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Biomedical subjects

H R Brunner

Publications and source records attributed to H R Brunner.

At least 55 records · Page 3Linked to original sources
PubMed1999

Pharmacokinetic and pharmacodynamic effects of YM087, a combined V1/V2 vasopressin receptor antagonist in normal subjects.

OBJECTIVE: The pharmacokinetic and pharmacodynamic properties of YM087, (4'-[(2-methyl-1,4,5,6- tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)-carbonyl]-2-p henylbenzanilide monohydrochloride), a new orally active, dual V1/V2 receptor antagonist were characterised in healthy normotensive subjects. METHODS: Six subjects were randomly allocated to receive, at 1-week intervals, a single oral dose of 60 mg YM087 and a single i.v. dose of 50 mg YM087 in an open-label, crossover study. RESULTS: YM087 had an oral bioavailability of 44% and a short half-life. Upon oral and i.v. administration of YM087, a significant sevenfold increase in urine flow rate and a fall in urinary osmolality (from 600 mosmol/l to less than 100-mosmol/l) were observed with a peak effect 2 h after drug intake suggesting effective vasopressin V2 receptor blockade. Simultaneously, significant increases in plasma osmolality (from 283 +/- 1.3 mosmol/l to 288 +/- 1.0 mosmol/l after i.v. and from 283 +/- 2.1 mosmol/l to 289 +/- 1.7-mosmol/l after oral administration) and vasopressin levels (from 1.5 +/- 0.3 pg/ml to 3.7 +/- 0.6 pg/ml after i.v. and from 0.9 +/- 0.1 pg/ml to 3.9 +/- 0.7 pg/ml after oral administration) were found. When administered i.v., YM087 inhibited the vasopressin-induced skin vasoconstriction, suggesting a blockade of V1 receptors. However, the YM087-induced antagonism of V1 receptors was less pronounced than V2 receptor blockade. CONCLUSION: These data show that YM087 is an effective dual V1/V2 receptor antagonist in man.

Administration, Oral↗
PubMed1999

Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects.

PURPOSE: To compare the renal hemodynamic and tubular effects of celecoxib, a selective inhibitor of cyclooxygenase-2 (COX-2) to those of naproxen, a nonselective inhibitor of cyclooxygenases in salt-depleted subjects. METHODS AND SUBJECTS: Forty subjects were randomized into four parallel groups to receive 200 mg celecoxib twice a day, 400 mg celecoxib twice a day, 500 mg naproxen twice a day, or a placebo for 7 days according to a double-blind study design. Blood pressure, renal hemodynamics, and urinary water and electrolyte excretion were measured before and for 3 hours after drug intake on days 1 and 7. RESULTS: Celecoxib had no effect on systemic blood pressure, but short-term transient decreases in renal blood flow and glomerular filtration rate were found with the highest dose of 400 mg on day 1. On the first day, both celecoxib and naproxen decreased urine output (P < .05) and sodium, lithium, and potassium excretion (P < .01). On day 7, similar effects on water and sodium excretion were observed. During repeated administration, a significant sodium retention occurred during the first 3 days. CONCLUSION: In salt-depleted subjects, selective inhibition of COX-2 causes sodium and potassium retention. This suggests that an increased selectivity for COX-2 does not spare the kidney, at least during salt depletion.

Adult↗
PubMed1999

Assessment of angiotensin II receptor blockade in humans using a standardized angiotensin II receptor-binding assay.

An in vitro angiotensin II (AngII) receptor-binding assay was developed to monitor the degree of receptor blockade in standardized conditions. This in vitro method was validated by comparing its results with those obtained in vivo with the injection of exogenous AngII and the measurement of the AngII-induced changes in systolic blood pressure. For this purpose, 12 normotensive subjects were enrolled in a double-blind, four-way cross-over study comparing the AngII receptor blockade induced by a single oral dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), and placebo. A significant linear relationship between the two methods was found (r = 0.723, n = 191, P<.001). However, there exists a wide scatter of the in vivo data in the absence of active AngII receptor blockade. Thus, the relationship between the two methods is markedly improved (r = 0.87, n = 47, P<.001) when only measurements done 4 h after administration of the drugs are considered (maximal antagonist activity observed in vivo) suggesting that the two methods are equally effective in assessing the degree of AT-1 receptor blockade, but with a greatly reduced variability in the in vitro assay. In addition, the pharmacokinetic/pharmacodynamic analysis performed with the three antagonists suggest that the AT-1 receptor-binding assay works as a bioassay that integrates the antagonistic property of all active drug components of the plasma. This standardized in vitro-binding assay represents a simple, reproducible, and precise tool to characterize the pharmacodynamic profile of AngII receptor antagonists in humans.

Angiotensin II↗
PubMed1999

Evaluation of noninvasive blood pressure recording by photoplethysmography in clinical studies using angiotensin challenges.

AIMS: Continuous noninvasive blood pressure measurement by photoplethysmography has been regularly used in the experimental paradigm of angiotensin challenges, applied to the phase I clinical testing of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists. This work aims to evaluate the performance of this measurement method, in terms of reliability, reproducibility and dependence on technical settings. METHODS: Data have been gathered from 13 clinical studies on antihypertensive drugs, using the Finapres device for measuring the response to exogenous angiotensin challenges. The agreement between simultaneous recordings at different fingers and the influence of the reading method are assessed. A literature review addresses the question of the concordance between results obtained noninvasively and through arterial cannulation. RESULTS: The relative precision of blood pressure monitoring by photoplethysmography allows reproducible determination of angiotensin-induced blood pressure peaks (agreement limits for systolic and diastolic peaks: 12 and 6 mmHg respectively). The reading method influences the results to a similar extent. As compared with blood pressure measured intra-arterially, the difference is usually within limits of clinical acceptability. CONCLUSIONS: In the context of phase I studies using the angiotensin challenges methodology, the reliability and reproducibility of noninvasive blood pressure measurement appear satisfactory, despite the technical limitations of this method. The impact of selected changes in the settings and reading methods is limited.

Angiotensin II↗
PubMed1999

Evaluation of the angiotensin challenge methodology for assessing the pharmacodynamic profile of antihypertensive drugs acting on the renin-angiotensin system.

AIMS: The performance of the experimental paradigm of angiotensin challenges with continuous non-invasive blood pressure measurement was evaluated. Angiotensin dose-response relationships were characterized, along with the influence of clinical covariates. The stability of angiotensin-induced peaks and the variability of the angiotensin doses were assessed. Finally, the predictive value of studies based on angiotensin challenges to determine drug doses effective in therapeutics was evaluated. METHODS: The data were gathered from 13 clinical studies on nine angiotensin II receptor antagonists, one ACE inhibitor and one dual ACE-NEP inhibitor, using Finapres for measuring the response to exogenous angiotensin challenges. Modelling of angiotensin dose-response curves and determination of the inter and intrasubject variability were performed by nonlinear regression (NONMEM). The different sources of variations in angiotensin I and II doses and angiotensin-induced peaks were evaluated by analyses of variance. The dose of ACE inhibitors and angiotensin II receptor antagonists inhibiting blood pressure increase by at least 75%, as measured by this method, was chosen for comparison with the labelled starting dose. RESULTS: Angiotensin challenges exhibited a clear dose-response relationship which can be characterized both by an Emax or a log linear model. The log linear model gave an average systolic/diastolic response of 24+/-6/20+/-5 mmHg for a unit dose of 1 microgram of angiotensin II equivalents, and an increase of 6/6 mmHg for each doubling of the dose. The angiotensin ED50 calculated values were 0.67 microgram for systolic and 0.84 microgram for diastolic blood pressure. The angiotensin doses for eliciting a given response and the angiotensin induced peaks were fairly constant between period and subject, but vary significantly between studies. Based on an inhibition of blood pressure by 75%, the agreement was good between the doses of ACE inhibitors and angiotensin receptor antagonists predicted from studies using the methodology of angiotensin challenges and the doses shown to be clinically efficacious, in spite of high intersubject and intrasubject variabilities. CONCLUSIONS: This experimental method represents a valid surrogate for the therapeutic target and a useful tool for the pharmacokinetic and pharmacodynamic profiling of drugs acting on the renin-angiotensin system.

Angiotensin II↗
PubMed1999

Effects of a dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240, on endocrine and renal functions in healthy volunteers.

OBJECTIVE: To investigate the endocrine and renal effects of the dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240. DESIGN: A randomized, placebo-controlled, crossover study was performed in 12 healthy volunteers. METHODS: MDL 100,240 was administered intravenously over 20 min at single doses of 6.25 and 25 mg in subjects with a sodium intake of 280 (n = 6) or 80 (n = 6) mmol/day. Measurements were taken of supine and standing blood pressure, plasma angiotensin converting enzyme activity, angiotensin II, atrial natriuretic peptide, urinary atrial natriuretic peptide and cyclic GMP excretion, effective renal plasma flow and the glomerular filtration rate as p-aminohippurate and inulin clearances, electrolytes and segmental tubular function by endogenous lithium clearance. RESULTS: Supine systolic blood pressure was consistently decreased by MDL 100,240, particularly after the high dose and during the low-salt intake. Diastolic blood pressure and heart rate did not change. Plasma angiotensin converting enzyme activity decreased rapidly and dose-dependently. In both the high- and the low-salt treatment groups, plasma angiotensin II levels fell and renin activity rose accordingly, while plasma atrial natriuretic peptide levels remained unchanged. In contrast, urinary atrial natriuretic peptide excretion increased dose-dependently under both diets, as did urinary cyclic GMP excretion. Effective renal plasma flow and the glomerular filtration rate did not change. The urinary flow rate increased markedly during the first 2 h following administration of either dose of MDL 100,240 (P < 0.001) and, similarly, sodium excretion tended to increase from 0 to 4 h after the dose (P = 0.07). Potassium excretion remained stable. Proximal and distal fractional sodium reabsorption were not significantly altered by the treatment. Uric acid excretion was increased. The safety and clinical tolerance of MDL 100,240 were good. CONCLUSIONS: The increased fall in blood pressure in normal volunteers together with the preservation of renal hemodynamics and the increased urinary volume, atrial natriuretic peptide and cyclic GMP excretion distinguish MDL 100,240 as a double-enzyme inhibitor from inhibitors of the angiotensin converting enzyme alone. The differences appear to be due, at least in part, to increased renal exposure to atrial natriuretic peptide following neutral endopeptidase blockade.

Adult↗
PubMed1999

Aortic connexin43 is decreased during hypertension induced by inhibition of nitric oxide synthase.

Connexin43 (Cx43), the predominant gap junction protein in vessels and heart, is involved in the control of cell-to-cell communication and is thought to modulate the contractility of the vascular wall and the electrical coupling of cardiac myocytes. We have investigated the effects of arterial hypertension induced by inhibition of nitric oxide synthase on the expression of Cx43 in aorta and heart as well as on the distensibility of the carotid artery. Administration of 0.4 g/L NG-nitro-L-arginine methyl ester (L-NAME) to rats in their drinking water for 4 weeks increased intra-arterial mean blood pressure, wall thickness of aorta and carotid artery (25%), and heart weight (17%). Analysis of heart mRNA demonstrated increased expression of the fetal skeletal alpha-actin and of atrial natriuretic peptide but not of Cx43. In contrast, Cx43 mRNA and protein were decreased by 50% in the aortas of L-NAME-treated rats that did not show increased carotid distensibility. Because these data contrasted with those obtained in the 2-kidney, 1 clip model of rat hypertension, which is characterized by increased arterial distensibility and Cx43 expression in aorta, we investigated by Western blot analysis the posttranslational modifications of Cx43. We found that Cx43 was more phosphorylated in the aorta of 2-kidney, 1 clip rats than in that of L-NAME or control rats, which indicated a differential regulation of Cx43 in different models of hypertension. The data suggest that the cell-to-cell communication mediated by Cx43 channels may help regulate the elasticity of the vascular wall.

Animals↗
PubMed1999

Angiotensin II receptor blockade in normotensive subjects: A direct comparison of three AT1 receptor antagonists.

Use of angiotensin (Ang) II AT1 receptor antagonists for treatment of hypertension is rapidly increasing, yet direct comparisons of the relative efficacy of antagonists to block the renin-angiotensin system in humans are lacking. In this study, the Ang II receptor blockade induced by the recommended starting dose of 3 antagonists was evaluated in normotensive subjects in a double-blind, placebo-controlled, randomized, 4-way crossover study. At 1-week intervals, 12 subjects received a single dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), or placebo. Blockade of the renin-angiotensin system was assessed before and 4, 24, and 30 hours after drug intake by 3 independent methods: inhibition of the blood pressure response to exogenous Ang II, in vitro Ang II receptor assay, and reactive changes in plasma Ang II levels. At 4 hours, losartan blocked 43% of the Ang II-induced systolic blood pressure increase; valsartan, 51%; and irbesartan, 88% (P<0.01 between drugs). The effect of each drug declined with time. At 24 hours, a residual effect was found with all 3 drugs, but at 30 hours, only irbesartan induced a marked, significant blockade versus placebo. Similar results were obtained when Ang II receptor blockade was assessed with an in vitro receptor assay and by the reactive rise in plasma Ang II levels. This study thus demonstrates that the first administration of the recommended starting dose of irbesartan induces a greater and longer lasting Ang II receptor blockade than that of valsartan and losartan in normotensive subjects.

Adult↗
PubMed1999

Effect of magnesium deficiency on blood pressure and mechanical properties of rat carotid artery.

The purpose of this study was to determine the effect of dietary Mg deficiency (80 mg/kg versus control diet: 960 mg/kg) on blood pressure and mechanical properties of the rat common carotid artery. The internal diameter and intra-arterial pressure of carotid artery were measured continuously with an echo-tracking device. At 19 weeks, systolic, diastolic, and mean blood pressures were higher in Mg-deficient rats. Histological examination showed an increase in cross-sectional area, intima-media thickness, and media-to-lumen ratio in carotid artery of Mg-deficient rats. Mg deficiency did not modify the arterial distensibility-blood pressure curve. At mean blood pressure, arterial distensibility was significantly less in 19-week-old rats than in 5-week-old rats of both control and Mg-deficient groups. A significant interaction between age and Mg-deficient diet on arterial distensibility (P<0.04) indicates an accelerated age-dependent decreased arterial distensibility with Mg deficiency. At 19 weeks, the artery was stiffer in hypertensive Mg-deficient rats, as illustrated by a shift to higher levels of the incremental elastic modulus-stress curve. In conclusion, the increased blood pressure and the vascular morphological alterations observed in Mg-deficient rats may contribute to an accelerated alteration of the wall material, which in turn leads to a stiffening of the carotid artery.

Age Factors↗
PubMed1999

Comparative antihypertensive effects of angiotensin II receptor antagonists.

Blockade of the renin-angiotensin system is recognized as an effective approach for the treatment of hypertension and congestive heart failure. It is possible to antagonize the effects of angiotensin II (AngII) by blocking its receptors, using nonpeptide receptor antagonists. Six angiotensin receptor blockers (ARB) have been approved for the treatment of hypertension: losartan, valsartan, irbesartan, candesartan, telmisartan, and eprosartan. These new drugs are highly selective for the AT1 receptor subtype and induce dose-dependent inhibition of the BP response to exogenous AngII. Numerous double-blind, placebo-controlled studies have demonstrated that ARB are efficacious for treating mild, moderate, and severe hypertension. When compared with other classes of antihypertensive agents, ARB are as effective as angiotensin-converting enzyme inhibitors, calcium antagonists, thiazide diuretics, and beta-blockers. One advantage of ARB as a class is their excellent tolerability and side effect profile. Several large clinical trials of ARB are now under way to demonstrate their benefits in hypertension, heart failure, and type II diabetic nephropathy.

Angiotensin II↗
PubMed1999

Clinical value of ambulatory blood pressure monitoring in the assessment of antihypertensive therapy.

Non-invasive ambulatory blood pressure monitoring (ABPM) is particularly useful for assessing the efficacy of antihypertensive drugs. It provides a large number of blood pressure readings during daytime as well as night-time, which results in a more precise assessment of prevailing blood pressure than can be obtained from sporadic measurements taken by a doctor. Because of this greater precision ABPM reduces the number of patients required in clinical trials to demonstrate differences. It also allows one to define precisely the profile of the blood-pressure-lowering effect of a given drug. Placebo has little effect on ABPM. Thus, a placebo phase is not absolutely necessary. ABPM makes it possible to evaluate the efficacy of an antihypertensive medication by analysing data for patients with a placebo effect separately from data for true responders to the medication. In everyday practice ABPM helps one to detect among patients with hypertension refractory to treatment those who exhibit controlled blood pressures outside the medical environment, thus permitting one to avoid an unnecessary step-up of treatment. In addition ABPM can also help one to identify symptoms occurring during antihypertensive treatment that are related to excessive drug-induced changes in blood pressure.

Antihypertensive Agents↗
PubMed1998

Diabetes mellitus and vascular lesions.

Cardiovascular complications represent by far the most severe manifestations of diabetes mellitus. Treatment aimed at stopping progression of vascular lesions may fall short if initiated when the disease becomes clinically evident. Therefore, identification of the earliest vascular disfunctions may offer the best opportunity to interfere with pathogenic mechanisms and avoid progression of diabetic vasculopathy. In this report, we present a few mechanisms that alter hemodynamic and metabolic homeostasis in the course of diabetes mellitus. Endothelial function with special emphasis on nitric oxide and oxidative stress, advanced glycation end products, and the renin angiotensin system are briefly discussed. New pharmacological agents that may favorably influence these parameters are presently undergoing clinical trials. However, tight control of plasma glucose and cardiovascular risk factors represent the cornerstone of the treatment in diabetes to slow progression of vascular disease.

Animals↗
PubMed1998

Endothelin inhibition as a biologic target for treating hypertension.

Endothelin, a 21-amino-acid peptide, binds to a specific receptor on vascular smooth muscle cells, thereby inducing vasoconstriction. Although plasma levels are not consistently elevated in hypertension, there is evidence that endothelin has an important role in its pathogenesis. Administration of endothelin antagonists has lowered blood pressure and reduced end-organ damage in some animal models. It has also reduced the cross-sectional area of neointima due both to hypertension and vascular injury. Coadministration of endothelin and angiotensin II to rats produced a synergistic hypertensive effect. Similarly, coadministration of an endothelin antagonist with an angiotensin converting enzyme inhibitor resulted in a synergistic lowering of blood pressure. Several preliminary clinical studies have been done. The endothelin antagonist bosentan has decreased vascular resistance and blood pressure and increased cardiac index in patients with congestive heart failure. Plasma endothelin levels are elevated in the acute phase of myocardial infarction and in chronic heart failure. The magnitude of this increase, measured 3 days after patients experienced myocardial infarction, had a significance at least equal to known risk factors in predicting 1 year survival. Thus, there are reasons to believe that endothelin antagonists may become a useful tool in the management of various cardiovascular disorders.

Animals↗
PubMed1998

Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor.

Neuropeptide Y (NPY) is a 36-amino-acid neurotransmitter which is widely distributed throughout the central and peripheral nervous system. NPY involvement has been suggested in various physiological responses including cardiovascular homeostasis and the hypothalamic control of food intake. At least six subtypes of NPY receptors have been described. Because of the lack of selective antagonists, the specific role of each receptor subtype has been difficult to establish. Here we describe mice deficient for the expression of the Y1 receptor subtype. Homozygous mutant mice demonstrate a complete absence of blood pressure response to NPY, whereas they retain normal response to other vasoconstrictors. Daily food intake, as well as NPY-stimulated feeding, are only slightly diminished, whereas fast-induced refeeding is markedly reduced. Adult mice lacking the NPY Y1 receptor are characterized by increased body fat with no change in protein content. The higher energetic efficiency of mutant mice might result, in part, from the lower metabolic rate measured during the active period, associated with reduced locomotor activity. These results demonstrate the importance of NPY Y1 receptors in NPY-mediated cardiovascular response and in the regulation of body weight through central control of energy expenditure. In addition, these data are also indicative of a role for the Y1 receptor in the control of food intake.

Animals↗
PubMed1998

Circadian variations of renal sodium handling in patients with orthostatic hypotension.

BACKGROUND: Sodium wasting during the night has been postulated as a potential pathophysiological mechanism in patients suffering from orthostatic hypotension due to severe autonomic deficiency. METHODS: In this study, the diurnal variations in creatinine clearance, sodium excretion and segmental renal tubular handling of sodium were evaluated in 18 healthy subjects and 20 young patients with orthostatic hypotension (OH). In addition, 24-hour ambulatory blood pressure and the neuro-hormonal response to changes in posture were determined. The patients and their controls were studied on a free sodium intake. In a second protocol, 10 controls and 10 patients were similarly investigated after one week of a high salt diet (regular diet + 6 g NaCl/day). RESULTS: Our results demonstrate that, in contrast to normal subjects in whom no significant changes in glomerular filtration, sodium excretion and segmental sodium reabsorption were observed throughout the day, patients with OH were characterized by a significant increase in glomerular filtration rate during the nighttime (P = 0.03) and significant increases in urinary lithium excretion (P < 0.05) and lithium clearance (P = 0.05) during the night, suggesting a decreased proximal reabsorption of sodium. On a high sodium diet, the symptoms of orthostatic hypotension and the circadian variations in sodium reabsorption were significantly blunted. CONCLUSIONS: These results suggest that, while the patient is in a supine position the effective blood volume of those with OH becomes excessive due to the increased venous return. Hence, the kidney responds with an increase in glomerular filtration and a relative escape of sodium from the proximal tubular segments. These circadian variations in renal sodium handling may contribute to the maintenance of the orthostatic syndrome.

Adolescent↗
PubMed1998

Effect of indomethacin on the renal response to angiotensin II receptor blockade in healthy subjects.

BACKGROUND: Non-steroidal anti-inflammatory drugs are known to promote sodium retention and to blunt the blood pressure lowering effects of several classes of antihypertensive agents including beta-blockers, diuretics and angiotensin converting enzyme (ACE) inhibitors. The purpose of the present study was to investigate the acute and sustained effects of indomethacin on the renal response to the angiotensin II receptor antagonist valsartan and to the ACE inhibitor enalapril. METHODS: Twenty normotensive subjects maintained on fixed sodium intake (100 mmol sodium/day) were randomized to receive for one week: valsartan 80 mg o.d., enalapril 20 mg o.d., valsartan 80 mg o.d. + indomethacin 50 mg bid and enalapril 20 mg o.d. + indomethacin 50 mg bid. This single-blind study was designed as a parallel (valsartan vs. enalapril) and cross-over trial (valsartan or enalapril vs. valsartan + indomethacin or enalapril + indomethacin). Renal hemodynamics and urinary electrolyte excretion were measured for six hours after the first and seventh administration of each treatment regimen. RESULTS: The results show that valsartan and enalapril have comparable renal effects characterized by no change in glomerular filtration rate and significant increases in renal plasma flow and sodium excretion. The valsartan- and enalapril-induced renal vasodilation is not significantly blunted by indomethacin. However, indomethacin similarly abolishes the natriuresis induced by the angiotensin II antagonist and the ACE inhibitor. CONCLUSIONS: This observation suggests that although angiotensin receptor antagonists do not affect prostaglandin metabolism, the administration of a non-steroidal anti-inflammatory drug blunts the natriuretic response to angiotensin receptor blockade.

Adult↗
PubMed1998

Angiotensin II receptor antagonists in hypertension.

Blockade of the renin-angiotensin system is now recognized as an effective approach to the treatment of hypertension and congestive heart failure. Today, it is possible to antagonize the effects of angiotensin II more specifically by blocking its receptors by using nonpeptide receptor antagonists. These compounds that first have been used to recognize the various subtypes of angiotensin II receptors are now available clinically. Four of them have recently been launched on the market and several others are preregistered for the treatment of hypertension. These new molecules are as effective as ACE inhibitors, calcium antagonists and beta-blockers in lowering blood pressure in hypertensive patients. When compared to ACE inhibitors, they appear to have comparable favorable effects on systemic and renal hemodynamic properties. One of the major characteristics of angiotensin II receptor antagonists as a class is the excellent tolerability with an incidence of side effects that is generally similar to that of placebo. Large clinical trials are now underway to demonstrate the long-term benefits of these agents in hypertension, heart failure and type II diabetic nephropathy.

Angiotensin Receptor Antagonists↗