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Biomedical subjects

J Menard

Publications and source records attributed to J Menard.

At least 73 records · Page 4Linked to original sources
PubMed1990

Effects of captopril and minoxidil on left ventricular hypertrophy in resistant hypertensive patients: a 6 month double-blind comparison.

In a double-blind 6 month trial, the cardiac effects of captopril and minoxidil, administered as third step treatments, were compared in 34 men with essential hypertension and diastolic blood pressure greater than 95 mm Hg who were taking 200 mg/day of metoprolol and 80 mg/day of furosemide. Average daily doses of captopril and minoxidil were 269 mg (range 150 to 300) and 20 mg (range 7.5 to 30), respectively. At the end of the 6 months' treatment, blood pressure had dropped significantly in both groups, but echocardiographic criteria of hypertrophy improved only in the captopril group (intragroup comparison): blood pressure, thickness of the intraventricular septum and posterior wall, and the left ventricular mass index, respectively, decreased from 163/102 to 135/89 mm Hg (p less than 0.001), 17.4 to 15.9 mm (p less than 0.05), 14.5 to 13.4 mm (p less than 0.05) and 236 to 198 g/m2 (p less than 0.001). In the minoxidil group, blood pressure dropped from 160/99 to 137/87 mm Hg (p less than 0.001), but echocardiographic criteria were not significantly modified. Fractional shortening remained normal in both groups. These results show that in patients with severe left ventricular hypertrophy, captopril-based triple therapy reduces left ventricular mass without altering systolic performance, whereas minoxidil-based therapy does not.

Adult↗
PubMed1990

Physiological and immunopathological consequences of active immunization of spontaneously hypertensive and normotensive rats against murine renin.

Spontaneously hypertensive Okamoto-strain rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were actively immunized with mouse renin to investigate the effect on blood pressure of blocking the renin-angiotensinogen reaction. Ten male SHR and 10 male WKY rats were immunized with purified mouse submandibular gland renin. Control rats were immunized with bovine serum albumin. Antirenin antibodies were produced by both SHR and WKY rats, but renin-immunized SHR had higher titers of circulating renin antibodies after three injections. The increase in renin antibody in renin-immunized SHR was associated with a significant drop in blood pressure (tail-cuff method) that became similar to that of the WKY control rats after four injections. The blockade by antirenin immunoglobulins of the renin-angiotensinogen reaction also decreased the blood pressure of normotensive rats. Perfusion of renin-immunized rats with mouse submandibular renin (10 micrograms) in vivo caused no increase in blood pressure. Perfusion of renin-immunized, salt-depleted SHR with converting enzyme inhibitor caused no further decrease in blood pressure but significantly decreased blood pressure in salt-depleted control rats. The presence of circulating renin antibodies was associated with low plasma renin activity (0.31 +/- 0.23 ng angiotensin I [Ang I]/ml/hr). Plasma renin activity was unchanged in control animals (13.1 +/- 3.9 ng Ang I/ml/hr in control SHR, 13.9 +/- 3.2 ng Ang I/ml/hr in control WKY rats). Renin antibody-rich serum produced a dose-dependent inhibition of rat renin enzymatic activity in vitro. The chronic blockade of the renin-angiotensinogen reaction in renin-immunized SHR produced an almost-complete disappearance of Ang II (0.8 %/- 7 fmol/ml; control SHR, 30.6 +/- 15.7 fmol/ml) and a 50% reduction in urinary aldosterone. Renin immunization was never associated with a detectable loss of sodium after either 10 or 24 weeks. The glomerular filtration rate was not decreased 10 weeks after renin immunization, whereas blood pressure was significantly decreased, plasma renin activity was blocked, and renal plasma flow was increased. The ratio of left ventricular weight to body weight after 24 weeks was significantly below control levels in renin-immunized WKY rats and SHR. Histological examination of the kidney of renin-immunized SHR showed a chronic autoimmune interstitial nephritis characterized by the presence of immunoglobulins, mononuclear cell infiltration, and fibrosis around the juxtaglomerular apparatus. These experiments demonstrate that chronic specific blockade of renin decreases blood pressure in a genetic model of hypertension in which the renin-angiotensin system is not directly involved.(ABSTRACT TRUNCATED AT 400 WORDS)

Aldosterone↗
PubMed1989

Predictive factors of the blood pressure fall induced by intravenous nicardipine.

The effect on blood pressure of the dihydropyridine derivative nicardipine was studied in 87 essential hypertensive patients aged 25-77 years. A total cumulative dose of 8.75 mg nicardipine was administered over a 30-min period by continuous intravenous infusion. The dose was doubled every 10 min from 1.25 to 5.0 mg. The mean blood pressure fall and the heart rate rise were both dose-related. At 30 min, mean blood pressure fell by 18.9 +/- 7.5% vs. baseline values (p less than 0.001), heart rate increased by 28.0 +/- 11.8% (p less than 0.001), and the renin level by 20.7 +/- 32.5% (p less than 0.001). The blood pressure fall was correlated positively with age (r = 0.521; p less than 0.001) and negatively with the rise in heart rate (r = -0.308; p less than 0.01) and renin level (r = -0.205; p = 0.05). After eliminating the linear effects of age by the partial correlation method, blood pressure fall and the initial renin level were no longer correlated (r = -0.046, NS), whereas the positive correlation between age and blood pressure fall persisted after eliminating the effect of renin (r = 0.464; p less than 0.001). The slope of the regression line for the heart rate rise vs. the blood pressure fall was taken to reflect the baroreflex sensitivity. This sensitivity was negatively correlated to age (r = -0.515; n = 51; p less than 0.001) in the 51 of the 87 patients for whom it could be calculated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Pharmacological investigations of a new renin inhibitor in normal sodium-unrestricted volunteers.

1. CGP 38 560 A, a low-molecular-weight, non-peptidic renin inhibitor, was well tolerated upon intravenous and oral administration to recumbent healthy volunteers on an unrestricted-sodium diet. 2. After intravenous infusion over 30 min at a rate of 100 ml h-1, doses of 50, 125 and 250 micrograms kg-1 appear to induce a long-lasting inhibition of plasma renin activity. Plasma angiotensin II was decreased in a dose-dependent manner during the infusion and thereafter reverted to the initial level. A concomitant dose-related increase in active plasma renin was observed. Blood pressure was unaffected. The plasma levels of CGP 38 560 reached during infusion were at least 2000-fold higher than the theoretical inhibitory concentration based on in vitro results. 3. After oral administration in doses of 50, 100 and 200 mg CGP 38 560 A, inhibition of plasma renin activity was observed, but plasma active renin was unchanged. Blood pressure also remained unaffected. 4. CGP 38 560 was rapidly cleared from plasma with a half-life of 7.6 min for the first phase and 63 min for the second phase. Plasma levels were 100-fold lower after oral administration than after infusion, indicating a low degree of absorption (less than 1% oral bioavailability).

Administration, Oral↗
PubMed1989

Renin inhibition: immunological procedures and renin inhibitor peptides.

Renin inhibitors represent an alternative to angiotensin-converting enzyme inhibitors (ACEI) for the treatment of hypertension. They inhibit the renin-angiotensin system at its first and rate limiting step, the renin-angiotensinogen reaction. Passive administration of angiotensinogen or renin antibodies lowers blood pressure in primates to the same extent as ACEI. Chronic active immunization against renin decreases blood pressure markedly in normotensive marmosets. Renin can be inhibited by peptides derived from its prosegment. The design of compounds based on pepstatin and on angiotensinogen sequence has led to very potent and specific human renin inhibitors. Such inhibitors are active by the IV route in primates but still lack of good oral activity.

Animals↗
PubMed1989

Angiotensinogen's role in ANG formation, renin release, and renal hemodynamics in isolated perfused kidney.

Isolated perfused rat kidneys were used to investigate the effects of the addition of pure angiotensinogen or renin-free plasma to the perfusate on angiotensin I (ANG I) and angiotensin II (ANG II) generation, renal hemodynamics, and renin release. When no angiotensinogen or plasma is added, a very small amount of angiotensinogen is initially detected in the perfusate. Whereas renin secreted by the kidney accumulates in the perfusate, angiotensinogen disappears during the perfusion and immunoreactive ANG II cannot be detected. The addition of angiotensinogen reactivates the renin-angiotensin system. ANG I, [des-Asp1] ANG I, ANG II, and [des-Asp1] ANG II are progressively generated in the perfusate. At a constant perfusion pressure, as well as at a variable perfusion pressure, a progressive fall in renal perfusate flow is observed that is significantly correlated to the level of immunoreactive ANG II. ANG II significantly blunts the rise in renin, and renin release in the perfusate is negatively correlated to immunoreactive ANG II levels. Comparison of the ANG I and ANG II levels in in vitro incubated perfusates and circulated perfusates shows that in plasma-injected perfusates the level of immunoreactive ANG II is dependent on both the production of ANG I and its conversion to ANG II by renal and perfusate converting-enzyme activity, and on ANG I and ANG II degradation by the kidney and the perfusate.

Angiotensin I↗
PubMed1989

Response of plasma prorenin and active renin to chronic and acute alterations of renin secretion in normal humans. Studies using a direct immunoradiometric assay.

We employed a novel immunoradiometric assay to measure plasma levels of active renin and prorenin in physiologic and pharmacologic studies designed to characterize renin biosynthesis and processing in response to both chronic and acute stimuli of renin secretion in normal human subjects. Stimulation of renin secretion with prolonged dietary sodium restriction or amiloride resulted in marked increases in the plasma levels of prorenin, active renin, and plasma renin activity (PRA); suppression of renin secretion with indomethacin resulted in parallel decreases in prorenin, active renin, and PRA. In contrast, acute stimulation with upright activity or administration of an angiotensin-converting enzyme inhibitor, which increased active renin and PRA from 2- to 15-fold, had no effect on prorenin levels. Based on studies in cultured human juxtaglomerular tumor cells, it has been proposed that prorenin is secreted constitutively whereas active renin is stored in and released from secretory granules through a regulated pathway. Our studies are consistent with such a model: the parallel changes in active renin and prorenin with experimental maneuvers of long duration suggest that both the constitutive and regulated pathways are altered under these conditions. The increase in active renin levels in the absence of a change in prorenin that occurs in response to acute stimuli presumably represents the release of preformed active enzyme that is stored in secretory granules.

Adult↗
PubMed1989

[Influence of acetylation phenotype on the pharmacokinetics and pharmacodynamics data of cadralazine in normotensive subjects].

Cadralazine is a new antihypertensive drug, acting as a peripheral arteriolar vasodilator through its hydrazinopyridazine metabolite. Since this metabolite actively contributes to the activity of the drug, we administered in a double blind randomized study 10 mg/placebo o.d. to 6 healthy fast and 6 slow normotensive acetylators in order to investigate the influence of the acetylator status on hemodynamics and pharmacokinetics. Blood pressure was measured with a DINAMAP apparatus, forearm hemodynamics with a pulsed doppler and central hemodynamics with impedance-cardiography; active renin (RIA), cadralazine and its metabolite (HPLC) were measured during the 11 measurement points. The results were analysed with repeated analysis of variance (ANOVA). Heart rate significantly increased (p less than 0.001), until the 24th hour (p less than 0.05), meanwhile blood pressure and forearm hemodynamics did not change. Cardiac output was increased as a consequence of the elevation in venous return. The rise in active renin paralleled the increase in heart rate with a significant correlation (r' = 0.580, p less than 0.05). The magnitude of the increase was higher in slow than that in fast acetylators, but did no reached the significance. No differences were found for AUC, Cmax and Tmax between the two groups but the active metabolite was eliminated slower than that of cadralazine. The time course of the effects on heart rate and plasma renin was not parallel to the plasma levels of cadralazine and its metabolite. With respect to the power of the study (1-beta = 80 p. 100), no significant differences were found between the two groups.

Acetylation↗
PubMed1988

Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria.

STUDY OBJECTIVE: To assess the effectiveness of inhibition of angiotensin converting enzyme in preventing diabetic nephropathy. DESIGN: Randomised follow up study of normotensive diabetics with persistent microalbuminuria (30-300 mg/24 hours) treated with enalapril or its matched placebo for one year. Double blind for first six months, single blind for last six months. SETTING: Diabetic clinic in tertiary referral centre. PATIENTS: Treatment group and placebo group each comprised 10 normotensive diabetics with persistent microalbuminuria. INTERVENTIONS: Treatment group was given enalapril 20 mg daily and controls matched placebo. Patients were given antihypertensive treatment after one year. END POINT: Albumin excretion, arterial pressure, and renal function. MAIN RESULTS: In last three months of trial three of 10 patients taking placebo had diabetic nephropathy (albumin excretion greater than 300 mg/24 hours). No patients taking enalapril developed nephropathy and five showed normal albumin excretion (less than 30 mg/24 hours) (p = 0.005, Mann-Whitney test). Mean arterial pressure was reduced by enalapril throughout study (p less than 0.005) but increased linearly with placebo (p less than 0.05). Albumin excretion decreased linearly with enalapril but not placebo. An increase in albumin excretion with placebo was positively related to the increase in mean arterial pressure (r = 0.709, p less than 0.05, Spearman's rank test). With enalapril total renal resistances and fractional albumin clearances improved progressively (time effect, p = 0.0001). CONCLUSION: Inhibition of angiotensin converting enzyme prevents development of nephropathy in normotensive diabetics with persistent microalbuminuria. This may be due to reduction in intraglomerular pressure and to prevention of increased systemic blood pressure. Future studies should compare long term effects of inhibitors of converting enzyme with other antihypertensive drugs.

Adult↗
PubMed1988

The juxtaglomerular apparatus in Bartter's syndrome and related tubulopathies. An immunocytochemical and electron microscopic study.

A comparative immunocytochemical and electron microscopic study was performed on renal biopsies from two children with classical Bartter's syndrome (BS) and three children with a recently described variant, the so-called hyperprostaglandin E-syndrome (HES). Compared to age-matched controls, kidney specimens from patients with BS and HES disclosed a marked hypertrophy and hyperplasia of the juxtaglomerular apparatus (JGA). In addition, in HES focal tubular and interstitial calcifications accompanied by interstitial fibrosis and tubular atrophy were noted. On immunocytochemistry, chronic stimulation of the JGA in BS and HES was characterized by an increase in the number of renin-positive cells, particularly in the media of afferent arterioles, but also in efferent arterioles and in the glomerular stalk. The length of the renin-positive portion of the preglomerular arterioles was significantly increased when compared to controls (100 +/- 32 vs. 49 +/- 17 microns; p less than 0.001). In addition, the immunoreactivity of individual renin-positive cells was markedly enhanced. On electron microscopy, "hypertrophy" of the RER and of Golgi complexes with paracrystalline deposits in dilated RER cisterns and protogranules indicated an increased renin synthesis. Renin could be identified in mature secretory granules as well as protogranules by immune electron microscopy. Angiotensinogen was present in hypertrophied epithelial cells of Bowman's capsule. Converting-enzyme reactivity was observed in controls as well as in BS and HES in the brush border of the proximal tubule. In contrast to previous reports, Angiotensin II was completely negative in control as well as in diseased kidneys. We conclude from our results that both BS and HES are characterized by a marked activation of the JGA and severe stimulation of the renin-angiotensin system. Since activation of this system, however, leads--independently of the primary stimulus--to qualitatively very similar morphological reactions, these results do not implicate a common pathogenetic mechanism to both conditions.

Bartter Syndrome↗
PubMed1987

Efficacy and tolerance of spironolactone in essential hypertension.

The long-term efficacy and tolerance of spironolactone in essential hypertension was evaluated among 20,812 patients referred to the Broussais and St. Joseph systemic hypertension clinics between 1976 and 1985 by using information prospectively collected in the computerized ARTEMIS data bank. In 182 patients (51 men, 131 women) treated with spironolactone alone during a mean follow-up period of 23 months, a mean dose of 96.5 mg decreased systolic and diastolic blood pressure (BP) by 18 and 10 mm Hg, respectively, below pretherapeutic levels. The BP decrease was greater with doses of 75 to 100 mg (12.4% and 12.2%) than with doses of 25 to 50 mg (5.3 and 6.5%, p less than 0.001), but no additional decrease was found with doses above 150 mg. Plasma creatinine level increased modestly (8.3 mumol/liters), as did plasma potassium level (0.6 mmol/liters) (both p less than 0.001); uric acid level increased, but not significantly (10.5 mumol/liter). Fasting blood glucose and total cholesterol levels did not change, triglyceride levels increased slightly (0.1 mmol/liter, p less than 0.05). These changes were similar in both sexes and were not influenced by length of follow-up. Among the 699 men prescribed spironolactone alone or in association with another antihypertensive treatment, 91 cases of gynecomastia developed (13%). Gynecomastia was reversible and dose-related; at doses of 50 mg or less the incidence was 6.9%, but 52.2% for doses of 150 mg or higher. Despite limitations inherent in the interpretation of data banks, it is concluded that spironolactone administered in daily practice reduced BP without inducing adverse metabolic adverse effects and that in patients with essential hypertension, doses should be kept below 100 mg.

Aged↗
PubMed1987

Comparative enzymatic studies of human renin acting on pure natural or synthetic substrates.

Some of the essential structural requirements for the enzymatic reaction of pure human renin acting on pure human and rat angiotensinogen and on their synthetic tetradecapeptide substrates were investigated. The five carboxy terminal amino acids of synthetic tetradecapeptides played a significant role in substrate recognition and/or hydrolysis by human renin. Kinetic constants Km, Kcat and kcat/Km of the various human renin assays were different according to the substrate used. The presence of either an asparagine or a threonine residue in the S'4 renin subsite did not affect significantly the kinetic constant values. A tyrosine residue, rather than a histidine residue, in the S'3 renin subsite gave the best synthetic substrate studied. When tyrosine residue was present in the S'2 renin subsite an important decrease in kcat was observed. Human angiotensinogen was hydrolysed by human renin with lower Km and kcat values than those measured with human and porcine synthetic substrates, suggesting that the 3-dimensional structure of human angiotensinogen plays a key role in the hydrolysis. This finding was supported by assays performed with rat angiotensinogen, which was cleared by human renin with the same kcat value as rat tetradecapeptide, but with a 49-fold lower Km. Between human and rat angiotensinogen a kcat/Km value of only 2-fold higher has been found in the renin assay using human substrate.

Amino Acid Sequence↗
PubMed1987

Production and characterization of human renin antibodies with region-oriented synthetic peptides.

Polyclonal and monoclonal antibodies were raised against pure human renin, but nothing was known about the regions against which they were directed. Using a three-dimensional model of mouse submandibular renin, we selected seven peptide sequences as belonging to potential epitopes. The main criteria for their choice were the location of the peptide sequences near the catalytic region and on the surface of the renin molecule and their hydrophilicity. After transposition of the regions to the 340-amino acid sequence of human renin, the seven peptides (corresponding to amino acids 50-60, 63-71, 81-90, 118-126, 162-169, 247-255, and 287-295) were synthesized, coupled to bovine serum albumin, and injected into rabbits. Five of these peptides elicited antibodies, and 50-68% binding of the corresponding iodinated peptide was obtained with a 1:25 dilution of antiserum. The antisera titers ranged from 1:5,000 to 1:100,000 when tested by enzyme-linked immunosorbent assay. The same antisera bound 15-65% of labeled pure human renin at a final dilution of 1:2.5, the highest percentage being obtained with peptide 81-90 antiserum. At a 1:5 dilution, the five antisera inhibited renin activity by 23-68% in human plasma with a high renin activity (40 ng of angiotensin I/h/ml). At a final dilution of 1:50, peptide 81-90 antiserum was still capable of producing 25% inhibition. Purified IgG (0.6 mg) from this antiserum inhibited pure human renin activity by up to about 40%, as measured by its reaction with pure synthetic human tetradecapeptide substrate. Antigenic peptides that mimic a part of the human renin sequence, especially peptide 81-90 representing the "flap" covering the cleft between the two renin lobes, constitute promising tools for the development of a synthetic antirenin vaccine.

Amino Acid Sequence↗
PubMed1987

Earliest renin containing cell differentiation during ontogenesis in the rat. An immunocytochemical study.

The differentiation of renin containing cells was studied by immunocytochemistry in normal rat fetuses by the use of highly specific renin, angiotensin I and II antisera. Renin synthesizing cells were detectable as early as the 15th day of gestation outside the nephrogen territories within the walls of mesonephrotic-gonadic and renal arteries. Intrarenal differentiation began at the 17th day and progressed along the intrarenal arterial tree. AII immunostaining appeared concomitantly in the renin containing cells and developed considerably during ontogenesis, suggesting intracellular biosynthesis. It can be suggested that in the fetus newly synthesized AII may contribute to the early systemic and renal blood pressure regulation.

Angiotensin II↗
PubMed1987

Renal excretion capacity in hydrated desert rodents (Jaculus orientalis and Jaculus deserti).

The capacity to excrete a water load was studied in rats and in two desert rodents (Jaculus orientalis and Jaculus deserti) adapted to either 5 or 30 degrees C ambient temperature. The rat is able to eliminate the entire water load regardless of thermal adaptation. Cold-adapted J. orientalis and J. deserti excreted 60% of the water load in comparison to 20-30% in warm-adapted jerboas. At both adaptation temperatures, antidiuretic hormone (ADH) concentration was estimated at maximum diuresis in the two desert species. Though hydration induced a significant decrease in ADH concentration in both species, its level in the plasma remained relatively high. The decrease was more pronounced in J. orientalis than J. deserti.

Acclimatization↗