ang II antagonist losartan43 in the treatment of postmenopausal women with essential hypertension.
Methods The study population included 89 postmenopausal women, aged 51 to 60 years (mean age, 55.5 years) with mild-tomoderate, uncomplicated essential hypertension (diastolic blood pressure [DBP] ⬎90 and ⬍110 mm Hg). Menopausal status was defined as the cessation of menses for at least 1 year and was confirmed by plasma follicle-stimulating hormone levels higher than 20 U/L, higher concentrations of follicle-stimulating hormone than luteinizing hormone and plasma 17--estradiol levels ⬍50 pmol/L. Women who had taken hormone replacement therapy during the 6 months preceding the study were excluded from the study as were those with diabetes mellitus, obesity, smoking habits, myocardial infarction, or stroke within the previous 6 months, history of breast cancer or thromboembolic diseases, major systemic diseases, and any condition that would require the use of concomitant medications. The study protocol was approved by the local ethics committee and informed consent was obtained from each participant at the time of enrollment. After an initial 4-week washout period with placebo, patients were randomly given 2 mg of trandolapril (n ⫽ 45) or 50 mg of losartan (n ⫽ 44) according to a double-blind, parallel group design. Both trial medications were given once daily in the morning between 8 and 9 AM, for 12 weeks. From the time of enrollment until the completion of the study, each participant maintained her diet, usual level of physical activity, and avoided a change in body weight. At the end of the placebo and active treatment period, BP, PAI-1 antigen levels, and insulin sensitivity were evalu-
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ated. The BP measurements were obtained from each patient (right arm) in the seated position by using a standard mercury sphygmomanometer (Korotkoff I and V) with a cuff of appropriate size. Measurements were taken in the morning before daily drug intake (ie, 24 h after dosing, at trough) and after the subject had rested 10 min in a quiet room. Three successive BP readings were obtained at 1-min intervals and averaged. After BP measurements, after the subjects had fasted 12 h overnight, an intravenous catheter was placed in an antecubital vein for blood sampling and a second catheter was inserted into a contralateral vein for infusion of insulin and 20% glucose. Blood was drawn during the morning because PAI-1 concentration peaks during this period.44 The PAI-1 antigen levels were determined by a commercially available sandwich enzyme-linked immunosorbent assay (TintElize PAI-1, Biopool, Inc., Ulmeå, Sweden), following a procedure described by Ranby et al.45 Insulin sensitivity was assessed by the euglycemic, hyperinsulinemic clamp, according to the technique of De Fronzo et al.46 It was calculated from the mean glucose uptake rate for the last 30 min of the clamp and expressed as the amount of glucose infused during that time (glucose infusion rate [GIR]) in milligrams per kilograms per minute. Blood glucose in the fasting state and during glucose clamp studies was measured by the glucose oxidase method (Beckman Auto-Analyzer, Fullerton, CA). Plasma insulin concentrations were determined by radioimmunoassay (RIA). Metabolic parameters including total cholesterol (TC), HDL-cholesterol (HDL-C), and triglycerides (TG), as well as body mass index (BMI) were measured at the end of the placebo and active treatment periods. The TC and TG were determined by the enzymatic method of the Chemetron Company (Frankfurt, Germany). The HDL-C was determined by the enzymatic method of Roschlau47 and LDL and very low density lipoprotein precipitation with polyethylene glycol 6000 by the method of Viikari.48 Body weight and height were measured in the fasting state with the subjects only wearing underclothes and BMI was computed as weight in kilograms divided by height in meters squared. Data are expressed as means ⫾ standard deviation. The statistical analysis of the results was performed by analysis of variance for repeated measures and Spearman’s rank correlation test. A P value ⬍ .05 was considered statistically significant.
Results All the 89 patients enrolled in the trial completed the study. Table 1 shows their demographic and clinical characteristics at the end of the placebo period; there were no significant differences in age, BMI, BP values, TC, HDL-C, TG, fasting glycemia, plasma PAI-1 antigen, and insulin levels between the two treatment groups. The main results of the study are reported in Table 2.
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Table 1. Baseline demographic and clinical characteristics of postmenopausal hypertensive women in the two treatment groups
Parameters Age (y) BMI (kg/m2) SBP (mm Hg) DBP (mm Hg) HR (beats/min) PAI-1 (ng/mL) TC (mg/dL) HDL-C (mg/dL) TG (mg/dL) Glycemia (mg/dL) Insulin (pmol/L)
Trandolapril Group (n ⴝ 45) 55.7 26.1 162.1 101.2 76.1 36.9 231 50 128 92 74
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
2 2.2 12 5 7 21 31 15 59 10 36
Losartan Group (n ⴝ 44) 56.1 25.9 160.6 100.5 75.9 35.3 227 49 120 93 77
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
2 2.1 12 5 7 22 33 16 51 9 39
BMI ⫽ body mass index; SBP ⫽ systolic blood pressure; DBP ⫽ diastolic blood pressure; HR ⫽ heart rate; PAI-1 ⫽ plasminogen activator inhibitor type 1; TC ⫽ total cholesterol; HDL-C ⫽ high density lipoprotein-cholesterol; TG ⫽ triglycerides. P ⫽ not significant.
Both trandolapril and losartan significantly decreased systolic BP (SBP) (by a mean of 17 mm Hg and 15 mm Hg, respectively, P ⬍ .01 v placebo) and DBP (by a mean of 13 mm Hg and 12 mm Hg, respectively, P ⬍ .01 v placebo) with no difference between the two treatments. The PAI-1 antigen levels were significantly reduced by trandolapril (by a mean of 9 ng/dL, P ⬍ .05), but were not affected by losartan; the difference between the two treatments being statistically significant (P ⬍ .05). The mean rate of glucose uptake for the last 30 min of the clamp (GIR), considered as an index of insulin sensitivity, was significantly increased by trandolapril (by a mean of 1.3 mg/min/kg), but not by losartan (⫹0. 2 mg/min/kg, P ⫽ not significant); the difference between the two active treatments being statistically significant. The trandoloapril-induced decrease in PAI-1 antigen levels showed a significant but rather weak correlation
923
with the increase in GIR (r ⫽ 0.35 P ⫽ .045). Such a correlation became more significant when considering only women with reduced insulin sensitivity at baseline (r ⫽ 0.60, P ⫽ .0081) (Fig. 1). There was no significant change in body weight, BMI, fasting blood glucose, plasma insulin, TC, HDL-C, and TG during treatment with both trandolapril and losartan (Table 2).
Discussion In comparison to men, women appear to lose their relative protection from coronary heart disease on becoming postmenopausal.49 Increased levels of PAI-1 as well as insulin resistance with consequent hyperinsulinemia, which may promote PAI-1 synthesis by hepatocytes and endothelial cells, have been observed in postmenopausal women and can both contribute to their increased cardiovascular risk.8,9,13,14,24 In agreement with these observations, in the present study postmenopausal women presented with baseline mean levels of PAI-1 antigen greater than the upper limit of the normal range and insulin resistance was noted in about 50% of the subjects. The concomitant presence of hypertension might have contributed to such abnormalities in fibrinolysis and glucose metabolism,5,6 thus enhancing the risk of congestive heart disease. The results of this study indicated that the ACE inhibitor trandolapril and the Ang II antagonist losartan were both effective in significantly reducing BP values in hypertensive postmemopausal women, with no statistical difference between the two drugs. However, despite their similar BP-lowering effect, losartan did not significantly affect PAI-1 antigen concentrations and insulin sensitivity, whereas trandolapril produced a significant decrease in PAI-1 antigen levels and enhanced insulin sensitivity. The dissimilar effects of trandolapril and losartan on PAI-1 levels might result from their different effects on insulin sensitivity. Such a hypothesis, which is in agree-
Table 2. Mean values of SBP, DBP, PAI-1 antigen levels, GIR, TC, HDL-C, TG, fasting glycemia, and BMI during treatment with trandolapril and losartan Trandolapril Parameters SBP (mm Hg) DBP (mm Hg) PAI-1 (ng/mL) GIR (mg/min/kg) TC (mg/dL) HDL-C (mg/dL) TG (mg/dL) Glycemia (mg/dL) BMI (kg/m2)
Placebo 162.1 101.2 36.9 6.67 231 50 128 92 26.1
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
12 5 21 0.56 31 15 59 10 2.2
Losartan
Treatment 145.2 88.1 27.2 7.99 226 50 125 89 26.0
GIR ⫽ glucose infusion rate; other abbreviations as in Table 1. * P ⬍ .05; † P ⬍ .01 v placebo; ‡ P ⬍ .05 v placebo and v losartan.
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
10† 4† 17*‡ 0.65* 29 16 57 10 2.2
Placebo 160.6 100.5 35.3 6.74 227 49 120 93 25.9
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
12 5 22 0.47 33 16 51 9 2.1
Treatment 145.4 88.6 37.1 6.96 224 48 123 92 25.9
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
11† 5† 23 0.50 31 17 50 10 2.1
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FIG. 1. Relationship between glucose infusion rate (GIR) changes (last 30 min) and PAI-1 changes in the trandolapril-treated women.
ment with the results of intervention studies aimed at reducing insulin resistance that produced a parallel decrease in plasma insulin and PAI-1 levels,21,24,50 is supported by the observation that in the present study the trandolapril-induced decrease in PAI-1 levels was significantly correlated with the increase in GIR, considered as an index of insulin sensitivity. Such a correlation was particularly evident in women with baseline insulin resistance. The dissimilar effects of the ACE inhibitor and the Ang II antagonist on insulin sensitivity may depend on their different action on the RAS. Unlike AT1 antagonists, which do not alter the metabolism of bradykinin,51 ACE inhibitors prevent the degradation of bradykinin and increase bradykinin plasma levels.52 In the present study we did not measure bradykinin concentrations or muscle blood flow, but data from the literature suggest that bradykinin or other vasoactive mediators, which are released in response to bradykinin such as prostaglandins and nitric oxide, might improve the glucose metabolism by enhancing muscle blood flow and consequently the rate of insulin and glucose delivery to the target tissues.53,54 In addition, bradykinin has been shown to facilitate the translocation of the glucose transport proteins GLUT 1 and GLUT 4 across the cell membrane,55,56 and to accelerate oxidation of plasma glucose and attenuate increased rates of hepatic glucose production.57 However, mechanisms other than the effects on insulin sensitivity might explain the lowering effect on PAI-1 concentrations by the ACE inhibitors and not by the Ang II antagonist. Angiotensin II has been demonstrated to increase the synthesis of PAI-1 in the vascular endothelium25,26 and this response is mediated by its hexapeptide metabolite Ang IV, which acts through a pharmacologically and biochemically distinct form of the angiotensin receptor.58,59 The reduction of Ang II levels by an ACE inhibitor, limiting the conversion of Ang II to smaller peptides, prevents the endothelial expression of PAI-1.59
In contrast, AT1 receptor antagonists are associated with increased plasma levels of Ang II,60 which might lead to increased Ang IV production. If this was the case, one would expect to observe increased PAI-1 levels during AT1 antagonism, although downregulation of the AT4 receptor by its ligand could attenuate such an effect. In conclusion, the results of this study showed that monotherapy of hypertension with the ACE inhibitor trandolapril in postmenopausal hypertensive women improved the fibrinolytic balance and the insulin sensitivity, whereas the Ang II antagonist losartan did not. These findings indicate that trandolapril has some theoretic clinical advantages beyond BP lowering in the antihypertensive treatment of these subjects who are at greater risk of cardiovascular complications because of the presence of fibrinolytic and metabolic disorders in addition to high blood pressure values. It remains to be seen whether these findings apply to other patient populations.
References 1.
2.
3.
4.
5.
6.
Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH: Endogenous tissue-plasminogen activator and risk of myocardial infarction. Lancet 1993;341:1165–1168. Ridker PM, Hennekens CH, Stamper MJ, Manson JAE, Vaughan DE: Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994;343:940 –943. Thompson SG, Kienast J, Pyke SDM, Haverkate F, Van de Loo JCW: Haemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332:635– 641. Salomaa V, Stinson V, Kark JD, Folsom AR, Davis CE, Wu KK: Association of fibrinolytic parameters with early atherosclerosis: the ARIC study. Circulation 1995;91:284 –290. Jeng JR, Sheu WHH, Jeng CY, Huang SH, Shieh SH: Impaired fibrinolysis and insulin resistance in patients with hypertension. Am J Hypertens 1996;9:484 – 490. Landin K, Tengborn L, Smoth U: Elevated fibrinogen and plasminogen activator inhibitor (PAI-1) in hypertension are related to metabolic risk factors for cardiovascular disease. J Intern Med 1990; 227:273–278.
AJH–September 2001–VOL. 14, NO. 9, PART 1
7.
8.
9.
10.
11. 12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
Eliasson M, Jansson JH, Nilsson P, Asplund K: Increased levels of tissue plasminogen activator inhibitor antigen in essential hypertension: a population-based study in Sweden. J Hypertens 1997;15: 349 –356. Gebara OCE, Mittleman MA, Sutherland P, Lipinska I, Matheney T, Xu P, Welty FK, Wilson PW, Levy D, Muller JE: Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation 1995;91:1952– 1958. Kon Koh K, Horne MDK, Csako G, Waclawiw MA, Cannon RO: Relation of fibrinolytic potentiation by estrogen to coagulation pathway activation in postmenopausal women. Am J Cardiol 1999;83: 466 – 469. Winther K, Gleerup G, Hedner T: Enhanced risk of thromboembolic disease in hypertension from platelet hyperfunction and decreased fibrinolytic activity: has antihypertensive therapy any influence? J Cardiovasc Pharm Ther 1997;19(suppl 3):S1–S24. Ferrannini E, Buzzigoli G, Bonadonna R: Insulin resistance in essential hypertension. N Engl J Med 1987;317:350 –357. Pollare T, Lithell H, Berne C: Insulin resistance is a characteristic feature of primary hypertension independent of obesity. Metabolism 1990;39:167–174. Walton C, Godsland IF, Proudder AJ, Wynn W, Stevenson JC: The effects of menopause on insulin sensitivity, secretion and elimination in non-obese, healthy women. Eur J Clin Invest 1993:23:466 – 473. Lindheim SR, Buchanan TA, Duffy DM, Vijod MA, Kojima T, Stanczyk FZ, Lobo RA: Comparison of estimates of insulin sensitivity in pre and postmenopausal women using the insulin tolerance test and the frequently sampled intravenous glucose tolerance test. J Soc Gynecol Invest 1994;1:150 –154. Pyorala K: Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two population studies in Finland. Diabetes Care 1979;2:131–141. Welborn TA, Weame K: Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care 1979;2:154 –160. Ducimetiere P, Eschwege E, Papoz L, Richard JL, Claude JF, Rosselin G: Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia 1980;19:205–221. Juhan-Vague I, Roul C, Alessi MC, et al: Increased plasminogen activator inhibitor activity in non-insulin-dependent diabetic patients. Relationship with plasma insulin. Thromb Haemost 1989;61: 370 –373. Vague P, Juhan Vague I, Chabert V, Alessi MC, Atlan C: Fat distribution and plasminogen activator inhibitor activity in nondiabetic obese women. Metabolism 1989;38:913–915. Juhan Vague I, Alessi MC, Joly P, Thirion X, Vague P, Declerck PJ, Serradimiqni A, Collen D: Plasma plasminogen activator inhibitor in angina pectoris. Influence of plasma insulin and acute-phase response. Arteriosclerosis 1989;9:362–367. Vague P, Juhan Vague I, Aillaud MF, Badier C, Viard R, Alessi M, Collen D: Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level and relative body weight in normal and obese subjects. Metabolism 1986;35:250 – 253. Kooistra T, Bosma PJ, Tons HAM, Van de Berg P, Meyer P, Princen HMG: Plasminogen activator inhibitor 1: biosynthesis and mRNA level are increased by insulin in cultured human hepatocytes. Thromb Haemost 1989;62:723–728. Nordt TK, Schneider DJ, Sobel BE: Augmentation of the synthesis of plasminogen activator inhibitor type-1 by precursors of insulin. A potential risk factor for vascular disease. Circulation 1994;89:321– 330. Juhan Vague I, Alessi MC, Vague P: Increased plasma plasminogen activator inhibitor 1 levels. A possible limk between insulin resistance and atherothrombosis. Diabetologia 1991;34:457– 462.
TRANDOLAPRIL, LOSARTAN, AND FIBRINOLYSIS IN POSTMENOPAUSAL WOMEN
925
25. Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE: Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Circulation 1993;87:1969 –1973. 26. Vaughan DE, Lazos SA, Tong K: Angiotensin II regulates the expression of plasminogen activator inhibitor -1 in cultured endothelial cells. J Clin Invest 1995;95:995–1001. 27. Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE: Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. Hypertension 1998;32:965–971. 28. Wright RA, Flapan AD, Alberti KGMM, Ludlam CA, Fox KAA: Effects of captopril therapy on endogenous fibrinolysis in men with recent uncomplicated myocardial infarction. J Am Coll Cardiol 1994;24:67–73. 29. Vaughan DE, Rouleau JC, Ridker P, Arnold JMO, Menapace FJ, Pfeffer MA: Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. Circulation 1997; 96:442– 447. 30. Sakata K, Shirotani M, Yoshida H, Urano T, Takada Y, Takada A: Differential effects of enalapril and nitrendipine on the fibrinolytic system in essential hypertension. Am Heart J 1999;137:1094 –1099. 31. Lithel HOL: Effects of antihypertensive drugs on insulin, glucose and lipid metabolism. Diabetes Care 1991;14:203–209. 32. Paolisso G, Gamardella A, Verza M: ACE inhibition improves insulin sensitivity in aged insulin-resistant hypertensive patients. J Hum Hypertens 1992;6:175–179. 33. Tomiyama H, Kushiro T, Abeta H, Ishii T, Takahashi A, Furukawa L, Asagami T, Hino T, Saito F, Otsuka Y: Kinins contribute to the improvement of insulin sensitivity during treatment with angiotensin converting enzyme inhibitor. Hypertension 1994;23:450 – 455. 34. Carvalho CR, Thirone AC, Gontijo JA, Velloso LA, Saad MJ: Effect of captopril, losartan and bradykinin on early steps of insulin action. Diabetes 1997;46:1950 –1957. 35. Fogari R, Zoppi A, Lazzari P, Preti P, Mugellini A, Corradi L, Lusardi P: ACE inhibition but not angiotensin II antagonism reduces plasma fibrinogen and insulin resistance in overweight hypertensive patients. J Cardiovasc Pharmacol 1998;32:616 – 620. 36. Fogari R, Zoppi A, Corradi L, Lazzari P, Mugellini A, Lusardi P: Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive patients. Br J Clin Pharmacol 1998;46:467– 471. 37. Seljeflot I, Moan A, Kjeldsen S, Sandvik E, Arnesen H: Effect of angiotensin II receptor blockade on fibrinolysis during acute hyperinsulinemia in patients with essential hypertension. Hypertension 1996;27:1299 –1304. 38. Laakso M, Karjalaainen L, Lempiainen-Kuosa P: Effects of losartan on insulin sensitivity in hypertensive subjects. Hypertension 1996; 28:392–396. 39. Moan A, Hoieggen A, Seljeflot I, Risanger T, Arnesen H, Kjeldsen SE: The effect of angiotensin II receptor antagonism with losartan on glucose metabolism and insulin sensitivity. J Hypertens 1996; 14:1093–1097. 40. Brown NJ, Agirbasli M, Vaughan DE: Comparative effect of angiotensin-converting enzyme inhibition and angiotensin II type-1 receptor antagonism on plasma fibrinolytic balance in humans. Hypertension 1999;34:285–290. 41. Goodfield N, Newby DE, Ludlam CA, Flapan AD: Effects of acute angiotensin II type 1 receptor antagonism and angiotensin converting enzyme inhibition on plasma fibrinolytic parameters in patients with heart failure. Circulation 1999;99:2983–2985. 42. Brown N, Badel MY, Benzoni F, Zanirato J, Vincent JC, Fichelle J, Worcel M: Angiotensin converting enzyme inhibition, antihypertensive activity and haemodynamic profile of trandolapril (RU 44570). Eur J Pharmacol 1988;148:79 –91. 43. Goa KL, Nagstaff AJ: Losartan potassium. A review of its pharmacology, clinical efficacy and tolerability in the management of hypertension. Drugs 1996;51:820 – 845.
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44. Grimaudo V, Hauert J, Backmann F, Kruithof EKO: Diurnal variation of the fibrinolytic system. Thromb Haemost 1988;59:495– 499. 45. Ranby M, Bergsdorf N, Nilsson T, Mellbring G, Winblad B, Butch A: Age dependence of tissue plasminogen activator concentrations in plasma, as studied by an improved enzyme linked immunosorbent assay. Clin Chem 1986;32:2160 –2165. 46. De Fronzo RA, Tobin JA, Andres B: Glucose clamp technique, a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:214 –223. 47. Roschlau P: Enzymatische Bestimmung des Gesamtcholesterin in Serum. Z Clin Chem Klin Biochem 1974;12:403. 48. Viikari J: Precipitation of plasma lipoproteins by PEG-6000 and its evaluation with electrophoresis and ultracentrifugation. J Lab Invest 1976;36:265. 49. Gordon T, Kannel WB, Hjortland MC, McNamara PM: Menopause and coronary heart disease: The Framingham Study. Ann Intern Med 1978;89:157–161. 50. Vague P, Juhan-Vague I, Alessi MC, Badier C, Valadier J: Metformin decreases the high plasminogen activator inhibitor capacity, plasma insulin and triglycerides levels in non diabetic obese subjects. Thromb Haemost 1987;57:326 –328. 51. Cockcroft JR, Sciberras DG, Goldberg MR, Ritter JM: Comparison of angiotensin converting enzyme inhibition with angiotensin II receptor antagonism in the human forearm. J Cardiovasc Pharmacol 1993;22:579 –584. 52. Brown NJ, Ryder D, Gainer JV, Morrow JD, Nadeau J: Differential
AJH–September 2001–VOL. 14, NO. 9, PART 1
53.
54.
55.
56.
57.
58. 59.
60.
effects of ACE-inhibitors on the vasodepressor and prostacyclin responses to bradykinin. J Pharmacol Exp Ther 1996;279:703–712. Rett K, Wicklay R, Diewtze GJ: Metabolic effects of kinins: historical and recent developments. J Cardiovasc Pharmacol 1990;15: S57–S59. Dyer SM, Frewin DB, Head RJ: The influence of chronic captopril treatment and its withdrawal on endothelium dependent relaxation. Blood Pressure 1997;1:247–253. Henriksen EJ, Jacob S, Augustin HJ, Dietze GJ: Glucose transport activity in insulin-resistant rat muscle. Diabetes 1996;45(suppl 1): S125–S128. Kishi K, Muromoto N, Nakaya Y, Miyata I, Hagi A, Hayashi H, Ebina Y: Bradykinin directly triggers GLUT4 translocation via an insulin-independent pathway. Diabetes 1998;47:550 –558. Hartl WH, Jauch KW, Wolfe RF, Schildberg FW: Effects of kinins on glucose metabolism in vivo. Horm Metab Res Suppl Ser 1990; 22:79 – 84. Saksela O, Rifkin DB: Cell-associated plasminogen activation: regulation and physiologic functions. Annu Rev Cell Biol 1988;4:93–126. Kerins DM, Hao Q, Vaughan DE: Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV. J Clin Invest 1995;96:2515–2520. Goldberg MR, Bradstreet TE, McWilliams EJ, Tanaka WK, Lipert S, Bjornsson TD, Waldman SA, Osborne B, Pivadori L, Lewis G: Biochemical effects of losartan, a nonpeptide angiotensin II receptor antagonist, on the renin-angiotensin-system in hypertensive patients. Hypertension 1995;25:37– 46.