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Biomedical subjects

H R Brunner

Publications and source records attributed to H R Brunner.

At least 163 records · Page 9Linked to original sources
PubMed1993

[Blood pressure recording in outpatient service: experience with the Sandoz Pressure System].

The Sandoz Pressure System (SPS) is a widely used device for ambulatory blood pressure recording. The accuracy of blood pressure profiles recorded in daily routine with this device has been demonstrated. In 34 untreated hypertensive patients the blood pressure values were in good agreement with measurements taken by auscultation. The variability of recordings was less or equal to 5 mmHg in 10% of patients for the systolic and in 94% of patients for the diastolic value. During daily activity 100 +/- 6% (mean +/- standard deviation) of the values expected by programming were available for analysis. These results confirm that arterial pressure under ambulatory conditions cannot be reliably predicted based on blood pressure measurements in the doctor's office.

Adult↗
PubMed1993

Pharmacologic profile of trandolapril, a new angiotensin-converting enzyme inhibitor.

Trandolapril is a newly developed angiotensin-converting enzyme (ACE) inhibitor that is rapidly hydrolyzed mainly in the liver to its biologically active metabolite trandolaprilat. The time to reach peak plasma concentrations of trandolaprilat is about 6 hours; the effective plasma half-life of accumulation at steady state is 24 hours. The active metabolite trandolaprilat has very high lipophilicity in comparison with other ACE inhibitors, which should contribute to an improved tissue penetration of the substance. The very high affinity of trandolaprilat to the ACE and the corresponding low dissociation rate are probably the two main reasons for the prolonged duration of action. The high potency of trandolaprilat in ACE inhibition is reflected by its low IC50 (concentration needed to inhibit 50% of the enzyme activity). With repeated once-daily administration of trandolapril, plasma ACE activity was reduced in a dose-dependent fashion, but increasing the dose beyond 2 mg did not further reduce angiotensin II levels, apparently because of the compensatory increase in plasma renin levels. Therefore trandolapril in a dose of 2 mg once a day reduces blood pressure consistently throughout the 24 hour-period after intake. Because of its particularly long half-life, trandolapril, probably more than any other drug of its class, can be considered a true, once-a-day antihypertensive drug.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Endothelial function in congestive heart failure.

There is evidence that the endothelium plays an important role in the control of human vascular tone by releasing endothelium-derived nitric oxide and, therefore, a defective endothelial function could be involved in the increased peripheral vasoconstriction of patients with chronic congestive heart failure. To investigate endothelial function in humans in vivo, agents such as acetylcholine, a short-acting stimulator of the release of endothelium-derived nitric oxide, has been used. Conversely, N-mono-methyl-L-arginine, a specific inhibitor of nitric oxide synthesis from L-arginine, has recently been shown to decrease blood flow during infusion into the brachial artery of healthy volunteers (control subjects) by inhibiting the basal release of nitric oxide. Consistent with experimental studies, the blood flow response to acetylcholine is blunted in patients with chronic heart failure compared with healthy age-matched volunteers. In contrast, the decrease in blood flow induced by N-mono-methyl-L-arginine appears to be exaggerated in congestive heart failure. The blood flow response to nitroglycerin or sodium nitroprusside, endothelium-independent vasodilators, is usually preserved in patients with chronic, nonedematous heart failure, indicating a normal response of the vascular smooth muscle of resistance vessels to exogenous nitric oxide. In contrast, the dilator response of the radial artery diameter to nitroglycerin and flow-dependent dilation is impaired in patients with chronic heart failure, indicating that the abnormal flow-mediated relaxation of large arteries may be caused by both endothelial and structural abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

High level expression of human neuropeptide Y receptors in mammalian cells infected with a recombinant vaccinia virus.

Neuropeptide Y (NPY) is a 36 amino acid peptide present in the central and peripheral nervous system. Numerous studies point to a role of NPY in cardiovascular regulation. NPY effects are mediated through stimulation of specific cell surface G protein-coupled receptors. To allow biochemical studies of the receptor and of its interaction with the ligand, we have developed a potent expression system for NPY receptors using a recombinant vaccinia virus. A human NPY receptor cDNA was fused to a strong vaccinia virus promoter and inserted into the viral genome by homologous recombination. Recombinant viruses were isolated and tested for their ability to induce NPY binding site expression following infection of mammalian cell lines. Using saturation and competition binding experiments we measured a Bmax of 5-10 x 10(6) NPY binding sites per cell. The Kd for the binding of NPY is about 20 nM. Labelling of infected cells with a fluorochrome-labelled NPY indicated that the recombinant protein integrates into the cell membrane.

Base Sequence↗
PubMed1993

Elastic behaviour of the carotid artery in intact spontaneously hypertensive rats.

Intact spontaneously hypertensive rats (SHR) were studied to assess the effect of prolonged antihypertensive treatment on the elastic behaviour of the external carotid artery. Thirty-week-old SHR received the ACE inhibitor captopril, the arteriolar dilator hydralazine or their vehicle for 6 weeks. These rats were compared to normotensive, vehicle treated WKY rats. The internal diameter of the carotid artery was measured continuously in halothane-anaesthetized rats using an echo-tracking device, and intra-arterial pressure was also monitored continuously, on the contralateral side. Captopril- and hydralazine-treated SHR as well as normotensive controls had similar blood pressure values. No significant shift in the distensibility-pressure curves was observed among vehicle-treated SHR and WKY rats or the SHR which had received captopril or hydralazine. Histological examination of the carotid artery fixed ex vivo with paraformaldehyde showed a significant increase in cross-sectional area in vehicle-treated SHR as compared to their normotensive counterparts. These results therefore suggest that the elastic behaviour of elastic arteries is not necessarily altered by the structural changes developing in response to hypertension.

Animals↗
PubMed1993

Isobaric compliance of the radial artery is increased in patients with essential hypertension.

OBJECTIVES: Hypertension is known to decrease arterial elasticity and systemic compliance. However, the arterial tree is not a homogeneous system, and whether a distal medium-sized artery such as the radial artery behaves like proximal arteries has not been determined. The aims of the present study were, first, to characterize non-invasively the mechanical properties of the radial artery through the determination of the pressure-diameter curve, the distensibility-pressure curve and the compliance-pressure curve, and, secondly, to compare untreated hypertensive patients with normotensive subjects. METHODS: A new high-precision echo-tracking device was developed which allows the diameter of peripheral arteries to be measured continuously. By relating the changes in internal diameter (cross-sectional changes) to those in blood pressure, the cross-sectional arterial compliance could be determined. PARTICIPANTS: Seventy-eight untreated mild or moderate essential hypertensive patients aged 24-78 years were compared with 44 normotensive subjects aged 22-81 years. In order to increase the database and provide independent assessments of the variables examined, the cross-sectional study was performed independently using a standardized procedure in three different research centres. RESULTS: The major finding was that diameter, distensibility and compliance of the radial artery of hypertensive patients were not significantly different from those of normotensive controls when the two populations were studied at their mean arterial pressure. Furthermore, when the two populations were compared for the same level of blood pressure, using distensibility--and compliance--pressure curves, it was clear that isobaric distensibility and compliance of hypertensives were not significantly lower than those of normotensives, being either unchanged or higher. CONCLUSIONS: These findings are in contrast with the well-known decrease in compliance of proximal large arteries due to hypertension. Whether such a difference between proximal large arteries and distal medium-sized arteries may be related to the structural vascular changes observed with long-standing hypertension is still difficult to analyse in humans, and requires further investigation.

Adult↗
PubMed1993

The renin-angiotensin system and arterial wall behavior.

To assess the behavior of the arterial wall in hypertensive patients, we developed a noninvasive ultrasonic device. Simultaneous recordings of internal diameter and blood pressure over the whole cardiac cycle are used to establish compliance-pressure curves. Blood pressure, which is a co-determinant of compliance, is thus taken into account. This method allows one to compare arteries from patients with different blood pressures. Arterial compliance and distensibility were first investigated in healthy young volunteers administered either lisinopril (20 mg), atenolol (100 mg) or nitrendipine (20 mg) once a day. After 8 days of treatment, only lisinopril was found to increase arterial compliance. Subsequently, we compared arterial diameter- and distensibility-pressure curves from newly diagnosed and untreated hypertensive patients with those of matched normotensive control patients. Diameter-pressure curves did not differ significantly between the groups and distensibility was not reduced. Similar findings were later obtained in an animal model, when mechanical properties of carotid arteries were compared between spontaneously hypertensive rats and normotensive counterparts (Wistar-Kyoto rats). These results, although interesting by providing noninvasive information on the elastic response of the wall, call for further development of the technique to be able to measure arterial wall thickness. Stress-strain relationship could ultimately be established to thoroughly characterize physical properties of blood vessel walls.

Animals↗
PubMed1993

Neuropeptide Y and cardiovascular regulation.

Neuropeptide Y is a vasoactive peptide and is widely distributed throughout the central and peripheral nervous systems. Neuropeptide Y is co-released with noradrenaline by perivascular nerve endings. At high concentrations, it has a direct vasoconstrictor effect. In addition, it enhances the vascular effect of various agonists, including noradrenaline and angiotensin II. Moreover, neuropeptide Y has an inhibitory effect on renin secretion. This peptide may have an important role in cardiovascular regulation.

Animals↗
PubMed1993

Spontaneous diameter oscillations of the radial artery in humans.

In this study we investigated whether there exists a periodic contractile activity of the radial artery, and we evaluated the impact of such an oscillatory behavior on the mechanical properties of this medium-sized muscular vessel. The internal diameter of the right radial artery was measured noninvasively in six healthy male volunteers aged 18-42 yr using a high-precision ultrasonic echo-tracking device. Blood pressure was simultaneously recorded on the same side at the middle finger by photoplethysmography. The electrical activity of the heart was monitored during the entire experiment by electrocardiography. The frequency components of the arterial diameter, blood pressure, and heart rate were obtained using spectral analysis. Under resting conditions, the radial arterial diameter exhibited a spontaneous oscillation with a period ranging from 45 to 70 s and an amplitude of 80 +/- 14 microns (+/- SE). No very low-frequency mode (< or = 0.02 Hz) was identified in either heart rate or blood pressure. These diameter oscillations affected the distensibility-pressure curves acquired simultaneously. Thus the 3-4% oscillatory variation in arterial diameter was paralleled by a 1.5- to 2-fold change in distensibility. These low-frequency oscillations of large arteries seem to be mediated by an intrinsic vascular mechanism.

Adolescent↗
PubMed1993

Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects.

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n = 7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P < .05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P < .05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin II antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Neuropeptide Y expression and regulation in a differentiated rat insulin-secreting cell line.

Neuropeptide-Y (NPY) is a 36-amino acid peptide known to inhibit glucose-stimulated insulin secretion in various animal models in vitro and in vivo. NPY is thought to be one of the mediators of sympathetic action in the pancreas through nerve endings surrounding the islets, and it has recently been shown to be synthesized within the islets of Langerhans. To elucidate the potential role of NPY in the endocrine pancreas, we studied the expression and regulation of NPY secretion in a rat insulinoma cell line (INS-1). NPY mRNA and peptide are highly expressed and secreted by INS-1 cells. NPY levels were determined by a sensitive and specific two-site amplified enzyme-linked immunosorbent assay. Incubation of INS-1 cells with various glucose concentrations did not modify NPY secretion; however, stimulation of adenylate cyclase by forskolin induced a dose- and time-dependent increase in NPY release in the medium. The glucagon-like peptide-I-(7-36) amide (GLP-1), a known gluco-incretin in humans, induced at low concentration (10(-9) M) a similar expression of NPY mRNA and peptide secretion in INS-1 cells. On the other hand, the inhibition of cAMP accumulation by the alpha 2-adrenergic agonist clonidine decreased NPY secretion. In conclusion, 1) high levels of gene expression and secretion of NPY are found in a rat insulinoma cell line (INS-1). 2) Accumulation of cAMP induced by forskolin or a gluco-incretin (GLP-1) induces a further increase in NPY gene expression and release. 3) NPY secretion is not modulated by low or high glucose concentrations in the medium. 4) Induction of NPY, a known inhibitor of insulin secretion, may represent a novel counterregulatory mechanism of insulin secretion, limiting the stimulatory effect of GLP-1 on insulin secretion.

Adenylyl Cyclases↗
PubMed1993

Angiotensin II antagonists.

Acute blockade of the renin-angiotensin system with the parenterally active angiotensin II antagonist saralasin has been shown to effectively lower blood pressure in a large fraction of patients with essential hypertension and to improve hemodynamics in some patients with congestive heart failure. It is now possible to antagonize chronically angiotensin II at its receptor using the non-peptide angiotensin II inhibitor losartan (DuP 753, MK 954). When administered by mouth, this compound induces a dose-dependent inhibition of the pressor response to exogenous angiotensin II. This effect is closely related to circulating levels of the active metabolite E3174. Preliminary studies performed in hypertensive patients suggest that losartan has a blood pressure lowering action equivalent to that of an ACE inhibitor. Whether this compound will compare favorably with ACE inhibitors requires however further investigation.

Angiotensin II↗
PubMed1993

Ambulatory blood pressure monitoring to assess antihypertensive therapy in private practice.

Non-invasive ambulatory blood pressure monitoring has proved to be very useful in evaluating hypertensive patients. However, most previous studies were performed in specialised centres. Here the results of two trials are presented in which private physicians used ambulatory BP monitoring to assess the efficacy of antihypertensive drugs. The results were very similar to those observed previously in specialised clinics. In the individual patient, the level of ambulatory recorded pressure could not be predicted based on BP readings taken at the doctor's office. Also, the BP response to antihypertensive therapy was more reproducible when evaluated by ambulatory BP monitoring than by the doctor. Thus, the use of noninvasive ambulatory BP monitoring is also very appropriate in everyday practice for the management of hypertensive patients.

Ambulatory Care↗
PubMed1993

Clinical experience with angiotensin II receptor antagonists.

The new generation of antihypertensive agents, the angiotensin II receptor antagonists, lower blood pressure by intervening in the RAA system. Angiotensin II is the major effector compound in the RAA cascade; therefore, blockade of the angiotensin II receptor represents a particularly effective way of preventing its hypertensive effects. Losartan (DuP 753, MK954) is the first of a new series of non-peptide orally-active angiotensin II receptor antagonists. Preliminary results of ongoing pharmacology and efficacy studies with losartan indicate that it may have an improved clinical profile when compared with other antihypertensive agents. The results of these studies have indicated that the effective antihypertensive dose of losartan is 50 mg once daily.

Angiotensin II↗
PubMed1993

Control of vascular tone by renin and angiotensin in cardiovascular disease.

The tools which have led to a better understanding of the role of the renin-angiotensin system in determining the tone of peripheral arteries in cardiovascular disease consist of highly specific and sensitive methods to measure the different components of the renin-angiotensin system and in specific probes used to inhibit the renin-angiotensin system at several points of the enzymatic cascade. The therapeutic efficacy of these more and more specific probes undoubtedly provides strong circumstantial evidence that angiotensin II plays an important role in determining peripheral vascular tone. While this has considerably increased our understanding of the regulatory mechanism involved in blood pressure maintenance in normotensive subjects and hypertensive patients, the role of the renin-angiotensin system as an aetiological factor in the development of essential hypertension still remains unclear.

Angiotensin II↗
PubMed1993

Angiotensin II blockade compared with other pharmacological methods of inhibiting the renin-angiotensin system.

AIM: To compare angiotensin II receptor blockade, angiotensin converting enzyme (ACE) inhibition and renin inhibition as pharmacological methods of inhibiting the renin-angiotensin system. METHOD: Review of published results of studies using the three methods, with a particular emphasis on measurement problems. RESULTS: Whenever an attempt is made to block the renin-angiotensin system, by whatever approach, there is a compensatory rise in renin secretion which determines the effect of the drug. Accurate biochemical methods must be available to assess the efficacy of each approach. ACE inhibitors have been very successful and are generally well tolerated but cough is a common side effect, possibly related to their lack of specificity. High doses stimulate renin secretion. Renin inhibitors are theoretically more attractive than ACE inhibitors because of their specificity, and renin inhibitors with adequate oral bioavailability are now available. Due to the reactive rise in renin, however, the effects of the renin inhibitors so far available appear to be very short in duration. There is insufficient evidence to show whether prolonged administration may be successful. With present methods, only circulating angiotensin I and II levels can give an accurate indication of the effectiveness of the drug. The first non-peptide angiotensin II inhibitor, losartan (DuP753, MK 954), is still undergoing clinical trials. Dose-dependent inhibition of the pressor response to exogenous angiotensin II has been obtained in normotensive volunteers, the effect being closely related to circulating levels of the active metabolite E 3174. The reactive rise in plasma renin activity and angiotensin II was highly variable. A preliminary study in hypertensive patients showed effective blood pressure reduction at doses based on the results obtained in normotensive volunteers. CONCLUSIONS: Renin inhibitors and angiotensin antagonists represent potentially exciting alternatives to the ACE inhibitors. At present, only orally active angiotensin II antagonists are available for extensive clinical evaluation, and the results so far look promising. Whether these compounds will compare favourably with ACE inhibitors requires further investigation.

Angiotensin Receptor Antagonists↗