Regulation of group II metabotropic glutamate receptors by G protein-coupled receptor kinases: mGlu2 receptors are resistant to homologous desensitization.

We examined the regulation of mGlu2 and mGlu3 metabotropic glutamate receptor signaling prompted by the emerging role of these receptor subtypes as therapeutic targets for psychiatric disorders, such as anxiety and schizophrenia. In transfected human embryonic kidney 293 cells, G-protein-coupled receptor kinase (GRK) 2 and GRK3 fully desensitized the agonist-dependent inhibition of cAMP formation mediated by mGlu3 receptors. In contrast, GRK2 or other GRKs did not desensitize the cAMP response to mGlu2 receptor activation. Desensitization of mGlu3 receptors by GRK2 required an intact kinase activity, as shown by the use of the kinase-dead mutant GRK2-K220R or the recombinant GRK2 C-terminal domain. Overexpression of beta-arrestin1 also desensitized mGlu3 receptors and did not affect the cAMP signaling mediated by mGlu2 receptors. The difference in the regulation of mGlu2 and mGlu3 receptors was signal-dependent because GRK2 desensitized the activation of the mitogen-activated protein kinase pathway mediated by both mGlu2 and mGlu3 receptors. In vivo studies confirmed the resistance of mGlu2 receptor-mediated cAMP signaling to homologous desensitization. Wild-type, mGlu2(-/-), or mGlu3(-/-) mice were treated intraperitoneally with saline or the mixed mGlu2/3 receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0]-exhane-4,6-dicarboxylic acid (LY379268; 1 mg/kg) once daily for 7 days. Inhibition of forskolin-stimulated cAMP formation by LY379268 was measured in cortical slices prepared 24 h after the last injection. Agonist pretreatment fully desensitized the cAMP response in wild-type and mGlu2(-/-) mice but had no effect in mGlu3(-/-) mice, in which LY379268 could only activate the mGlu2 receptor. We predict the lack of tolerance when mixed mGlu2/3 receptor agonists or selective mGlu2 enhancers are used continually in patients.

Expression of the Wnt inhibitor Dickkopf-1 is required for the induction of neural markers in mouse embryonic stem cells differentiating in response to retinoic acid.

Cultured mouse D3 embryonic stem (ES) cells differentiating into embryoid bodies (EBs) expressed several Wnt isoforms, nearly all isotypes of the Wnt receptor Frizzled and the Wnt/Dickkopf (Dkk) co-receptor low-density lipoprotein receptor-related protein (LRP) type 5. A 4-day treatment with retinoic acid (RA), which promoted neural differentiation of EBs, substantially increased the expression of the Wnt antagonist Dkk-1, and induced the synthesis of the Wnt/Dkk-1 co-receptor LRP6. Recombinant Dkk-1 applied to EBs behaved like RA in inducing the expression of the neural markers nestin and distal-less homeobox gene (Dlx-2). Recombinant Dkk-1 was able to inhibit the Wnt pathway, as shown by a reduction in nuclear beta-catenin levels. Remarkably, the antisense- or small interfering RNA-induced knockdown of Dkk-1 largely reduced the expression of Dlx-2, and the neuronal marker beta-III tubulin in EBs exposed to RA. These data suggest that induction of Dkk-1 and the ensuing inhibition of the canonical Wnt pathway is required for neural differentiation of ES cells.

Eccentric atherosclerotic plaques with positive remodelling have a pericardial distribution: a permissive role of epicardial fat? A three-dimensional intravascular ultrasound study of left anterior descending artery lesions.

AIMS: The transversal distribution of coronary atherosclerotic plaques (AP) (myocardial vs pericardial) affects vessel remodelling. The aim of this study was to define the impact of transversal lesion distribution on vessel remodelling in proximal and distal coronary segments using a 3D intravascular ultrasound (IVUS) reconstruction. METHODS: The study group included 70 lesions located in the left anterior descending artery within 5mm of the septal take-off, and imaged using 3D-IVUS. The take-off of the septal branch was used to divide the plaque into a myocardial and pericardial surface. The IVUS index of vessel remodelling was calculated as: [narrowest external elastic membrane (EEM) site cross-sectional area (CSA)-reference EEM CSA)/reference EEM CSAx100]. The lesions with an intermediate vessel remodelling index (between -25% and +15%) were excluded from analysis. RESULTS: Of the 38 APs with a pericardial distribution, 34 (89%) showed positive remodelling (P<0.001). The distal lesions had a positive vessel remodelling index regardless of transversal plaque distribution. At multivariate analysis, pericardial distribution and the distal location of AP were the only independent variables predictive of positive remodelling. CONCLUSIONS: The transversal distribution of atherosclerotic plaque affects vessel remodelling in left anterior descending coronary lesions, probably because of an extravascular splinting effect. Distal lesions usually show positive remodelling regardless of transversal plaque distribution.

An Italian chart for cardiovascular risk prediction. Its scientific basis.

A risk chart for primary prediction of major coronary and cerebrovascular events based on Italian population data was created. Material from three Italian population studies was available: the Italian Rural Areas of the Seven Countries Study (no. 1712), the Gubbio Study (no. 3061) and the ECCIS Study (no. 4998) for a total of 9771 men and women aged 35 to 74 years and followed-up from 5 to 15 years, for a total of over 55,000 person/years. Sex, age, diabetes, cigarette smoking, systolic blood pressure and serum cholesterol were selected as risk factors, while the endpoint was established as the occurrence of the first major coronary or cerebrovascular event in 10 years. The accelerated failure time model was used as the predictive model. Two models were adopted, i.e., for relatively younger subjects (45-59 years) and for relatively older subjects (60-74 years). Both produced highly significant coefficients for each of the selected risk factors. The two models carried a satisfactory discriminating power, with 40% to more than 50% of all events located in the upper quintile of the estimated risk. Sex, age (6 classes), diabetes, cigarette smoking (4 classes), systolic blood pressure (4 classes) and serum cholesterol (5 classes) were considered for the creation of a risk map derived from multivariate models. A total of 1920 cells were filled with different colors corresponding to 6 classes of absolute risk. A similar set of cells was filled with another color scale for the estimate of the relative risk versus subjects of the same age and sex carrying Italian mean levels of risk factors. The chart is being distributed to the Italian medical profession as a practical tool to select high-risk individuals for the primary prevention of major cardiovascular diseases.

Angiotensin-converting enzyme inhibitors and kidney protection: the AIPRI trial. The ACE Inhibition in Progressive Renal Insufficiency (AIPRI) Study Group.

A protective effect of angiotensin-converting enzyme (ACE) inhibitors has been shown in patients with diabetic nephropathy but has not been clearly established in nondiabetic renal disease. A multicenter European study was designed to determine whether the ACE inhibitor benazepril was safe and effective in protecting residual renal function in patients with various renal diseases and mild to moderate renal failure. The trial involved 583 patients from 49 centers in Italy, France, and Germany. The patients were randomized to receive benazepril or placebo plus other antihypertensive agents, the target being a diastolic blood pressure of less than 90 mm Hg. Thirty-one patients in the benazepril group and 57 patients in the placebo group reached the end point [the time elapsed from entry to (a) doubling of serum creatinine (SCr) concentrations and (b) start of renal replacement therapy; p < 0.001 at 3 years]. The associated reduction in the relative risk of reaching the end point was 53% in benazepril-treated patients, with actuarial renal survival probability significantly better at 3 years. The best survival of renal function was observed in patients with chronic glomerular diseases and proteinuria greater than 1.0 g/24 h. Benazepril is effective in slowing the rate of progression and improving the survival of renal function in patients with renal diseases of various origins. This protective effect is associated with a clinically relevant decrease in both blood pressure and proteinuria.

Benazepril causes in hypertension a greater reduction in left ventricular mass than does nitrendipine: a randomized study using magnetic resonance imaging.

To assess the comparative effects of benazepril and nitrendipine monotherapies on left ventricular mass index (LVMI) in hypertensive patients with echocardiographically determined left ventricular hypertrophy, patients with diastolic blood pressure (BP) > or = 100 mm Hg were randomized to benazepril, 10 mg, or nitrendipine, 20 mg, both given once or twice daily. After 4 weeks, only the responders (diastolic BP <90 mm Hg) entered a 5-month maintenance period. At baseline, and after 3 and 6 months, LVMI was blindly estimated by means of magnetic resonance imaging (MRI) and, for comparison, by means of echocardiography. Of the 50 randomized patients, three were excluded from the study as nonresponders after 4 weeks; moreover, two patients taking benazepril and one taking nitrendipine discontinued the treatment after 2 months for adverse effects. Both monotherapies reduced systolic and diastolic BP to a similar extent. After 3 months, MRI-estimated LVMI decreased by 21.5 g/m2 in the benazepril and 8.8 g/m2 in the nitrendipine group, with an adjusted mean difference between the two groups of 11.1 g/m2 (95% CI, 7.3-14.8 g/m2; p = 0.0001). After 6 months, it decreased by 23.6 g/m2 and 10.0 g/m2, respectively, with an adjusted mean difference of 11.3 g/m2 (95% CI, 7.5-15.5; p = 0.0001) in favor of benazepril. In conclusion, despite a similar antihypertensive effect, benazepril led to a greater reduction in MRI-measured LVMI than did nitrendipine (-16.2% vs. -7.2%) in hypertensive patients with left ventricular hypertrophy.

Fixed combination of benazepril and low-dose amlodipine in the treatment of mild to moderate essential hypertension: evaluation by 24-hour noninvasive ambulatory blood pressure monitoring.

The antihypertensive efficacy and tolerability of a fixed combination of benazepril (10 mg) and low-dose amlodipine (2.5 mg) were assessed in 24 patients (mean age, 43.9 years) with uncomplicated mild to moderate essential hypertension [supine diastolic blood pressure (DBP) > or = 95 and < or = 120 mm Hg)]. After 2 weeks of washout taking placebo, patients were randomized to receive the fixed combination or placebo, both administered once daily for 3 weeks, according to a double-blind, crossover design. Patients were checked at the end of the washout period and every 3 weeks thereafter. At each visit, 24-h ambulatory BP monitoring (ABPM) was performed by a noninvasive device (Spacelabs 90207); casual BP (by mercury sphygmomanometer), heart rate (HR), and body weight also were measured. The fixed combination significantly reduced systolic (SBP) and DBP values throughout the 24 h as compared with placebo, without affecting the normal BP circadian variability. The antihypertensive effect of the fixed combination could be observed to a similar extent during the day and night and was still significant 24 h after dosing. HR and body weight were not affected by the treatment. The fixed combination of benazepril 10 mg/amlodipine 2.5 mg was well tolerated, and no patient withdrew from the study because of side effects.

Long-term progression of chronic renal insufficiency in the AIPRI Extension Study. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group.

The Angiotensin-converting-enzyme Inhibition on Progressive Renal Insufficiency (AIPRI) Study showed that the ACE inhibitor benazepril provides protection against loss of renal function in patients with chronic renal insufficiency (CRI) caused by various renal diseases. As a result of unexpectedly low mortality in the placebo group, there was a substantial imbalance in mortality during the course of this study (8 patients on benazepril vs. 1 on placebo). The aim of the extension study was to follow-up the patients from the AIPRI core study until autumn 1996, focusing on CRI progression and mortality. Data collection was post hoc. Patients were treated according to investigators' usual practices, without knowledge of the core study trial medication or (initially) the core trial results. A new primary efficacy parameter was defined as the time from the start of core study treatment to the occurrence of the first event in the combined composite end-point of dialysis, renal transplantation or death related to renal disease. Serial serum creatinine levels and all-cause mortality were also recorded. The median total follow-up for core + extension periods was 6.6 years. Many patients from both treatment groups (64% on benazepril and 61% on placebo) received ACE inhibitors during follow-up. In the intention-to-treat analysis of the core + extension data, only 79 of 300 patients from the benazepril group, compared to 102 of the 283 patients from the placebo group needed dialysis or renal transplantation, or died related to renal disease (P < 0.013, log-rank test). The mortality imbalance seen in the core trial was not evident with the longer follow-up (25 deaths in the benazepril and 23 in the placebo group, before dialysis). These data clearly demonstrate a long-term beneficial effect in patients randomized to take benazepril during the core study, but because treatment during the extension period was not randomized, the results of this intention-to-treat analysis need to be interpreted with care.

Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group.

BACKGROUND: Drugs that inhibit angiotensin-converting enzyme slow the progression of renal insufficiency in patients with diabetic neuropathy. Whether these drugs have a similar action in patients with other renal diseases is not known. We conducted a study to determine the effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of renal insufficiency in patients with various underlying renal diseases. METHODS: In a three-year trial involving 583 patients with renal insufficiency caused by various disorders, 300 patients received benazepril and 283 received placebo. The underlying diseases included glomerulopathies (in 192 patients), interstitial nephritis (in 105), nephrosclerosis (in 97), polycystic kidney disease (in 64), diabetic nephropathy (in 21), and miscellaneous or unknown disorders (in 104). The severity of renal insufficiency was classified according to the base-line creatinine clearance: 227 patients had mild insufficiency (creatinine clearance, 46 TO 60 ml per minute), and 356 had moderate insufficiency (creatinine clearance, 30 to 45 ml per minute). The primary end point was a doubling of the base-line serum creatine concentration or the need for dialysis. RESULTS: At three years. 31 patients in the benazepril group and 57 in the placebo group had reached the primary end point (P<0.001). In the benazepril group, the reduction in the risk of reaching the end point was 53 percent overall (95 percent confidence interval, 27 to 70 percent), 71 percent (95 percent confidence interval, 21 to 90 percent) among the patients with mild renal insufficiency, and 46 percent (95 percent confidence interval, 12 to 67 percent) among those with moderate renal insufficiency. The reduction in risk was greatest among the male patients; those with glomerular diseases, diabetic nephropathy, or miscellaneous or unknown causes of renal disease; and those with base-line urinary protein excretion above 1 g per 24 hours. Benazepril was not effective in patients with polycystic disease. Diastolic pressure decreased by 3.5 to 5.0 mm Hg in the benazepril group and increased by 0.2 to 1.5 mm Hg in the placebo group. CONCLUSIONS: Benazepril provides protection against the progression of renal insufficiency in patients with various renal diseases.

Antianginal effect of transdermal nitroglycerin and oral nitrates given for 24 hours a day in 2,456 patients with stable angina pectoris. The Italian Multicenter Study.

The effect of transdermal and oral nitrates on anginal symptoms were compared in a randomized trial of 2,456 out-patients with stable angina pectoris recruited in 206 cardiological centers in Italy. Half of the patients had effort-induced angina, 12% rest angina and 38% "mixed angina". Before enrollment, all of the patients were on stable treatment with oral nitrates either as monotherapy or in combination with other antianginal agents. After a 2-week run-in period on the previous oral nitrate regimen, two thirds of the patients were randomized to receive a nitroglycerin patch 5 mg/24 hours for 2 weeks, the remaining one third continued their previous treatment. The patients subsequently reporting > or = 1 anginal attack/2 weeks were titrated to transdermal nitroglycerin 10 mg/24 hours or to the maximum dose of oral nitrates suggested by the manufacturer for the following 4 weeks; asymptomatic patients continued on the initial dosages. The 2-week anginal attack rate was reduced from 4.9 +/- 5.3 to 1.4 +/- 2.5 in the transdermal nitroglycerin group (-71%), and from 4.5 +/- 4.7 to 1.5 +/- 2.7 (-67%) in the oral nitrate group. The proportion of patients free of angina increased from 12% to 54% (+343%) with transdermal nitroglycerin and from 15% to 49% with oral nitrates (+218%) (p < 0.05). The reduction in angina frequency was similar during the day and during the night. Nocturnal angina was rare in patients with effort angina. However, about half of the patients with rest and "mixed" angina had had nocturnal episodes, the number of which was significantly reduced by both regimens: nighttime asymptomatic patients increased from 45% to 82% in the rest angina group, and from 50% to 83% in the "mixed" angina group, with no differences between treatments. Withdrawals due to side-effects were rare: 1.5% with transdermal nitroglycerin and 1.3% with oral nitrates. Headache was the most common side-effect and was more frequently reported with oral nitrates. Although the lack of a placebo control precludes an absolute evaluation of efficacy, the results of the present study suggest that both transdermal nitroglycerin and oral nitrates may provide relief of anginal symptoms over 24 hours in the majority of stable angina patients. Nocturnal angina, reported by 50% of the patients with rest and mixed angina, is effectively reduced by the administration of nitrates over 24 hours.

Fixed combination of benazepril and very low dose hydrochlorothiazide in the treatment of mild to moderate essential hypertension: evaluation by 24-hour non invasive ambulatory blood pressure monitoring.

A double-blind, crossover, placebo-controlled study was undertaken in order to assess the antihypertensive efficacy of a fixed combination of benazepril and hydrochlorothiazide in two different dosages by ambulatory blood pressure monitoring (ABPM). After a three-week placebo wash-out period, 18 patients with mild to moderate essential hypertension, all males, aged 41-60 years, were randomized to receive benazepril 5 mg + hydrochlorothiazide 6.25 mg, benazepril 10 mg + hydrochlorothiazide 12.5 mg or placebo, all given once daily for 4 weeks, according to a 3 crossover period, arranged in a 3 x 3 latin square design. Patients were checked after the wash-out period and every 4 weeks thereafter. At each visit, 24-hour ABPM was performed by a non-invasive device (Spacelabs 90202); causal BP (by mercury sphygmomanometer) and HR were also measured. Both dosages of the fixed combination were equally effective in reducing systolic and diastolic BP values throughout the 24-hour period as compared to the placebo. The antihypertensive effect of the drug could be observed to a similar extent both during the day and night and was still significant 24-hour post-dosing. In addition, the fixed combination did not affect the normal BP circadian variability.

Evaluation by 24-hour ambulatory blood pressure monitoring of efficacy of benazepril 20 mg plus hydrochlorothiazide 25 mg fixed combination as compared to captopril 50 mg [corrected] plus hydrochlorothiazide 25 mg fixed combination in treating mild to moderate hypertension: a double-blind, within-patient, placebo-controlled study.

In a double-blind, placebo-controlled, three-period cross-over, randomized study we evaluated the efficacy and tolerability of a fixed combination of benazepril 20 mg and hydrochlorothiazide 25 mg (BN + HCT) as compared with the fixed combination of captopril 50 mg and hydrochlorothiazide 25 mg (CP + HCT) by ambulatory blood pressure monitoring (ABPM) in patients with mild to moderate hypertension. Eighteen outpatients, 16 men and 2 women aged 41-58 years, were randomized to receive BN + HCT, CP + HCT, or placebo, all administered once daily for 4 weeks according to a three-period cross-over arranged in a 3 x 3 latin square design. Patients were checked after an initial 3-week washout period and every 4 weeks thereafter. At each visit, 24-h ABPM was performed by a noninvasive device (Spacelabs 5300); causal BP and heart rate (HR) were also measured. Both fixed combinations had a clear-cut antihypertensive effect in comparison with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of benazepril on stress testing blood pressure in essential hypertension.

The effects of different doses of the angiotensin-converting enzyme inhibitor benazepril on cardiovascular response to a set of standardized laboratory tasks were analyzed. Eighteen patients (15 men and 3 women) with mild-to-moderate essential hypertension were randomly allocated to receive 10 or 20 mg of benazepril, or placebo, each administered once daily for 2 weeks, according to a double-blind, 3-period design. At the end of each treatment period, patients were examined at resting baseline and while performing mental arithmetic, handgrip and cycle ergometry tests. In comparison with placebo, the average reductions in resting systolic blood pressure (BP) were 8.7 mm Hg (95% confidence intervals [CI] -15.2 to -2.1) with 10 mg of benazepril, and 7.8 mm Hg (95% CI -14.4 to -1.3) with 20 mg; the corresponding reductions in resting diastolic BP were 5.1 mm Hg (95% CI -8.7 to -1.4) and 6.8 mm Hg (95% CI -10.4 to -3.1) (all p < 0.05). During mental arithmetic, the reductions in systolic BP were 10.4 mm Hg (95% CI -17.4 to -3.4) with 10 mg of benazepril, and 13.8 mm Hg (95% CI -20.8 to -6.8) with 20 mg; diastolic BP was reduced by 4.5 mm Hg (95% CI -8.5 to -0.5) and 8.3 mm Hg (95% CI -13.2 to -4.3), respectively (all p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of evening versus morning benazepril on 24-hour blood pressure: a comparative study with continuous intraarterial monitoring.

In a single-blind, in-patient, crossover study, the influence on the circadian blood pressure (BP) profile of the 9:00 a.m. versus the 9:00 p.m. acute administration of a single dose of benazepril 10 mg, a new angiotensin-converting-enzyme inhibitor, was assessed in 10 hypertensive patients by means of 24-hour intraarterial ambulatory BP monitoring. Mean 24-hour BP for the three treatments (placebo, benazepril a.m., benazepril p.m.) were 155/93, 131/83 and 138/86 mmHg, respectively. No significant differences between the two benazepril schedules were found in terms of either 24-hour or day-time and night-time mean BP values. However, hourly averages showed that benazepril a.m. had a more sustained antihypertensive effect than benazepril p.m., where a loss of efficacy was observed 19 hours after the administration. BP responses to static and dynamic exercise and to cold pressor test were unchanged after both benazepril schedules, as were BP peaks. These results demonstrate that acute benazepril administration markedly reduces systolic and diastolic BP. The morning administration is preferable because it more effectively covers the whole 24 hours than an evening dose.

Short-term metabolic effects of the ACE-inhibitor benazepril in type 2 diabetes mellitus associated with arterial hypertension.

To assess the short-term metabolic effects a long-acting non-sulphydryl ACE-inhibitor benazepril on glycaemic control in Type 2 diabetes mellitus and arterial hypertension, 10 hypertensive diabetic patients treated with glibenclamide were studied in a double-blind, crossover fashion over two 10-day periods in which either benazepril (10 mg/day) or placebo was given. At the end of the 10 day treatment, both blood pressure and plasma glucose concentrations were lower after benazepril versus placebo (benazepril, blood pressure: 143 +/- 11/83 +/- 5 mmHg, plasma glucose: 7.1 +/- 1.2 mmol/l; placebo: blood pressure: 157 +/- 10/99 +/- 2 mmHg, plasma glucose: 8.2 +/- 1 mmol/l, p < 0.05). In response to an oral glucose tolerance test combined with 1 mg intravenous glibenclamide, plasma glucose levels were lower after benazepril versus placebo (0-460 min: 8.4 +/- 0.8 versus 10.5 +/- 0.9 mmol/l, p < 0.05), whereas plasma insulin, C-peptide and glibenclamide concentrations were not different. It is concluded that a short-term administration of benazepril in Type 2 diabetes mellitus reduces blood pressure and improves blood glucose control, most likely by decreasing insulin resistance.

Effect of cigarette smoking and of a transdermal nicotine delivery system on glucoregulation in type 2 diabetes mellitus.

The effect of nicotine absorbed transdermally from a patch (TNS) and from cigarette smoking on insulin secretion and action in Type 2 diabetes has been compared. Twelve Type 2 diabetic smoking patients, aged 51 y, with diabetes for 9 y, treated either with diet and/or oral hypoglycaemic agents, were studied on three occasions, according to a double-blind, placebo-controlled, cross-over design. The subjects were investigated 12 h after their last cigarette or application of one patch of TNS 30 cm2 or TNS placebo, or whilst smoking their usual cigarette. Insulin secretion was assessed by a glucagon (1 mg IV) stimulation test. On a second occasion, insulin action was assessed by a hyperglycaemic-hyperinsulinaemic clamp, the spontaneous hyperglycaemia of the fasting state (8.61 mmol.l-1) being maintained during a 4 h insulin infusion (at 0.1 mU.kg-1.min-1 for the initial 2 h, and 1 mU.kg-1.min-1 during the last 2 h). TNS and the cigarette did not affect endogenous insulin secretion as compared to placebo. During the initial 2 h of the clamp study, plasma insulin increased from 88 to 155 pmol.l-1, hepatic glucose production (3-3H-glucose) was less suppressed after TNS (4.31 mumol.kg-1.min-1) than after placebo (2.5 mumol.kg-1.min-1), but was more suppressed than after cigarette smoking (5.61 mumol.kg-1.min-1). In the last 2 h of the clamp (plasma insulin 646 pmol.l-1), glucose utilization was less stimulated after TNS (36.1 mumol.kg-1.min-1) vs placebo (39.8 mumol.kg-1.min-1), but more than after cigarette smoking (33.6 mumol.kg-1.min-1), primarily because of a decrease in glucose storage.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term effects of benazepril on ambulatory blood pressure, left ventricular mass, diastolic filling and aortic flow in essential hypertension.

We investigated the long-term effects of benazepril, a new non-sulfydryl angiotensin converting enzyme inhibitor, on ambulatory blood pressure (BP) and left ventricular (LV) anatomy and function in 13 never treated hypertensive patients (mean age 55 years--SD 9). Non-invasive ambulatory BP monitoring (Spacelabs 90202, a reading every 15 min for 24 hours) and standard and pulsed Doppler echocardiography were performed basally and after 12 months of therapy. Echocardiography was performed also at the end of 18th month of treatment. Eleven patients required a single daily dose of benazepril 10 (n = 9) or 20 (n = 2) mg, and two patients of 20 mg plus chlorthalidone 25 mg, to achieve clinical BP control. Average 24 h systolic/diastolic BP was 156/100 mmHg (SD 17/5) basally and 144/90 mmHg (SD 16/7) at the end of the 12th month of treatment (all p less than 0.01), LV mass index was 133 g/m2 basally and 113 g/m2 at the 12th month (p less than 0.01), early transmitral flow velocity (peak E) was 0.43 m/s (SD 0.11) basally and 0.62 (SD 0.13) m/s at the 12th month (p less than 0.01), and late transmitral flow velocity (peak A) did not change [0.67 (SD 0.10) m/s basally and 0.64 (SD 0.11) m/s at the 12th month]. Peak A/peak E ratio decreased from 1.69 (SD 0.57) to 1.31 (SD 0.37) (p less than 0.01). Peak aortic velocity, aortic acceleration time and aortic acceleration did not change. The per cent reduction of LV mass index was more closely related to the reduction of average 24 h systolic (r = 0.66, p = 0.013) and diastolic (r = 0.72, p = 0.005) BP than to the reduction of casual systolic (r = 0.37, p = NS) and diastolic (r = 0.42, p = NS) BP. None of the echocardiographic indices changed between the 12th and 18th month of treatment. In a control group of 13 age- and sex-matched healthy normotensive volunteers who underwent 24 h ambulatory BP monitoring and echocardiography twice, 12 months apart, there were no statistically significant BP or echographic changes. In summary, long-term antihypertensive treatment with benazepril provided and effective 24 h BP control, associated with regression of LV hypertrophy and improvement in LV diastolic filling, without changes in LV systolic function.

A comparison of metoprolol OROS with antenolol in the treatment of effort angina pectoris: a randomized double-blind study.

The antianginal efficacy of metoprolol OROS has been investigated in comparison with that of atenolol in a multicenter double-blind cross-over trial carried out in patients with stable effort angina. OROS (ORally OSmotic) is a new semi-permeable delivery system with very slow osmotic release of the active drug, which is maintained at virtually constant plasma levels throughout the 24 hours. At the end of a 2-week run-in period, 53 patients with chronic coronary artery disease and documented ischemia during bicycleergometric exercise test were given, on double-blind condition, metoprolol OROS 21/285 and atenolol 100 mg in random order for 4 weeks each. On the last day of each cross-over period, patients underwent a bicycleergometric exercise test 24 hours after the last drug intake. The mean number of anginal attacks (2.54 during the 2-week run-in period) decreased under both metoprolol OROS (1.29 and 1.13 after 2 and 4 weeks of treatment, respectively) and atenolol (1.29 and 0.73 after 2 and 4 weeks of treatment, respectively), with no difference between the two beta-blockers. The same behaviour was observed as regards the nitroglycerin tablets consumption. The exercise test variables (i.e. duration of exercise, maximum workload and peak exercise values of systolic and diastolic blood pressure, heart rate and ST-segment depression) did not differ between the two treatments and did not show a time-effect. The percentage of patients reporting adverse effects was low with both treatments. Two patients were withdrawn from the study during atenolol (gastralgia and heartburn, respectively), and one during metoprolol OROS (gastralgia).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of cadralazine in a large group of hypertensive patients chronically treated with cadralazine: advantage over a conventional study in a small group of patients.

The concentrations of cadralazine in plasma were studied in 101 hypertensive patients treated with oral doses of 10, 15, or 20 mg of cadralazine once daily. Most of the patients received additionally a beta-blocking drug (n = 87) and a diuretic (n = 52). Few blood samples were collected in each patient on several occasions during the treatment, which usually lasted for more than 6 months. No accumulation of cadralazine in plasma occurred in any of the patients and the maximum concentrations were similar to those recorded in a small sample of healthy volunteers. The terminal half-life of elimination (3.6 h) was longer than that observed in healthy subjects (approximately 2.5 h). Conversely, the total clearance (197 ml/min) was lower (285 ml/min in healthy). The half-life and the total clearance in plasma were not dose dependent. In the patients treated for more than 6 months, no change in the pharmacokinetics of cadralazine was detected. The description of the distribution of concentrations showed that one-half of the patients behaved similarly to healthy subjects concerning half-life and total clearance. The other half presented a slower elimination of the drug (t 1/2 = 4.4 h and ClT = 130 ml/min) and these patients were significantly older (p = 0.01) than the former. This suggests that special attention should be paid to old hypertensive patients when a dose higher than 15 mg once daily is prescribed. Though concentrations were proportional to the dose, the body weight was not found to be a determining factor for dose adjustment.(ABSTRACT TRUNCATED AT 250 WORDS)