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Biomedical subjects

A Zanchetti

Publications and source records attributed to A Zanchetti.

At least 145 records · Page 8Linked to original sources
PubMed1996

Excretory responses to renal nerve stimulation during inhibition of neutral metalloendopeptidase and angiotensin-converting enzyme in the rat.

To evaluate the interaction between renal nerves, the atrial natriuretic peptide (ANP), and the renin-angiotensin system (RAS), electrical stimulation of renal nerves was performed in spontaneously hypertensive rats (SHR) and in their normotensive controls, Wistar Kyoto rats (WKY), before and after pharmacologic treatment with (a) a neutral endopeptidase inhibitor (NEP-i) to enhance the intrarenal ANP activity; (b) an ACE inhibitor (ACE-i) to block RAS; (c) both NEP-i and ACE-i; and (d) the vehicle of the drugs. Renal nerve stimulation did not change arterial pressure (AP) but reduced renal blood flow (RBF), glomerular filtration rate (GFR), and urinary sodium excretion (UNa+V) in both WKY and SHR. NEP-i treatment in WKY and SHR had no systemic or renal hemodynamic effects but increased GFR and urinary cyclic guanosine monophosphate (GMP) excretion; UNa+V increased (+2.78 +/- 0.31 microEq/min) in WKY, whereas it did not change in SHR (+0.83 +/- 0.79 microEq/min). In both strains, ACE-i treatment reduced AP, increased RBF, and did not change GFR and UNa+V. The combined treatment with NEP-i and ACE-i did not modify the natriuretic effect observed in NEP-i treated WKY (+4.29 +/- 1.25 microEq/min), but it elicited a natriuretic effect in SHR (+3.98 +/- 1.29 microEq/min). Pharmacologic treatment did not change the hemodynamic and excretory responses to renal nerve stimulation in both WKY and SHR. In conclusion, NEP-i treatment increased UNa+V in normotensive rats without changing AP. In hypertensive rats, the natriuretic effect of NEP-i became evident only after block of RAS by ACE-i. Neither NEP-i nor ACE-i, even in combination, could modify the renal responses to sympathetic stimulation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Functional evidence of inhibitory reno-renal reflexes in spontaneously hypertensive rats.

The experiments were performed to study the role of the renal nerves and the reno-renal reflexes in the control of water and sodium excretion in spontaneously hypertensive rats (SHR) compared to their normotensive controls, Wistar Kyoto (WKY) rats. Unilateral renal denervation in anaesthetized animals produced a slight, progressive decrease in arterial pressure in both WKY and SHR rats. The glomerular filtration rate temporarily increased in the kidney that underwent the denervation in the SHR group only. After unilateral renal denervation a sharp increase in water and sodium excretion from the ipsilateral kidney was observed in both WKY and SHR. One hour after the denervation, the percent changes in water and sodium excretion were smaller in WKY (+32 +/- 19% and +24 +/- 17%) than in SHR rats (+84 +/- 15% and +93 +/- 20%). In the kidney contralateral to the denervation a reduction in water and sodium excretion was observed and this reduction was prompter in SHR than in WKY rats. One hour after the denervation, the percent changes in water and sodium excretion were similar in WKY (-21 +/- 8% and -18 +/- 7%) and SHR (-19 +/- 6% and -19 +/- 7%). In control groups, sham denervation did not cause significant changes in glomerular filtration rate, and urinary water and sodium excretion. Arterial pressure slightly and progressively decreased in both control groups. Electrical stimulation of the efferent renal nerves performed in WKY and SHR produced similar decreases in renal blood flow, glomerular filtration rate, and water and sodium excretion in the two groups for the same frequencies of stimulation. As this finding indicates that renal targets in hypertensive rats are normally responsive to the neural drive, our data demonstrate that renal responses to unilateral renal denervation in hypertensive rats are equal to the responses observed in normotensive rats. Our results indicate that tonically active inhibitory renorenal reflexes normally operate in spontaneously hypertensive rats.

Animals↗
PubMed1996

Safety aspects of treatment with lacidipine--a slow-onset, long-acting calcium antagonist.

OBJECTIVE: The aim was to review the clinical safety profile of lacidipine with the help of the rather comprehensive datafile of the manufacturer- a novel approach which may be of some value while awaiting the outcome of calcium antagonist treatment in prospective, randomised trials of cardiovascular morbidity and mortality. DESIGN: This paper includes data from clinical trials finished before 1 January 1995. Since 1985, 50 phase III-IV trials have been performed investigating antihypertensive efficacy in patients with hypertension; 32 were controlled trials with comparison treatment and 18 were open studies of lacidipine treatment. SUBJECTS: In all, 16,590 patients received lacidipine; 13,419 in open studies and 3171 in double blind, comparative trials. Altogether, these patients contributed 5 124 person-years (p.y.). Furthermore, active comparative treatment was given to 1810 patients and placebo to 451. MAIN OUTCOME MEASURES: Both fatal and non-fatal cardiovascular events have been estimated. Efficacy (change in blood pressure and heart rate), adverse event rates, and drop-out rates have been compared for the different treatment regimes. Also the reasons for dropping out of studies have been compared. Adverse effects were also analysed as to their time of occurrence and duration. RESULTS: Blood pressure was lowered by 2-6 mg lacidipine; in the controlled trials from 166/102 to 144/85 mmHg. Heart rate dropped from 75.6 to 74.1 beats per minute. The estimated event rate for a possible myocardial infarction in all studies was 5.46 per 1000 p.y. The fatal (all causes) event rate was 5.27 per 1000 p.y., and the estimated fatal cardiovascular event rate 2.93 per 1 000 p.y. In one long-term study (48 weeks) comprising 2282 patients (1658 p.y.), the observed fatal (all causes) event rate was 4.2 per 1 000 p.y. The overall incidence in the comparative studies of (one or more) adverse events was: for lacidipine 30.3%, other calcium antagonists 43.8%, diuretics 18.7%, beta-receptor blockers 48.7%, ACE inhibitors 10.4%, and placebo 15.7%. The adverse effects of lacidipine were the expected ones, e.g. headache, flushing, pedal oedema, and palpitations. CONCLUSION: When analysing the data on file for lacidipine and some comparatory drugs in almost 19000 hypertensive patients we have found lacidipine to be an effective and well tolerated drug with a reasonable adverse profile typical for a calcium antagonist of the dihydropyridine group. Our study has the obvious limitations of a retrospective analysis of data obtained from a large cohort of patients, most of whom received lacidipine for a relatively short period of time. The present results indicate a lower fatal event rate than previously reported in the actively treated hypertensives in Collins' meta-analyses, comprising ten times more person-years than our analysis. Prospective studies with lacidipine focusing on possible reductions of atherosclerosis as well as incidence of cardiovascular disease are required and are well under way.

Adult↗
PubMed1996

Job strain and ambulatory blood pressure levels in a population-based employed sample of men from northern Italy.

OBJECTIVES: The purpose of this cross-sectional study was to examine the associations between categories of perceived job strain and blood pressure, measured by clinical and ambulatory devices on a population-based sample of employed men in northern Italy. METHODS: The study included 527 employed normotensive or mild hypertensive nonmedicated men enrolled in an age-gender stratified random sample of 821 25- to 64-year-old residents of the city of Monza (in the vicinity of Milan). The job-strain categories were classified according to the traditional quadrant-term approach and also a new approach based on the comparison of extreme tertile categories in order to enhance contrasts. Clinical blood pressure was measured according to the standardized MONICA procedure; 24-h, work, leisure, and nighttime blood pressure values were obtained with an ambulatory device. Disparities, calculated as differences between clinical and ambulatory measurements, were also analyzed. RESULTS: Among normotensive working men the highest mean for systolic blood pressure was found in the high-strain group, and progressively lower values were found in the passive, active and low-strain categories. These patterns were observed for both the clinical and ambulatory measurements. Among the mild hypertensive subjects, lower mean values for ambulatory systolic and diastolic blood pressure were found in the passive and high job-strain categories when the tertile term approach was adopted. The passive group also showed the highest mean difference between the clinical and ambulatory measurements; this finding indicates that they may be more susceptible to alarm reactions. CONCLUSIONS: The results indicate that job strain affects blood pressure in population-based samples and the effect is consistent across sociocultural contexts.

Adult↗
PubMed1996

Humoral effects of selective adenosine agonists in spontaneously hypertensive rats.

OBJECTIVE: We studied the dose-response effects of acute administration of the selective A1 adenosine receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), the selective A2A agonists 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA) and 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680) and the non-selective agonist N-ethylcarboxamidoadenosine (NECA) on plasma renin activity, atrial natriuretic peptide, cyclic guanosine 3',5'-monophosphate (cGMP) and endothelin-1 in spontaneously hypertensive rats. METHODS: The drugs were administered intraperitoneally in four doses to conscious rats. Systolic blood pressure and heart rate were measured by the tail-cuff technique. Both humoral and hemodynamic parameters were determined 1 h after dosing in separate sets of animals. RESULTS: All the compounds induced a dose-dependent decrease in systolic blood pressure that was associated with different changes in heart rate. Heart rate was decreased by all doses of CCPA and by the higher doses of the non-selective compound (NECA) and increased by both A2A agonists. Plasma renin activity also changed in opposite directions, being decreased by CCPA but increased dose-dependently by 2HE-NECA and CGS 21680 and only moderately by NECA. Plasma atrial natriuretic peptide and cGMP levels increased dose-dependently after CCPA and NECA, but were unaffected by the A2A agonists. None of the compounds altered plasma endothelin-1 levels. CONCLUSIONS: These results indicate that the renin-suppressive effect of the A1 agonist, which is associated with a cardiodepressant action, may be attributed either to a direct inhibition of renin release or to the concomitant increments in plasma atrial natriuretic peptide and its second messenger, cGMP. In contrast, the renin-stimulating effect of the A2A agonists may result either from direct stimulation of renin secretion or from reflex sympathetic activation secondary to the fall in blood pressure.

Adenosine↗
PubMed1996

Prevalence of carotid atherosclerosis in hypertension: preliminary baseline data from the European Lacidipine Study on Atheroscelerosis (ELSA).

In the ELSA trial, the effects of lacidipine-based treatment and beta-blocker (atenolol)-based treatment on the development and progression of carotid wall alterations are assessed in hypertensive patients. The primary endpoint of this study is the rate of change in the intima-media thickness of the carotid artery wall, measured with B-mode ultrasound. About 2300 hypertensive patients have been recruited and randomized to either of the antihypertensive agents. Baseline data for 1965 patients are available, showing a high prevalence of carotid wall lesions: about 82% of the subjects have an intima-media thickness > or = 1.3 mm, defined as plaque in the ELSA protocol; 16% of the subjects have intima-media thickening (> or = 1.0 mm, < 1.3 mm) and only about 1% have normal carotid artery walls. Analysis of demographic data and risk factor prevalence in ELSA patients, and comparison of these preliminary observations with data from other intervention or observational studies indicate that high blood pressure is a very important risk factor for carotid atherosclerosis.

Antihypertensive Agents↗
PubMed1996

[Therapy of arterial hypertension: benefits, costs, challenges].

For more than 30 years the benefits of antihypertensive therapy have been assessed by randomized trials measuring cardiovascular events. Even greater benefits are found if prevention of congestive heart failure, left ventricular hypertrophy, and progression to more severe hypertension are considered. Quantifying the benefits in order to calculate cost-effectiveness of treatment is not easy, however. Taking absolute risk and absolute benefit as a guide to treatment decision, though an important approach, may result in limiting therapy to elderly and complicated hypertensives only. Furthermore randomized trials, whose duration is necessarily short, are likely to underestimate treatment benefits. An alternative is the actuarial approach, by which treatment benefits are calculated from the actuarial data showing the reduction in life expectancy associated with any given blood pressure increase. The cost of antihypertensive therapy per year of life gained, as calculated by the actuarial approach, is much lower than the cost calculated on the basis of the outcomes of randomized trials. In an uncertain area such as that of cost-effectiveness evaluation, it is important that both approaches be brought to the consideration of physicians, patients, politicians, and officers of national health systems.

Actuarial Analysis↗
PubMed1995

Vascular wall thickness in hypertension: the Perindopril Regression of Vascular Thickening European Community Trial: PROTECT.

A high prevalence of increased intima/media thickness of the arterial wall has been documented in hypertension. These alterations in vascular wall structure may be potent determinants for the promotion of the development of atherosclerosis. Direct histologic data from animal models of hypertension, and indirect data from hypertensive patients, have demonstrated a marked regression of increased intima/media thickness by angiotensin-converting enzyme (ACE) inhibition. Long-term effects of ACE inhibition on structural wall changes in humans have not been examined. Therefore, a multicenter, randomized, double-blind European trial was designed to compare the effects of the ACE inhibitor perindopril and the diuretic hydrochlorothiazide in slowing or reversing progression of increased intima/media thickness of carotid and femoral arteries in hypertensive patients. A total of 800 patients at 17 clinical centers in 7 European countries, aged 35-65 years, with hypertension and ultrasonographically proven intima/media thickness > or = 0.8 mm of the common carotid artery will be randomly assigned to receive in a double-blind fashion either perindopril or hydrochlorothiazide and will be followed for 24 months. High resolution duplex sonography will be used to quantify intima/media thickness at baseline and twice a year during follow-up. A change of 0.1 mm of intima/media thickness from baseline is considered to be detectable, and the standard deviations of the changes from baseline are expected not to be higher than 0.2 mm. The primary endpoint of the study is the comparison of changes in intima/media thickness of the common carotid artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Vascular complications in hypertension: the VHAS study. Verapamil-Hypertension Atherosclerosis Study.

The VHAS (Verapamil-Hypertension Atherosclerosis Study) Investigators entered 1464 patients with essential hypertension and blood pressure (BP) values > or = 160 mmHg systolic and 95 mmHg diastolic (DBP) but excluded those with a DBP > or = 115 mmHg, and those with diabetes mellitus or previous myocardial infarction or cerebrovascular episodes. Patients were randomly allocated to drug therapy for 2 years with either slow-release verapamil 240 mg once daily or chlorthalidone 25 mg once daily, with nonresponders receiving additional captopril 25 mg daily. A random group of eligible patients (n = 494) was followed for a more extended period (4 years) using beta-mode ultrasound. The end point is the development of atherosclerosis detected by ultrasound imaging. The most interesting observation thus far is that in this population of middle-aged hypertensives without a history of previous cardiovascular events, about two thirds had asymptomatic carotid alterations. The study is ongoing.

Adult↗
PubMed1995

Lack of placebo effect on ambulatory blood pressure.

Several studies have reported that, at variance with clinic blood pressure, ambulatory blood pressure is not reduced by treatment with placebo. However, this evidence has usually been obtained in small groups of subjects and no data are available from a larger sample of patients. To address this issue we have analyzed data from 116 outpatients involved in placebo-controlled studies on antihypertensive treatment. The patients were studied before and at the end of a 6- to 8-week period of placebo. In all patients, blood pressure was measured by sphygmomanometry and over the 24 h by automatic ambulatory monitoring. Administration of placebo was accompanied by a significant reduction in systolic and diastolic clinic blood pressure (-5.3 +/- 1.1 and -4.4 +/- 0.6 mm Hg, respectively; P < .01), but not in 24-h, daytime and nighttime blood pressure. Hourly systolic and diastolic blood pressure profiles were virtually superimposable in the two different periods, except for the first 4 h, in which systolic blood pressure was slightly but significantly lower during than before placebo (149.5 +/- 1.2 v 146.4 +/- 1.2 mm Hg; P < .05). These results provide a large database indicating that 24-h average blood pressure is not reduced by placebo, thus it is not necessary to include a placebo control group in antihypertensive drug studies in which ambulatory blood pressure monitoring is employed. A small placebo effect occurs, however, in the first hours of ambulatory monitoring. This may lead to a slight overestimation of the peak blood pressure effect of a drug and an underestimation of its trough-to-peak ratio if placebo correction of the data is not made or if the first part of ambulatory blood pressure monitoring is not excluded from data analysis.

Blood Pressure↗
PubMed1995

Effects of exposure to high altitude on plasma endothelin-1 levels in normal subjects.

OBJECTIVE: To assess whether the hypoxia associated with exposure to high altitude affects plasma endothelin-1 levels, and whether changes in endothelin-1 are related to those in systemic and pulmonary blood pressure. DESIGN: Eight normal subjects ascended Mount Everest to an altitude of 5050 m within a period of 8 days (study 1) and 10 ascended Mount Rosa in the Italian Alps to an altitude of 4559 m within 2 days (study 2). In study 1 systemic blood pressure, heart rate, haematocrit, haemoglobin oxygen saturation (evaluated by percutaneous oximetry) and venous plasma endothelin-1 were measured several times during the ascent, and twice more during the time spent at high altitude. In study 2 the same parameters as well as systolic pulmonary pressure by echocardiography were evaluated on the second day of resting at 4559 m. In both studies, data obtained during the expeditions were compared with those collected from the same subjects at sea level. RESULTS: In study 1 plasma endothelin-1 increased progressively up to 4240 m (from 1.8 +/- 0.1 pg/ml at sea level to 2.7 +/- 0.2 pg/ml) and decreased slightly thereafter; these increments were directly related to the decrements in percutaneous oxygen saturation, which, at that altitude, fell from 98.6 +/- 0.2% at sea level to 80.8 +/- 0.4%. Blood pressure and haematocrit also rose in response to exposure to high altitude but these changes were not related to changes in endothelin-1. In study 2 the increments in plasma endothelin-1 were similar to those observed in study 1 and the changes again correlated with changes in oxygen saturation as well as with those in systolic pulmonary pressure. On average, systolic pulmonary pressure increased from 19 +/- 1 to 26 +/- 1.9 mmHg, whereas systemic blood pressure and haematocrit were unchanged. CONCLUSION: Exposure to high altitude is associated with consistent increases in plasma endothelin-1. This is probably the result of augmented secretion of the peptide in response to hypoxia and may contribute to the physiological adaptation of the pulmonary circulation to this condition.

Adult↗
PubMed1995

Calculation of trough:peak ratio of antihypertensive treatment from ambulatory blood pressure: methodological aspects.

OBJECTIVE: To address several methodological questions related to calculation of trough:peak ratio from 24 h ambulatory blood pressure (BP) recordings. METHODS: Data from patients with mild essential hypertension who were included in parallel group (n = 280) or cross-over studies (n = 39) were pooled. 24 h ambulatory BP recordings were available after 2- to 4-week washout from treatment and at the end of a 4- to 8-week period of treatment with calcium antagonists (n = 143), angiotensin converting enzyme inhibitors (n = 103) or placebo (73 patients from parallel group studies and 39 from a cross-over study). Each recording started between 0900 and 1000 h, immediately after the drug or placebo intake during the treatment phase. BP was measured at 15 min intervals during the day and at 15-20 min intervals during the night. Peak changes were calculated from systolic BP and diastolic BP 2-8 h after drug intake, and trough changes from readings taken during the last 4 h of the 24 h. RESULTS: Peak changes induced by drug treatment were progressively reduced when data were averaged over 1, 2, 4 and 6 h. BP reproducibility showed a concomitant increase and the best compromise between correct estimate of peak changes and reproducibility was the average of the adjacent 2 h with the maximal BP fall. Peak and trough (average of last 2 h) changes showed a normal distribution, whereas trough:peak ratios showed non-normal distributions, large scatters and many individual values with no pharmacodynamic significance (namely, much above unity and below zero). Selecting responders to treatment reduced the dispersion and made the trough:peak ratio distribution normal. There was no correlation between trough:peak ratios and changes in BP variability (standard deviation of 24 h mean) induced by treatment. Placebo administration caused no trough but a modest peak fall. Peak changes during placebo also showed a wide scatter and a non-normal distribution, which makes correction with respect to average peak placebo data inappropriate in parallel-group studies. However, placebo correction may be performed for each subject in cross-over studies, leading to a reduction in peak changes and an increase in trough:peak ratio values. CONCLUSIONS: When the trough:peak ratio is assessed from ambulatory BP, peak and trough changes should preferably be computed over a 2 h time window. To remove values with no pharmacodynamic significance, the analysis should preferably be conducted only in responders to treatment at peak. Although placebo is accompanied by some peak effect, placebo correction might be appropriate only for individual subjects in cross-over studies.

Antihypertensive Agents↗
PubMed1995

ACE inhibitor ramipril is more effective than the beta-blocker atenolol in reducing left ventricular mass in hypertension. Results of the RACE (ramipril cardioprotective evaluation) study on behalf of the RACE study group.

OBJECTIVES: To compare the effect of the angiotensin converting enzyme (ACE) inhibitor ramipril with that of the beta-blocker atenolol on reversal of left ventricular hypertrophy, on blood pressure and on other echocardiographic parameters. DESIGN: The study was conducted in accord with the PROBE (prospective randomized open blinded endpoint) design. Randomized treatment either with ramipril or with atenolol was continued for 6 months, and echocardiograms were recorded before and after 3 and 6 months of treatment. The echo tracings were blindly evaluated in a single reading centre. METHODS: M-mode, two-dimensional guided echocardiography was used to measure left ventricular wall thicknesses and dimensions, from which left ventricular mass was calculated, according to the Penn convention. RESULTS: Of 193 patients at 16 centres, 111 had echocardiograms that could be quantitatively evaluated. The primary analysis of the study was performed using data from those patients. In addition, echocardiograms of 88 patients were analysed on an 'according to protocol' basis (patients with preset values of left ventricular mass). Systolic and diastolic blood pressures were significantly reduced both by ramipril and by atenolol without any significant difference between the two drug treatments. The heart rate was significantly reduced by atenolol only. Both the 'primary' and the 'according to protocol' analyses showed that the left ventricular mass was significantly reduced by ramipril only. Comparison between treatments according to a multivariate analysis demonstrated a significantly greater reduction in left ventricular mass during ramipril than during atenolol treatment. CONCLUSIONS: The present study is the first of suitably large size in which a direct comparison of the effects of an ACE inhibitor and a beta-blocker on echocardiographic left ventricular mass has been performed. It has demonstrated that ramipril is more effective than atenolol in reversing left ventricular hypertrophy in essential hypertensive patients.

Adrenergic beta-Antagonists↗
PubMed1995

Evaluating the benefits of an antihypertensive agent using trials based on event and organ damage: the Systolic Hypertension in the Elderly Long-term Lacidipine (SHELL) trial and the European Lacidipine Study on Atherosclerosis (ELSA).

AIMS: To assess the benefits of the calcium antagonist lacidipine on the prevention of cardiovascular events and the prevention of organ damage in two long-term clinical trials. SYSTOLIC HYPERTENSION IN THE ELDERLY LONG-TERM LACIDIPINE (SHELL) TRIAL: In the SHELL trial, the efficacy of lacidipine-based treatment is to be compared with that of thiazide-like diuretic (chlorthalidone)-based treatment in elderly patients with isolated systolic hypertension. The incidence of cardiovascular mortality and cardiovascular morbidity over a 5-year period are endpoints. EUROPEAN LACIDIPINE STUDY ON ATHEROSCLEROSIS (ELSA) TRIAL: In the ELSA trial, the effects of lacidipine-based treatment and beta-blocker (atenolol)-based treatment on the development and progression of carotid atherosclerosis are to be assessed in hypertensive patients. The primary endpoint of this study is the rate of change in the thickness of the carotid artery wall, measured with B-mode ultrasound.

Antihypertensive Agents↗