Effects of isradipine sustained release on platelet function and fibrinolysis in essential hypertensives with or without other risk factors.

The aim of this study was to assess the chronic effects of a highly selective dihydropiridine calcium channel blocker, israpidine, in its sustained release form (I-SRO), on platelet functions and fibrinolytic parameters in subjects with essential hypertension (EH) combined or not with other well-known cardiovascular risk factors, such as cigarette smoking (EH+S) and type II diabetes mellitus (EH+DM). Thirty-six patients with essential hypertension with sitting diastolic blood pressures of 96-104 mmHg without (EH, n = 12) or with other risk factors (EH+S, n = 12, EH+DM, n = 12) were enrolled. After a 4-week, single-blind, placebo run-in period, the subjects received I-SRO 5 mg once daily for 18 weeks. After both placebo and 6 and 18 weeks of I-SRO treatment, the following parameters were measured: sitting blood pressure by mercury sphygmomanometer; platelet aggregation, plasma beta-thromboglobulin (BTG), platelet factor-4 (PF4), and plasminogen activator inhibitor 1 (PAI-1) by means of ELISA methods; and euglobulin lysis time before (ELT) and after standardized (10 min) venous occlusion (ELT-VO). In the group of patients as a whole compared with placebo, I-SRO significantly reduced SBP/DBP platelet aggregation, BTG, PF4, ELT, and ELT-VO. Significant reductions in these parameters were also observed in each group. In addition to the antihypertensive effect, I-SRO chronic treatment may favorably affect the platelet function and fibrinolytic system in essential hypertension with or without other cardiovascular risk factors.

[Antihypertensive action of nicardipine retard in 24 hours and its effect on stress]. / Azione antiipertensiva della Nicardipina Retard nelle 24 ore e suo comportamento nello stress.

Thirty-six patients (17 males and 19 females), aged between 40 and 70 years old (mean age 55.9), suffering from slight or moderate arterial hypertension, were monitored for four weeks after 14 days of placebo treatment. In a double-blind and random study 24 patients were treated with Nicardipine Retard (40 mg twice a day) whereas a further 12 received placebo twice a day. Sphigomanometric controls carried out after two and four weeks showed a significant reduction in arterial pressure only in those patients receiving active treatment. 24-hour out-patient monitoring of arterial pressure, carried out using Spacelabs 5300, showed a reduction in both systolic and diastolic arterial pressure throughout the day in subjects treated with calcium-antagonists compared to the placebo group. The normal physiological 24-hour trend of arterial pressure was always taken into account. The pressure response to a cold pressor test, mental arithmetic test, isometric and dynamic effort tests, measuring using a cycloergometer, was not modified by anti-hypertensive treatment, thus confirming the preservation of normal physiological behaviour during daily activities. There was no significant change in heart rate and the drug was well tolerated.

[Slow-release nicardipine in the treatment of arterial hypertension: comparative study vs. an ACE inhibitor]. / Nicardipina a lento rilascio nel trattamento dell'ipertensione arteriosa: studio comparativo verso un aceinibitore.

The anti-hypertensive activity and influence on some forms of stress of slow-release Nicardipoine and Captopril were compared using a randomized 2:1 protocol. Thirty-six patients, mean age 55.9 years, suffering from slight or moderate arterial hypertension were treated with either 40 mg of Nicardipine retard twice a day (b.i.d.), or Captopril in a dose of 25 mg (b.i.d.) for 8 weeks. A significant reduction was observed in arterial pressure, both in orthostatism and clinostatism, following both treatments in comparison to the placebo period, but the group treated with slow-release Nicardipine showed a greater and statistically significant reduction in arterial pressure. No significant change in heart rate was reported using either drug. Non-invasive out-patient monitoring of arterial pressure, performed using Spacelabs 5300, showed a significant reduction in arterial pressure using both drugs and the conservation of the normal circadian rhythm of arterial pressure. The pressure response to the cold pressor test (CPT), mental arithmetic test (MAS), and to dynamic and isometric effort was positive with both drugs, thus revealing a degree of protection offered by treatment using these two substances. In overall terms, the two drugs were well tolerated.

Effects of atenolol and enalapril on kidney function in hypertensive diabetic patients.

The aim of the study was to evaluate the efficacy of enalapril and atenolol in decreasing the severity of proteinuria in hypertensive patients suffering from insulin-dependent diabetes mellitus. We studied 20 hypertensive patients. All patients had proteinuria (> 3 g/24 h) and were receiving insulin treatment. Proteinuria was measured monthly in the run-in period (3 months) and during the active drug treatment (8 months). Glomerular filtration rate, effective renal plasma flow, filtration fraction, and total renal resistance were determined after the run-in and treatment periods. The patients were randomly assigned to treatment with enalapril 20 mg/day or atenolol 100 mg/day for 8 months. In both groups blood pressure decreased significantly. After 8 months' treatment, severity of proteinuria significantly decreased both in the enalapril-treated group and in the group receiving atenolol. Glomerular filtration rate and effective renal plasma flow significantly increased, while total renal resistance decreased in the patients given enalapril, whereas glomerular filtration rate, renal plasma flow, and total renal resistance significantly decreased in the patients given atenolol. The results of this study show that enalapril and atenolol reduce proteinuria in hypertensive diabetic patients by a mechanism related to their antihypertensive effects; furthermore, the beneficial effects of enalapril might be also linked to intrarenal effects.

Forearm arterial distensibility in patients with hypertension: comparative effects of long-term ACE inhibition and beta-blocking.

Fifty patients with mild or moderate hypertension were assessed for the influence on peripheral hemodynamics of 10 months of treatment with lisinopril (25 patients) or metoprolol (25 patients). Two-dimensional Doppler flowmetry was used for the evaluation. Responding patients (blood pressure < 150/90 mm Hg) were monitored for another 4 weeks after treatment withdrawal to determine whether changes in forearm hemodynamics, if any, persisted. Twenty-two patients from either group (88%) were considered to be responders. Systolic and diastolic blood pressure in patients receiving lisinopril dropped by 6% and 15%, respectively (p < 0.001), in those receiving metoprolol the decrease was 5.9% and 14%, respectively (p < 0.001). Forearm hemodynamics was not significantly different before treatment and improved in patients receiving lisinopril, with increased compliance (p < 0.001) and lower vascular resistance (p < 0.001). No significant changes were observed with metoprolol. After withdrawal, blood pressure returned to baseline values in both groups. However, improvement in forearm hemodynamics persisted in the lisinopril group. Hemodynamics changes were statistically different on lisinopril versus metoprolol both after treatment and after withdrawal. Lisinopril, but not metoprolol, seems capable to induce regression of functional and/or structural changes of large arteries in patients with hypertension.

Glucose and lipid metabolism in essential hypertension: effects of diuretics and ACE-inhibitors.

Various aspects of carbohydrate and lipid metabolism were studied in two groups of patients with mild hypertension before and after 6 months' treatment with either lisinopril (n = 10) or hydrochlorothiazide (n = 10). A significant reduction of arterial blood pressure was seen after both treatment regimens. Circulating plasma glucose, insulin, C-peptide and triglyceride concentrations were measured at hourly intervals from 8.00 a.m. to 5.00 p.m. in patients on an isocaloric diet (35 cal/kg/day). Plasma glucose concentrations remained unchanged, while insulin and C-peptide concentrations were higher in association with hydrochlorothiazide treatment. Conversely, lisinopril-treated patients had lower C-peptide concentrations after treatment. The changes in daylong plasma glucose and insulin-stimulated glucose uptake increased after hydrochlorothiazide treatment and decreased following lisinopril. Lastly, plasma cholesterol concentrations did not change after lisinopril therapy, whereas plasma high density cholesterol decreased as a result of hydrochlorothiazide treatment.

Large artery compliance in essential hypertension. Effects of calcium antagonism and beta-blocking.

This study used 2D Doppler flowmetry to assess the effects on peripheral hemodynamics of effective treatment with nicardipine or atenolol in 40 patients with mild or moderate essential hypertension. Two groups of 20 patients received treatment with nicardipine or atenolol, respectively, for 8 months. Consequently, those patients considered to be responders (blood pressure less than 150/90 mm Hg) were monitored for another 4 weeks after the therapy was suspended in order to determine whether the changes, if any, in arterial compliance persisted. Following the 8-month therapy, four patients from each group were excluded from the study because of unsatisfactory blood pressure levels. After the treatment, there was a decrease in blood pressure in both groups (P less than .01). In the nicardipine group, there was a significant increase in diameter and compliance (P less than .01), whereas pulse wave velocity and resistance decreased (P less than .01). In the atenolol group, these parameters did not change significantly. After therapy was ended, blood pressure returned to baseline values in both groups. However, in the nicardipine group, the observed improvement in forearm hemodynamics persisted. This result may indicate that nicardipine is able to induce a regression of functional and/or structural changes in the large arteries of hypertensive patients.

Hypercholesterolaemia alters arterial and blood factors related to atherosclerosis in hypertension.

To evaluate the influence of hypercholesterolaemia on arterial and blood factors related to cardiovascular disease in hypertension, 20 normocholesterolaemic and 31 hypercholesterolaemic hypertensive patients underwent determinations of whole blood filterability (WBF), plasma fibrinogen concentration (PF) and aortic pulse wave velocity (PWV). Both of the groups had similar age, body mass index, cumulative smoking dose and blood pressure. Hypercholesterolaemics had lower WBF (P less than 0.02), higher PF (P less than 0.02) and higher PWV (P less than 0.01) than normocholesterolaemics. In the whole population WBF correlated with age (P less than 0.005), mean blood pressure (P less than 0.01), total cholesterol (P less than 0.05) and plasma fibrinogen (P less than 0.01). However, in a multivariate analysis where age and pressure were controlled as variables, only the association between WBF and PF remained significant (P less than 0.001). Thus, the higher fibrinogen affects whole blood filterability in hypercholesterolaemic hypertensive patients. In the whole population PWV correlated positively with HDL cholesterol (P less than 0.01) and age (P less than 0.001) and the association with HDL cholesterol remained significant in a multivariate analysis (P less than 0.001) where age was controlled. The effect of ageing on arterial rigidity seems to be similar in both hypertensive groups as deduced from the identical regression slopes relating pulse wave velocity to age. So in hypertension with high cholesterol, arterial rigidity was increased without changes in arterial stiffening with age.

Cardiovascular effects of cigarette smoking.

The risk of cardiovascular morbidity and mortality is greatly affected by cigarette smoking. In order to study the pressor response to smoking, 10 normotensive and 10 mild or moderate essential-hypertensive smokers (> 20 cigarettes daily) were compared with 2 comparable groups of non-smokers. All subjects were asked to smoke 4 cigarettes during 1 h; blood pressure (BP) and heart rate (HR) were monitored beat-to-beat by a non-invasive device (Finapres Ohmeda) during the smoking period and during the immediately preceding non-smoking hour. Furthermore, all subjects underwent 24-hour ambulatory BP monitoring. In all groups, each cigarette induced a similar and statistically significant increase from baseline for both BP and HR. The recovery from the marked rise in BP and HR was very slow so that in the smoking hours BP and HR were persistently higher than in non-smoking hours; there were no statistically significant differences between the four groups. During 24-hour ambulatory monitoring both normo- and hypertensive smokers showed higher BP values and higher BP variability in comparison with the respective non-smokers' group. In conclusion, smoking habits were associated with a persistent increase in BP in each group we studied, possibly contributing to a smoking-related cardiovascular risk.

Efficacy and tolerability of enalapril (20 mg)/hydrochlorothiazide (12.5 mg) combination therapy in essential hypertension.

The efficacy and tolerability of a preconstituted formulation combining enalapril (20 mg) and hydrochlorothiazide (12.5 mg) were evaluated in patients with essential hypertension unresponsive to enalapril monotherapy (20 mg/day). The duration of this open-lable, multicenter, noncomparative trial was 12 weeks: a two-week washout period followed by ten weeks of active treatment. During the active treatment period, patients received enalapril alone (up to 20 mg/day) for six weeks. At the end of week 6, patients with supine diastolic blood pressure greater than 90 mmHg were treated with the enalapril/hydrochlorothiazide combination therapy (EN/HCTZ). Of the 147 patients who were entered into the study, 81 were not normalized with enalapril alone. At the end of the study period, blood pressure was normalized (supine diastolic blood pressure less than or equal to 90 mmHg) in 60 (74%) of the 81 patients who had received the EN/HCTZ combination. Overall, 86% of the patients achieved satisfactory blood pressure control with this therapeutic regimen. Adverse reactions were mild and transient. Six patients experienced undesirable effects, the most frequent of which was coughing (2 cases). Neither enalapril (20 mg/day) alone nor the EN/HCTZ combination had any significant influence on any of the metabolic parameters evaluated. No hypokalemia and no significant changes in serum lipids occurred in the course of the study.

Risk factors and early extracoronary atherosclerotic plaques detected by three-site ultrasound imaging in hypercholesterolemic men. Prévention Cardio-vasculaire en Médecine du Travail METRA Group.

Ultrasonic detection of atherosclerotic plaque of carotid abdominal aortic and femoral arteries and evaluation of risk factors were performed in 208 hypercholesterolemic men without cardiovascular disease. Twenty-six percent of them had no plaque. Plaque at the carotid, aortic, and femoral sites was found in 37%, 48%, and 53% of subjects, respectively. Plaque was associated (1) in carotid arteries with increased total and low-density lipoprotein cholesterol; (2) in the aorta with increased age, pressure, glycemia, and smoking; and (3) in femoral arteries with increased age, systolic pressure, low-density lipoprotein cholesterol, and smoking. Multiple regression analysis showed correlations between carotid plaque and low-density lipoprotein cholesterol; aortic plaque and age, smoking, glycemia, and pressure; femoral plaque and age, smoking, and pressure. This suggests that multiple risk factors influence lesions, and risk profile differs according to atherosis site.

Enhanced constriction of the peripheral large artery in response to acute induction of a low-flow state in human hypercholesterolemia.

The diameter, blood velocity, and blood flow of the brachial artery were evaluated with a pulsed-Doppler apparatus before and after wrist occlusion in 16 normocholesterolemic and 27 hypercholesterolemic male subjects of similar age and body mass index. Before occlusion, no hemodynamic differences were observed between the two groups. Occlusion significantly reduced blood velocity and blood flow in the two groups (p less than 0.001), but such reductions were not different between hypercholesterolemic and normocholesterolemic groups. Occlusion decreased the arterial diameter in the hypercholesterolemic group only (p less than 0.001), and absolute diameter changes after occlusion were significantly different between the two groups (p less than 0.001). No correlation was found between the change in arterial diameter after occlusion and the baseline diameter before occlusion in the normocholesterolemic and hypercholesterolemic population overall. Absolute and percent diameter changes after occlusion were correlated with total cholesterol (r = -0.73, r = -0.72; p less than 0.001) and with low density lipoprotein (LDL) cholesterol (r = -0.68, r = -0.69; p less than 0.001) in the normocholesterolemic and hypercholesterolemic population overall, respectively. These findings indicate that the low-flow state induces a reduction in large-artery diameter in the hypercholesterolemic but not in the normocholesterolemic state and is closely related to the degree of elevation of blood cholesterol and of its LDL fraction.

Comparison of the effects of nicardipine and metoprolol on lipid and glycidic metabolism in hypertensive subjects.

Various aspects of carbohydrate and lipid metabolism have been studied in two groups of patients with mild hypertension before and after six months of treatment with either nicardipine (n = 10) or metoprolol (n = 10). A significant reduction of the arterial blood pressure was seen with both treatment regimens. Circulating plasma glucose, insulin, C peptide and triglyceride concentrations were measured at hourly intervals from 08 h 00 to 17 h 00, in patients on an isocaloric diet (35 kcalth/kg/die). Plasma glucose concentrations were unchanged and insulin and C peptide concentrations were higher in association with metoprolol treatment. In contrast, nicardipine-treated patients had similar plasma insulin, but lower plasma glucose, C peptide and triglyceride concentrations after treatment. The changes in day-long plasma glucose and insulin-stimulated glucose uptake had increased in association with metoprolol treatment and decreased following nicardipine. Finally plasma cholesterol concentrations did not change following metoprolol therapy, whereas plasma high density lipoprotein cholesterol increased in association with nicardipine treatment. The data seem to indicate that the negative effect of nicardipine on secretion of insulin is balanced by an improvement in glucose uptake.

Dynamic association between artery shear flow condition and platelet cytosolic free Ca2+ concentration in human hypertension.

1. Blood cells and vascular endothelial cells are subjected to a wide range of haemodynamically generated shear stress forces. In vitro, membrane stretching or shear stress have been observed to activate ion channels and cell metabolism and to facilitate erythrocyte and platelet aggregation. 2. The present study was designed to evaluate the participation of shear stresses in the control of apparent platelet cytosolic free Ca2+ concentration in hypertensive patients. 3. Shear conditions and platelet cytosolic free Ca2+ concentration in vitro were studied after a dynamic perturbation induced by 3 months of double-blind treatment with one of two beta-antagonists, carteolol and atenolol. Brachial artery wall shear rate and stress were estimated by means of a pulsed Doppler velocimeter, and blood viscosity was measured by a co-axial viscometer at a shear rate of 96 s-1. Platelet cytosolic free Ca2+ concentration was simultaneously measured by using the Quin-2 fluorescent chelator. The direct effect of atenolol and carteolol on platelet cytosolic free Ca2+ concentration in vitro was also measured after addition of the beta-blockers to platelet-rich plasma. 4. Atenolol and carteolol decreased blood pressure similarly but their effects on shear rate (P less than 0.02), shear stress (P less than 0.01) and platelet cytosolic free Ca2+ concentration (P less than 0.05) differed after 3 months of therapy. In contrast, neither of the drugs significantly altered platelet cytosolic free Ca2+ concentration, in vitro per se. 5. In the overall population, strong positive correlations existed not only between changes in platelet cytosolic free Ca2+ concentration and those in shear rate (r = 0.81, P less than 0.001) and shear stress (r = 0.83, P less than 0.001), but also between their absolute values, suggesting a possible haemodynamic shear-dependent modulation of transmembrane Ca2+ transport.

Relation of risk factors for cardiovascular disease to early atherosclerosis detected by ultrasonography in middle-aged normotensive hypercholesterolemic men. PCV Metra Group.

The relations between carotid arteries and/or abdominal aortic plaque and cardiovascular risk factors were investigated by ultrasonography in 161 untreated hypercholesterolemic normotensive men. Of them, 58 had no plaque (NP group), 34 had carotid but not aortic plaque (CP group), 34 had aortic but not carotid plaque (AP group) and 35 had both carotid and aortic plaques (CAP group). Groups significantly differed for age, smoking, blood pressure, and the ratio of total to HDL cholesterol. Age was higher in CAP group than in NP and CP groups and in AP and CP groups than in NP group. Life long smoking dose was higher in CAP group than in CP, AP, and NP groups. Systolic and diastolic pressures were higher in CAP group than in NP group, systolic pressure was higher in CAP group than in CP group, and diastolic pressure was higher in AP group than in CP and NP groups. The ratio of total to HDL cholesterol was higher in CAP group than in AP, CP, and NP groups. Multiple regression analysis showed that carotid plaque was only related to age, while aortic plaque and the number of sites affected by plaque were correlated to age, smoking and diastolic pressure. These findings suggest that in hypercholesterolemia risk factors other than lipids seem to influence arterial plaque and that risk profile differs according to the plaque location.

[Contrary effects of hypertension and cigarette smoking on the conditions of wall shear in large arteries]. / Effets opposés de l'hypertension artérielle et du tabagisme sur les conditions de cisaillement pariétal au niveau des grosses artères.

Systolic wall shear conditions were studied in the brachial artery of 4 groups of subjects including 11 non-smokers normotensives (NSNT), 25 non smokers hypertensives (NSHT), 21 smokers normotensives (SNT) and 10 smokers hypertensives (SHT). Brachial artery diameter (D) and systolic centerline blood velocity (VCLS) were measured with a pulsed Doppler device and blood viscosity at 96 sec-1 was measured with a coaxial cylinder viscometer. The wall shear rate (gamma S) corresponding to systolic velocity was calculated using a Womersley model of pulsatile flow according to the formula: alpha = (D/2) (omega/mu) 1/2, omega being the angular pulse frequency and mu the kinematic viscosity. The wall shear stress was then calculated as the product between wall shear rate and viscosity. The analysis of results in the 4 groups showed that both hypertension and smoking increased blood viscosity bu their effects on wall shear were opposite since hypertension decreased shear and stress while smoking did not change it. However, in hypertensive patients, smoking induced a clear elevation in wall shear rate and stress, whereas in smokers hypertension did not change shear conditions. Thus, opposite and interactive effects of hypertension and smokers exist on large artery wall shear phenomena which could induce differences in response of functional and structural endothelial cells to these two vascular risk factors.

Comparative long-term vasoactive effects of atenolol and carteolol on the properties of the small and large arteries of the upper extremities in human essential hypertension.

The long-term effects of selective (atenolol) and nonselective (carteolol) beta-blockers on brachial artery diameter velocity and flow and on vascular resistance (pulsed Doppler) were compared in two groups of 10 hypertensive patients at respective daily doses of 100 and 20 mg. The drugs decreased mean blood pressure (p less than 0.01) with similar magnitude, although systolic blood pressure was decreased more by atenolol than by carteolol (p less than 0.05). Heart rate was decreased by atenolol (p less than 0.01) but was unchanged by carteolol. The drugs did not change brachial circulation when the hand circulation was present. During hand exclusion (wrist occlusion) comparison from baseline showed that atenolol decreased velocity and flow (p less than 0.01, p less than 0.05) and increased resistance (p less than 0.05), whereas carteolol decreased resistance (p less than 0.05); after 3 months of treatment, velocity and flow were higher (p less than 0.01, p less than 0.001) and resistance was lower (p less than 0.01) with carteolol than with atenolol. Thus, hand exclusion demonstrated opposite drug effects on arterioles--dilation for carteolol and constriction for atenolol.