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J Ménard

Publications and source records attributed to J Ménard.

At least 19 recordsLinked to original sources
PubMed1995

Additive effects of combined angiotensin-converting enzyme inhibition and angiotensin II antagonism on blood pressure and renin release in sodium-depleted normotensives.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors do not decrease plasma angiotensin (Ang) II levels 24 hours after drug intake to the same extent as at peak. This intermittent partial "escape" is explained either by a renin-mediated reactive rise in plasma Ang I or by non-ACE-dependent Ang II generation. We therefore tested the hypothesis that a combination of ACE inhibition and Ang II blockade may have additive biological and hemodynamic effects. METHODS AND RESULTS: In a single-dose, double-blind, randomized, four-way, crossover study, an Ang II antagonist (losartan 50 mg), an ACE inhibitor (captopril 50 mg), their combination, and matched placebos were orally administered to 12 normotensive male volunteers maintained in mild sodium depletion. When captopril 50 mg and losartan 50 mg were given alone, the magnitude of their effects on blood pressure, plasma active renin, Ang I, and aldosterone was similar, whereas the kinetics of their effects were different, reflecting differences in drug pharmacokinetics. The losartan-captopril combination completely suppressed the rise in plasma Ang II induced by losartan 2 hours after drug intake (3.3 +/- 3.6 pg/mL versus 20.3 +/- 19.1 pg/mL, respectively, P < .05). Six hours after drug intake, the losartan-captopril combination induced a significantly greater decrease in mean blood pressure than that produced by either losartan or captopril alone (73 +/- 7 mm Hg versus 79 +/- 8 mm Hg versus 81 +/- 7 mm Hg, respectively, P < .05). The maximum placebo-subtracted falls in mean blood pressure for the losartan-captopril combination, captopril 50 mg, and losartan 50 mg were 14 +/- 5 mm Hg, 10 +/- 3 mm Hg, and 9 +/- 6 mm Hg, respectively (F2.22 = 3.45, P < .05). The duration of the mean blood pressure fall was not prolonged by the combination. After combined losartan-captopril administration, the area under the plasma active renin versus time curve (0 to 24 hours) was significantly increased when compared with either losartan or captopril alone (6404 +/- 2961 pg.h.mL-1 versus 3105 +/- 1461 pg.h.mL-1 versus 2092 +/- 867 pg.h.mL-1, respectively, P < .05). The combination had no additive effects on plasma aldosterone decrease when compared with either losartan or captopril alone (58 +/- 17% versus 51 +/- 20% versus 53 +/- 21%, respectively, NS). CONCLUSIONS: The combined administration of a standard single oral dose of an ACE inhibitor and an Ang II antagonist to mildly sodium-depleted normal subjects (1) had a major additive effect on plasma renin rise, (2) induced an additional mean blood pressure reduction, and (3) had no additive effect on plasma aldosterone fall.

Adolescent↗
PubMed1995

Comparison of the angiotensin II antagonist UP269-6 with the angiotensin converting enzyme inhibitor enalapril in normotensive volunteers challenged with angiotensin I.

We assessed the inhibitory effect of UP269-6, a new orally active angiotensin II (ANG II) receptor antagonist, on the pressor action of exogenous ANG I in healthy male volunteers maintained on an unrestricted sodium intake and compared it with that of enalapril. Seven different single doses of UP269-6 ranging from 5 to 180 mg, 20 mg enalapril, or placebo were administered to 16 subjects in a double-blind fashion. The order of placebo and enalapril was randomized, and UP269-6 was given in an ascending dose order. The peak systolic blood pressure (SBP) response to a test dose of ANG I was determined serially before and after oral drug administration by monitoring finger BP by a photoplethysmographic method. No drug-related side effect was observed. There was a dose-dependent inhibition of the SBP response to the ANG I challenge. Doses as low as 40 to 80 mg had blocking effects quite similar to that of enalapril 20 mg. Ten hours after the 20- and 40-mg doses of UP269-6, the SBP response was still attenuated when drug levels no longer were measurable in plasma. UP269-6 also produced a dose-related increase in active renin and ANG II levels at 24 h after drug intake. In these volunteers on unrestricted salt intake, no statistically significant effect on 24-h urinary aldosterone excretion was observed. Based on these preliminary data, the pharmacokinetic drug half-life (t 1/2) was estimated at 4.7 h and the EC50 was estimated at 41 ng/ml. UP269-6 appears to be a well-tolerated, potent, orally active, antagonist of ANG II receptors in men. Doses of 40-80 mg might block the ANG I pressor response as does enalapril 20 mg.

Administration, Oral↗
PubMed1995

Plasma angiotensin in binephrectomised mice.

Plasma renin-angiotensin parameters were measured before and 24h after binephrectomy (BNx) in male Swiss (Ren-1, Ren-2) and BALB/c (Ren-1) female mice (representing the extremes of differences in tissue renin expression), together with in vivo inhibition of residual renin. Plasma Ang II increased from 18.9 +/- 7.3 to 48.1 +/- 16.9 pg/ml after BNx in conscious Swiss mice (+/- sd, p < 0.001, n = 11&12), renin activity (PRA) increased 2.76 times, angiotensinogen (aogen) increased 4.57 times and renin concentration (PRC) fell by 65%. In BALB/c, Ang II+Ang III decreased slightly (56.6 +/- 11 to 37.7 +/- 14.7, p < 0.05, n = 5&6), PRA was unchanged, aogen increased 12 times and PRC fell by 93%. Plasma ACE decreased by 26% and 28% respectively. Aogen did not increase further when post BNx plasma renin was inhibited with antirenin in vivo during 20h. Thus plasma angiotensin is maintained or considerably increased following BNx in mice and the change is consistent with first-order kinetics with respect to renin and aogen in the circulation. Whether the strain carries one or two renin genes, high renal and extrarenal renin production combined with a low plasma aogen phenotype yields resting angiotensin levels similar to other mammals. A kinetic regulation of aogen levels is proposed in mice wherein Ang II production is limited by low substrate concentration thereby ensuring normotension in the face of abundant extrarenal renin secretion.

Angiotensin II↗
PubMed1995

Limiting factors in the control of BP: why is there a gap between theory and practice?

The benefits of BP reduction are undisputed, and management guidelines are well established. Nevertheless, epidemiological studies and randomised clinical trials have consistently shown that, although treated, BP frequently remains inadequately controlled. This failure to control BP adequately is not fully recognised by physicians or their patients. Furthermore, even when BP control is not achieved, there is evidence that many physicians do little to modify therapy. This gap between theory and practice in the control of hypertension is a multifactorial phenomenon. Patients may not take medication or adhere to their physician's advice; physicians appear satisfied with sub-optimal therapy; the underlying pathophysiology of hypertension is heterogeneous and thus it can be difficult to predict which patients will respond to a specific treatment; there is poor communication between physicians and their patients; and treatment guidelines may be too complex, theoretical and unclear to be followed in general practice. Despite these difficulties, it is clear that BP control can be improved by combining several antihypertensive drugs. This requires careful consideration with regard both to the mechanisms of action of the agents selected and their tolerability.

Antihypertensive Agents↗
PubMed1995

Structural changes and cyclic GMP content of the aorta after calcium antagonism or angiotensin converting enzyme inhibition in renovascular hypertensive rats.

OBJECTIVE: To evaluate the respective roles of elevated blood pressure and stimulation of the renin-angiotensin system in the development of structural changes in the aortae of rats with renovascular hypertension. MATERIALS AND METHODS: Renovascular hypertensive rats (two-kidney, one clip) were randomly allocated to three different groups and were treated with equihypotensive doses of an angiotensin converting enzyme (ACE) inhibitor (enalapril, 3 mg/kg per day) or of a new long-acting calcium antagonist (mibefradil, 30 mg/kg per day). A renovascular hypertensive group was left untreated. A sham-operated group of rats was used as a normotensive control group. At the end of the 5-week treatment period the rats were killed and their aortae were removed. Medial hypertrophy, elastin and collagen content and density of nuclei were evaluated using quantitative morphometry. The aortic cyclic GMP (cGMP) content was quantified by radioimmunoassay. RESULTS: Hypertension was associated with medial hypertrophy, a decreased elastin: collagen ratio, hypertrophy of the smooth muscle cells and increased cGMP content of the aorta. Mibefradil and enalapril equally prevented the morphological consequences of hypertension (i.e. medial hypertrophy and the decreased elastin:collagen ratio). The aortic cGMP content was increased by enalapril but not by mibefradil. CONCLUSION: The present results show that, even in a high-renin model (two-kidney, one clip), it is possible to prevent or suppress the vascular consequences of hypertension without interfering with the renin-angiotensin system. This suggests that the changes observed in the aorta are directly related to blood pressure or to other mechanisms independent of the renin-angiotensin system, which could be blocked by a calcium antagonist such as mibefradil.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Self-measurement of blood pressure at home to evaluate drug effects by the trough: peak ratio.

AIM: Studies were carried out to assess (1) the statistical and clinical meaning of the trough:peak ratio and (2) the value of self-measurement of blood pressure at home in monitoring the duration of action of antihypertensive drugs in individual patients and in groups of patients. PATIENTS AND METHODS: Data from previous single-blind trials in 44 individual patients were reanalysed. The trough:peak ratio was calculated from mean blood pressure values. RESULTS: There are two major limitations in using this method. (1) Estimates of the trough:peak ratio are biased by the inclusion of non-responders. These patients have the usual random variations in blood pressure, and small differences can result in a spuriously high trough:peak ratio which may lead to an overestimate of the actual ratio. (2) The standard deviation of the trough:peak ratio is large; for a given mean trough:peak ratio some patients have the required 24-h drug cover, whereas others do not. The large standard deviation is partly a result of statistical problems, since four different blood pressure values are used to calculate the ratio. It is therefore essential to increase the precision of the measurement to decrease the standard deviation. CONCLUSIONS: Self-measurement of blood pressure at home might be a useful and inexpensive way of estimating the trough:peak ratio. As repeated measurements of blood pressure can be carried out at home under standardized conditions, this method increases the precision of each measurement. It is possible, therefore, to calculate individual trough:peak ratios and the drug regimen (once or twice a day) can be individualized.

Antihypertensive Agents↗
PubMed1994

[Evaluation of a computer assisted training program for hypertensive patients].

ISIS tutorial program (French abbreviation for Animated and Computerized Initiation into Health) was carried out for Macintosh type computers to place a modern and interactive learning device at cardiovascular risk patients' disposal. Such a program combines strict scientific explanations and aesthetic attractiveness of multimedia communication. To test the effect of this device on health knowledge gain, 158 hypertensives admitted in one-day or in half-week clinics for an initial check-up or for a therapeutic adjustment were randomised into two groups: a control group (n = 79), receiving usual education (contacts with physicians, nurses, dieticians, health oriented booklets), and an experimental or "ISIS" group (n = 79) undergoing an interactive session with the computer during 30 to 60 minutes, in addition to usual education. Health knowledge of both groups was assessed through a 28-item questionnaire, before any education procedure, two months after the discharge, through a standardized interview by phone, thanks to the same investigator. On the whole, 69 + 69 = 138 complete case records could be analysed. Initial health knowledge mean score, at admission to the hospital, was 14.3 +/- 4.2 (range: 4 to 25). This score significantly improved among the whole population (difference between the two evaluations: 3.7 +/- 3.5 points; p = 0.0001). Improvement was greater in ISIS group than in controls (p = 0.02). Among hypertensives with initial scores < or = 16, improvement was respectively 4.5 +/- 3.6 and 2.9 +/- 3.0 for ISIS and control groups (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Effects of Ro 40-5967, a new calcium antagonist, and enalapril on cardiac remodeling in renal hypertensive rats.

The goal of the present study was to compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (enalapril) and a long-acting calcium antagonist (Ro 40-5967) on cardiac remodeling secondary to renovascular hypertension. For this purpose, two kidney-one clip (2K-1C) hypertensive rats, 6 weeks after renal artery clipping, were either untreated or treated for 5 weeks with equihypotensive doses of enalapril (3 mg/kg/day) and Ro 40-5967 (30 mg/kg/day). At the end of the treatment period, cardiac weight, maximum coronary blood flow ([MCBF], measured in isolated perfused hearts), and interstitial and perivascular collagen volume fraction (measured by morphometry) were evaluated in all rats. Both drugs similarly decreased arterial blood pressure (ABP) for 24 h. Enalapril was more effective than Ro 40-5967 in inducing regression of cardiac hypertrophy. MCBF was decreased in untreated hypertensive rats and was increased to the same extent by both treatments, although not normalized. Interstitial cardiac collagen content after 11 weeks of hypertension was not increased in untreated hypertensive rats. In contrast, the collagen volume fraction measured in the perivascular area was increased in untreated hypertensive rats and this increase was not significantly suppressed by either enalapril or Ro 40-5967. These results show that cardiac hypertrophy, decrease in MCBF and increase in myocardial collagen content, do not evolve in parallel in 2K-1C hypertensive rats. Two antihypertensive treatments, enalapril and Ro 40-5967, increased MCBF to the same extent but had different effects on cardiac hypertrophy despite having equal antihypertensive efficacy.

Animals↗
PubMed1993

[Vasodilator effect of nitric oxide is a necessary counter-regulation in the spontaneously hypertensive rat].

The chronic inhibition of NO-synthase by NG-nitro-L-arginine methyl ester (L-NAME, a L-arginine analogue) induces a dose-dependent decrease in aortic cGMP and an increase in blood pressure. We used this pharmacological approach to evaluate the release of NO in vivo in spontaneously hypertensive rats (SHR); 15 SHR and 10 Wistar-Kyoto rats (WKY) were given 25 mg L-NAME/kg/d by gavage for 15 days; 10 SHR and 10 WKY rats given water for the same period were used as control. During the trial, 10/15 SHR given L-NAME died. Systolic blood pressure (mmHg) increased from 132 +/- 6 to 170 +/- 4 in WKY given L-NAME and from 169 +/- 4 to 242 +/- 6 in SHR given L-NAME. Aortic cGMP content (fmol/mg protein) was 2,204 +/- 382 and 2,076 +/- 461 fmol/mg control WKY and SHR (NS), and was decreased to 324 +/- 44 and 641 +/- 70 in WKY and SHR given L-NAME respectively (p < 0.0001 each). L-NAME increased plasma atrial natriuretic factor only in SHR. In summary, basal aortic cGMP content, reflecting the basal release of NO, was similar in WKY and SHR. The decrease in aortic cGMP content of SHR given L-NAME, due to the blockade of NO-synthase, was accompanied by a large increase in systolic blood pressure and a tremendous mortality rate. Thus, basal release of NO is probably not impaired in SHR, but represents a major counterregulatory mechanism in this genetic model of arterial hypertension.

Amino Acid Oxidoreductases↗
PubMed1992

[Cooperative study of systolic arterial hypertension in the elderly patient (SHEP). Comments].

SHEP (Systolic Hypertension in the Elderly Program) is a multicenter controlled therapeutic trial which included 4,736 subjects aged 60 years and over, who had isolated systolic hypertension at three consecutive visits at the outpatient clinic. The treatment, based on low doses of diuretic (chlorthalidone 12.5-25 mg daily) combined, when necessary, with a cardioselective beta-blocker (atenolol 25 to 50 mg daily), significantly reduced the incidence of cerebrovascular and coronary events; the relative risk reduction for total mortality was not statistically significant. The beneficial cardiovascular effects were observed in both sexes, and in the 80+ age group. These results show that this particular therapy applied to this form of hypertension decreases the risk of both coronary and cerebral events, as was already suggested by the meta-analysis of the controlled therapeutic trials performed with diuretics, beta-blockers and other older antihypertensive drugs in patients with permanent diastolic hypertension. They also show the limitations of this therapeutic strategy, which controlled only 50 percent of the patients who were, however, highly selected, especially concerning the absence of associated morbid conditions and treatments. The need for, and feasibility of, new controlled therapeutic trials comparing the mortality and morbidity associated with various new antihypertensive therapies must now be discussed.

Adrenergic beta-Antagonists↗
PubMed1992

Decision to treat mild hypertension after assessment by ambulatory monitoring and World Health Organisation recommendations.

OBJECTIVE: To determine if one ambulatory blood pressure recording over 12 hours could detect those patients with mild hypertension who needed treatment according to the World Health Organisation-International Society of Hypertension (ISH) guidelines based on the causal measurement of diastolic blood pressure at successive visits to a clinic. DESIGN: Comparison of decision to treat based on one ambulatory measurement over 12 hours and standard blood pressure measurements over six months in the same patients. SETTING: Outpatient hypertension clinic. SUBJECTS: 130 men and women with diastolic blood pressure of 90-104 mm Hg at second visit to clinic. MAIN OUTCOME MEASURES: Blood pressure measurements over six months. Measurement from ambulatory monitoring. Decision to treat. RESULTS: Of the 130 patients included, 108 were followed up over the six months. Treatment was started according to WHO-ISH criteria in 44 (13 at the third visit, 13 at the fourth, 18 at the fifth). According to the selected criteria for ambulatory blood pressure monitoring 41 patients would have been treated. Both methods agreed that the same 27 patients required treatment and the same 50 did not, but they did not agree in 31 patients. When calculated at the optimal diastolic blood pressure threshold determined by a receiver operating characteristic curve, the sensitivity, specificity, and positive predictive value of ambulatory blood pressure monitoring were 71% (95% confidence interval 57% to 84%), 82% (72% to 92%), and 66% (51% to 81%), respectively. CONCLUSION: If the WHO-ISH criteria are accepted as the standard for deciding to treat patients with mild hypertension the predictive value of one ambulatory blood pressure recording over 12 hours is too low to detect with confidence those patients who need treatment when managed according to these criteria.

Blood Pressure Determination↗
PubMed1992

Investigation of the biochemical effects of renin inhibition in normal volunteers treated by an ACE inhibitor.

1. In order to investigate accurately the biochemical effects of renin inhibition in man, we have developed a sensitive assay to measure angiotensin I (1-10) decapeptide. 2. Angiotensins were extracted from plasma by adsorption to phenylsilylsilica, and angiotensin I (Ang I) was quantified by radioimmunoassay. The detection limit was 0.77 fmol ml-1, and the extraction recovery of [125I]-Ang I added to albumin buffer was 83% at the inflection point (10 fmol ml-1) of the standard curve. The overall recovery was 98.5 +/- 3.5%. The intra- and inter-assay reproducibility was 10.4% and 9.7% respectively. Cross-reactivity of the antiserum used was low (less than 0.3%) with all angiotensin peptides tested except Ang (2-10) nonapeptide. 3. A human pharmacological model was subsequently used to assess in vivo the biochemical effects of the renin inhibitor CGP 38560A. Six healthy volunteers received 20 mg lisinopril, a long-acting ACE-inhibitor. During the following 24 h, the renin-angiotensin system was reset with typically elevated active plasma renin and Ang I, at respectively 275 and 429% of basal values. 4. In a randomized three-way cross-over protocol, the six volunteers received a 30 min infusion of the renin inhibitor CGP 38560A (125 or 250 micrograms kg-1) or 5% glucose. The fall in plasma Ang I was 92% and 97.5% after the lowest and highest dose of the renin inhibitor, respectively. A concomitant increase in active plasma renin was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Improving hypertension treatment. Where should we put our efforts: new drugs, new concepts, or new management?

Despite the availability of numerous antihypertensive agents, a concerted research effort to develop new approaches to hypertension treatment is necessary. Published results of large multicenter trials emphasize the benefits of available treatments in highly selected patients. A critical look at the results shows that treatment failure is frequent and side effects are common. In the Systolic Hypertension in the Elderly Program, 28 to 35% of patients did not reach the goal blood pressure, 13% stopped treatment because of side effects, and 21% required medication other than a diuretic and a beta-blocker. Basic research may bring forth novel concepts of treatment, such as neutral endopeptidase inhibition, renin inhibition, or new techniques such as gene therapy. In the meantime, among many other lines of research, type 1 angiotensin II-receptor antagonists represent a promising new group of agents for the vast majority of hypertensive patients who are renin-dependent. A different global approach to hypertension management is also needed. Because hypertension is a heterogeneous disease, individual sequential monotherapy or the "N of 1" trial aim to select the most effective drug for each patient. To achieve the accurate assessment of drug efficacy that is a prerequisite for this approach, the number of blood pressure measurements before and during drug administration must be increased. For this purpose, self-blood pressure measurement and teletransmission of results to the physician will provide a major treatment advance.

Angiotensin Receptor Antagonists↗
PubMed1992

Unmasking of the hypotensive effect of nifedipine in normotensives by addition of the angiotensin converting enzyme inhibitor benazepril.

OBJECTIVE: To study the pharmacological interaction between a dihydropyridine derivative (nifedipine slow release 20 mg) and inhibition of the renin-angiotensin system (benazepril 10 mg). DESIGN: Single application at intervals of 2 weeks in an open-label three-way cross-over design. SETTING: Institutional pharmacological unit. PARTICIPANTS: Nine healthy male volunteers. MAIN OUTCOME MEASURES(S): Blood pressure and heart rate were recorded in the supine position for 24 h as well as plasma drug levels, plasma angiotensin converting enzyme activity and active plasma renin concentration. RESULTS: Nifedipine increased active plasma renin two-fold and benazepril increased it five-fold. The combination of the two drugs accelerated the increase of active renin during the first 2 h after drug intake. Whereas no hypertensive effect could be detected after nifedipine or benazepril alone, a significant fall in systolic and diastolic blood pressure was observed for up to 9 to 12 h after the combination. The increase in heart rate induced by nifedipine was minimized by the addition of benazepril. There was no interaction between the pharmacokinetics of benazeprilate and nifedipine which would explain these pharmacodynamic effects. CONCLUSION: These results demonstrate that, in normotensive volunteers, the renin-angiotensin system contributes to mask the hypotensive effect of a single oral dose of dihydropiridine. The concomitant administration of a converting enzyme inhibitor discloses the hypotensive effect and limits the baroreflex-mediated increase in heart rate secondary to vasodilation.

Adult↗
PubMed1991

[Validation of Oscillomat, a device for self-measurement of blood pressure. Comparison with mercury sphygmomanometers].

Self-measurement of arterial blood pressure (BP) is a valuable aid in the follow-up of hypertensive patients. Unfortunately, the devices utilized are not subject to certification and therefore must be validated. In this study, the accuracy and precision of BP measurement with the Oscillomat device were measured and simultaneously compared with those of a standard mercury sphygomomanometer in 60 subjects and with a random zero mercury sphygmomanometer in 44 subjects. The Oscillomat device correctly explored systolic and diastolic BP within a 55 to 210 mmHg range. Compared with the auscultatory method, it tended to underestimate systolic BP values by + 3 to -15 mmHg and diastolic B.P. values by + 1 to -15 mmHg.

Adult↗