G.D. Malamani

Differential effects of ACE-inhibition and angiotensin II antagonism on fibrinolysis and insulin sensitivity in hypertensive postmenopausal women.

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 (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.

Effect of benazepril addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients.

The aim of this study was to evaluate the effect of benazepril addition to amlodipine antihypertensive treatment on ankle–foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP), two objective measures of ankle oedema. A total of 32 mild to moderate essential hypertensives (DBP>90 and <110 mmHg), aged 30–70 years were studied. After a 4-week placebo period, they were randomized to amlodipine 5 mg o.d. or benazepril 10 mg o.d. or amlodipine 5 mg plus benazepril 10 mg o.d. for 4 weeks, according to a crossover design. At the end of the placebo period and of each active treatment period, blood pressure,AFV and PSTP were evaluated. AFV was measured using the principle of water displacement. PSTP was assessed using a system, the subcutaneous pretibial interstitial enviroment with a water manometer. Both amlodipine and benazepril monotherapy significantly reduced SBP (−18.2±4 and −17.8±4 mmHg, respectively, P<0.01 vs baseline) and DBP (−12.1±3 and −11.7±3 mmHg, respectively, P<0.01); the reduction was increased by the combination (−24.2±5 mmHg for SBP, P<0.001 and −16.8±4 mmHg for DBP, P<0.001). Amlodipine monotherapy significantly increased both AFV (+17.1%, P<0.001 vs baseline) and PSTP (+56.6%, P<0.001 vs baseline). As compared to amlodipine alone, the combination produced a less pronounced increase in AFV (+5.5%, P<0.05 vs baseline and P<0.01 vs amlodipine) and PSTP (+20.5%, P<0.05 vs baseline and P<0.01 vs amlodipine). Ankle oedema was clinically evident in 11 patients with amlodipine monotherapy and in three patients with the combination. These results suggest that ACE-inhibitors partially counteract the microcirculatory changes responsible for Ca-antagonists-induced oedema formation.

Plasma lipids during chronic antihypertensive therapy with different β-blockers

The aim of this study was to compare the effects of long-term monotherapy with five different beta-blockers on plasma lipids in patients with essential hypertension. We studied 99 male patients, aged 35-55 years, with mild to moderate hypertension, who worked in the same community. After a 1-month placebo period, patients were assigned to receive propranolol (160 mg/day), atenolol (100 mg/day), bisoprolol (10 mg/day), mepindolol (10 mg/day), or celiprolol (400 mg/day). Therapy was continued for 2 years. Blood pressure (BP), heart rate, and blood samples for evaluation of total cholesterol (TC), LDL-cholesterol (LDL-C), triglycerides (TG) and HDL-cholesterol (HDL-C) were taken before and after the initial placebo period, and subsequently every 6 months from the beginning of active treatment. All beta-blockers caused similar reductions in BP that were maintained throughout the study. None of the beta-blockers significantly affected TC or LDL-C. Propranolol, a nonselective beta-blocker, caused the most pronounced changes in TG (+33 to 43%) and in HDL-C (-30 to -32%). Atenolol, a beta 1-selective agent, had the same quantitative effects, but to a lesser extent (TG + 23 to 30%; HDL-C -15 to -19%). Bisoprolol, more beta 1-selective than atenolol, and mepindolol, nonselective with ISA, increased TG (+20 to 28% and +14 to 25%, respectively) but did not significantly affect HDL-C. In contrast, celiprolol, a highly cardioselective beta-blocker with beta 2-partial agonism, improved lipid risk factors by significantly reducing TG (-14 to -21%) and increasing HDL-C (+8 to 14%).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect on the development of ankle edema of adding delapril to manidipine in patients with mild to moderate essential hypertension: A three-way crossover study

BACKGROUND Use of the combination of an angiotensin-converting enzyme inhibitor (ACEI) and a calcium channel blocker (CCB) is considered a rational approach in patients whose hypertension is not controlled by monotherapy, providing better blood pressure (BP) control than the individual components with a lower incidence of adverse effects. In particular, such combinations have been found to reduce the incidence of ankle edema, the most common adverse effect of dihydropyridine annhypertensives. OBJECTIVE The present study was undertaken to evaluate the effect on the development of ankle edema of adding the ACEI delapril to the CCB manidipine in patients with mild to moderate essential hypertension. METHODS Patients between the ages of 30 and 70 years who had mild to moderate hypertension (diastolic BP [DBP] >90 and <110 mm Hg) were included in the study. After a 4-week placebo run-in period, eligible patients were randomized to receive 6 weeks each of manidipine 10 mg/d, delapril 30 mg/d, and both in a crossover fashion. There was a 2-week washout period between treatments. Ankle edema was assessed based on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP). Sitting BP, AFV, and PSTP were measured at the end of the placebo run-in period and the end of each active-treatment period. RESULTS The study enrolled 40 patients with previously untreated hypertension (21 women, 19 men). Both manidipine and delapril monotherapy were associated with significant reductions from baseline in systolic BP (SBP) (mean [SD], -17.3 [4] and -14.8 [4] mm Hg, respectively; both, P<0.01) and DBP (-14.6 [3] and -12.9 [3] mm Hg; both, P<0.01). Compared with monotherapy, the combination of manidipine and delapril was associated with greater reductions from baseline in SBP (-21.8 [5] mm Hg; P<0.001) and DBP (-18.6 [4] mm Hg; P<0.001). Manidipme monotherapy was associated with significant increases from baseline in both AFV (7.9%; P<0.001) and PSTP (36.6%; P<0.01). Compared with manidipine alone, the combination of manidipine and delapril was associated with less pronounced increases in AFV (3.3%; P<0.05) and PSTP (10.4%; P<0.05). Ankle edema was clinically evident in 3 patients after receipt of manidipine monotherapy and in 1 patient after receipt of combination treatment. CONCLUSION In these patients with mild to moderate essential hypertension, the addition of delapril to manidipine partially counteracted the manidipine-induced microcirculatory changes responsible for ankle edema.

Effects of four angiotensin II-receptor antagonists on fibrinolysis in postmenopausal women with hypertension

Abstract Background: Reduced fibrinolysis due to increased concentrations of plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of endogenous fibrinolysis, is associated with an increased risk for cardiovascular events. Objective: This study was undertaken to compare the effects of 4 angiotensin II (AII)-receptor antagonists with different pharmacokinetic properties—losartan, valsartan, irbesartan, and candesartan—on levels of PAI-1 antigen in postmenopausal women with hypertension. Methods: Postmenopausal women aged 51 to 60 years with mild to moderate hypertension (diastolic blood pressure [DBP] > 90 mm Hg and ≤105 mm Hg) who were not taking any hormone replacement therapy were studied. Patients with diabetes or obesity and patients who smoked were excluded. After a 2-week placebo washout period, patients were assigned to receive losartan 50 mg, valsartan 80 mg, irbesartan 150 mg, candesartan 8 mg, or placebo for 12 weeks according to a double-blind, randomized, parallel-group design, with a titration for nonresponders after 6 weeks. At the end of the placebo period and 6 and 12 weeks after active treatment, blood pressure, PAI-1 antigen levels, heart rate, and body mass index were measured. Results: A total of 156 patients were randomized to receive losartan (n = 31), valsartan (n = 32), irbesartan (n = 31), candesartan (n = 32), or placebo (n = 30); of these, 140 completed the study. All 4 active treatments significantly reduced DBP and systolic blood pressure, with no significant differences in efficacy between groups. Plasma PAI-1 levels decreased slightly after treatment with losartan (−0.9%) and valsartan (−3.8%) and increased slightly with irbesartan (+10.1%), but these values were not significantly different from placebo. In contrast, candesartan significantly increased PAI-1 values by 33.3% ( P Conclusions: These findings suggest that, despite a comparable antihypertensive efficacy, candesartan differs from the other AII-receptor antagonists studied in that it significantly increases PAI-1 antigen levels. This might be related to its specific pharmacologic characteristics, particularly its insurmountable antagonism of the AII AT1 receptor.

Effects of Amlodipine vs Enalapril on Microalbuminuria in Hypertensive Patients with Type II Diabetes

SummaryThe effects of once-daily amlodipine 10mg or enalapril 20mg on urinary albumin excretion (UAE) were evaluated over 12 months, in a randomised trial of 50 hypertensive patients with type II (non-insulin-dependent) diabetes mellitus and microalbuminuria. Both drugs significantly reduced systolic and diastolic blood pressure without affecting heart rate or glucose homeostasis. UAE was significantly reduced after 3 months of treatment with enalapril, and 6 months of therapy with amlodipine. The percentage reduction in UAE significantly correlated with the decrement in systolic blood pressure and duration of hypertension in both treatment groups. Creatinine clearance was unaffected by enalapril, but was significantly increased by amlodipine. Long term treatment with either amlodipine or enalapril was therefore effective in reducing UAE in hypertensive patients with type II diabetes and microalbuminuria.

The effect of celiprolol on the blood lipid profile in hypertensive patients with high cholesterol levels

SummaryThe aim of this study was to compare the effects of chronic antihypertensive therapy with either celiprolol or atenolol on plasma lipids in patients with hypercholesterolemia. Forty-six patients with essential hypertension and a total cholesterol (TC) concentration > 220 mg/dl were studied. After 1 month on placebo, patients were stratified into five classes on the basis of their plasma TC levels and then randomized to receive atenolol 100 mg/day or celiprolol 400 mg/day for 1 year. Blood pressure (BP), heart rate (HR), and blood samples for evaluation of TC, HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides (TG) were taken before and after the placebo period, and every 6 months from the beginning of the active treatment. Celiprolol and atenolol caused similar reduction in BP. Both atenolol and celiprolol decreased TC. Atenolol significantly reduced HDL-C, while celiprolol increased it (p<0.01 at 12 months), and the difference between the two drugs was statistically significant in this regard. LDL-C levels were not significantly affected by atenolol, but were progressively reduced by celiprolol (p<0.05 at 6 months, p<0.01 at 12 months). TG rose under atenolol but was reduced by celiprolol (p<0.05). The results of this study show that the celiprolol-induced changes in plasma lipids may be favorable and suggest that, in hypertensive patients with high cholesterol levels, beta-blocker therapy with celiprolol may be effective in lowering BP without worsening the lipid profile.

Nitrendipine 20 MG Once Daily Versus Nicardipine Slow Release 40 MG Twice Daily in Mild Essential Hypertension: Evaluation by 24-Hour Ambulatory Blood Pressure Monitoring

The extent and duration of the blood pressure (BP) lowering effect of 20 mg nitrendipine (NIT) once daily and 40 mg nicardipine slow release (NIC) twice daily were compared in 12 men (aged 39-55 years) with mild essential hypertension according to a randomized, cross over study. Twenty-four-hour non invasive ambulatory BP monitoring (Spacelabs 5200) was performed at the end of a 2-week placebo run-in and after 4 weeks of each active treatment; automatic BP measurements were programmed at 15-min intervals. Both treatments significantly (p less than .01) reduced mean 24-hour and daytime systolic (SBP) and diastolic (DBP) BP, but had different effects on daytime BP profiles. NIT decreased SBP and DBP (p less than .05) in 5 out of 8 two-hour subperiods (from 8 a.m. to 6 p.m.), followed by a loss of effect; NIC reduced SBP and DBP (p less than .05) in 7 out of 8 two-hour subperiods (from 8 a.m. to 10 p.m.). During the night-time, NIT reduced mean SBP (p less than .05) and NIC both mean SBP and DBP values (p less than .05; p less than .05 vs NIT for SBP). Heart rate was not affected by either treatment. Thus, after short-term treatment in mild essential hypertensives nitrendipine once daily was not as effective as nicardipine slow release twice daily in reducing blood pressure throughout the 24 hours.

Effect of trandolapril-verapamil combination on fibrinolytic function in hypertensive diabetic patients

Aim of this study was to evaluate the effect of trandolaprilverapamil combination on tissue plasminogen activator (tPA) and inhibitor 1 (PAI-1) in hypertensive type 2 diabetic patients, a population with a well known impaired fibrinolytic function. We studied 58 (28 men, 30 women) mild to moderate hypertensive (DBP . 95 # 105 mmHg) patients with well controlled NIDDM aged 46 to 65 years. After a 4 week placebo (P) period they were randomized to trandolapril 2 mg o.d. or verapamil 180 mg o.d. or their combination o.d. for 4 weeks; then after a new 2 week P period a cross-over was performed and the patients were treated for other 4 weeks with the alternative drug according to a latin square design. The last day of each treatment period BP was measured and a blood sample was taken to evaluate t-PA and PAI-1. The main results are as follows: