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Biomedical subjects

J Nussberger

Publications and source records attributed to J Nussberger.

At least 91 records · Page 5Linked to original sources
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

Converting enzyme inhibition modulates sympathetic neurotransmission in vivo via multiple mechanisms.

We investigated the mechanism(s) by which angiotensin-converting enzyme (ACE) inhibition influences peripheral sympathetic neurotransmission. Thus effects of the angiotensin II (ANG II) receptor antagonist losartan (Du Pont 753) were compared with those of the ACE inhibitor benazeprilat on sympathetic neurotransmission in canine gracilis muscle in situ, with alpha-adrenoceptors either intact or irreversibly blocked by phenoxybenzamine. Furthermore, effects of the bradykinin receptor antagonist HOE 140 and the prostaglandin synthesis inhibitor diclofenac were studied after ACE inhibition. Losartan reduced the vasoconstrictor response to exogenous ANG II by 76 +/- 4% at the dose used and lowered muscle perfusion pressures. ACE inhibition by benazeprilat reduced plasma ANG-(1-8) octapeptide levels (from 8 +/- 2 to 2 +/- 1 pM), mean arterial pressure, and muscle perfusion pressures. After ACE inhibition, both HOE 140 (at a dose that reduced the vasodilatory response to exogenous bradykinin by 80 +/- 3%) and diclofenac elevated basal perfusion pressures. Losartan reduced the nerve stimulation-evoked overflow of endogenous norepinephrine (NE) (-14 +/- 6%) and vasoconstrictor responses (alpha-adrenoceptors intact). ACE inhibition increased NE overflow when alpha-adrenoceptors were intact (+12 +/- 5%) and tended to reduce it when alpha-adrenoceptors were blocked (-12 +/- 4%). During ACE inhibition, HOE 140 reduced and diclofenac enhanced the evoked NE overflow. In the absence of ACE inhibition, neither HOE 140 nor diclofenac influenced NE overflow. Our findings indicate that ACE inhibition influences sympathetic neurotransmission via reduced ANG II formation and enhanced bradykinin and prostaglandin accumulation. The effects of ANG II on sympathetic neurotransmission are, however, small under these in vivo conditions.

Angiotensin II↗
PubMed1993

Natriuretic and vasoactive hormones and glomerular hyperfiltration in hyperglycaemic type 2 diabetic patients: effect of insulin treatment.

Evidence that an increase in plasma atrial natriuretic peptide (ANP) concentrations mediates, at least in part, glomerular hyperfiltration in diabetic rats prompted us to study the relationship between ANP and renal haemodynamics in hyperfiltering type 2 diabetic patients in association with other hormones implicated in the control of glomerular filtration rate (GFR) (catecholamines, vasopressin, renin) and in sodium tubular transport (aldosterone, ouabain-displacing factor, ODF). Since hyperglycaemia is also associated to hyperfiltration, diabetic patients who presented with secondary drug failure were studied both in hyperglycaemic and in normoglycaemic condition. For this purpose, 11 normotensive non-macroproteinuric hyperfiltering patients with type 2 diabetes were treated with an 8-day continuous insulin infusion (days 0-7). Dehydration was prevented or corrected and natriuresis was on day 0 above 100 mmol/day. The following parameters were determined on days 0 and 7: GFR and renal plasma flow (RPF) by 99mTc-DTPA and 131I-hippuran clearances; the extracellular volume, assimilated to the DTPA diffusion volume; urinary ODF by receptor-binding assay and urinary as well as plasma catecholamines by HPLC after extraction on alumin. Plasma ANP and antidiuretic hormone (ADH) were measured by radioimmunoassay after extraction on phenyl-silylsilica (ANP) and with ether (ADH). Unextracted plasma was used for radioimmunological measurement of plasma renin activity and aldosterone. When correcting hyperglycaemia to normoglycaemia GFR decreased from high to normal mean value (138 +/- 27 and 115 +/- 6 ml/min, p < 0.001), RPF followed the same trend, and the DTPA diffusion volume did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
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

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

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↗
PubMed1993

Inhibitors of the renin-angiotensin system.

Inhibition of the renin-angiotensin system with angiotensin-converting enzyme inhibitors is well established as a treatment modality for hypertension and congestive heart failure. While converting enzyme inhibitors are well tolerated, they still have some side effects, which rightly or wrongly are attributed to the lack of specificity of the target enzyme for the renin-angiotensin cascade. The attempt is therefore made to inhibit the more specific enzyme renin or to block the angiotensin II receptor. While so far renin inhibitors are generally hampered by insufficient oral bioavailability, potent orally active angiotensin II antagonists are currently in clinical development. Both pharmacologic principles, renin inhibition and angiotensin II antagonism, have been shown to actively reduce blood pressure of hypertensive patients. It remains to be seen whether these newer compounds will be able to replace the converting enzyme inhibitors and exhibit even fewer untoward effects.

Angiotensin II↗
PubMed1992

[What have we learned from converting enzyme inhibitors on renin-angiotensin system?].

Angiotensin-converting-enzyme (ACE) inhibitors are now widely used to treat patients with high blood pressure or heart failure. The favourable results obtained with these inhibitors of the renin-angiotensin system suggest that angiotensin II has a noxious effect on the development and/or course of these diseases. ACE inhibitors are usually well tolerated. Their most severe side-effects are mostly foreseeable and therefore avoidable. Chronic blockade of the renin-angiotensin system increasingly seems to be a good therapeutic approach to the protection of the vital organs.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

[Preliminary evaluation of the Profilomat, a new portable blood pressure recorder].

Ambulatory blood pressure monitoring is increasingly used in clinical evaluation of the hypertensive patient. The aim of the present study is to investigate the accuracy of non-invasive blood pressure measurements provided by the Profilomat, a new portable, automatic blood pressure recorder, in normotensive subjects and hypertensive patients. The results showed a good correlation between the blood pressure values measured by this apparatus and those determined simultaneously by the conventional auscultatory method (sphygmomanometer). Thus, the Profilomat appears to be a useful instrument for study of arterial blood pressure outside the doctor's office.

Adult↗
PubMed1992

[Practical consequences blood pressure variability].

Arterial pressure varies over the course of the day depending on activities. It increases frequently in the presence of the physician. Long term blood pressure recording makes available a multitude of measurements taken during usual activities of the patient. These measurements permit identification of hypertensive patients at high risk i.e. patients with high blood pressure not only when facing their physician.

Blood Pressure↗
PubMed1992

[The treatment of arterial hypertension: which drug for which patient?].

Hypertension is a multifactorial disease. Various antihypertensive drugs can lower arterial pressure in a given patient in a more or less efficient way. The sequential testing of several drugs is most promising for lowering blood pressure by monotherapy. If necessary a drug combination is preferable to dose adjustments of a single substance because of the risk for side effects growing with the dose.

Algorithms↗
PubMed1992

Drug concentration response relationships in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist.

The aim of this study was to investigate the relationships between plasma concentrations of losartan, an orally active angiotensin II inhibitor, its active metabolite EXP3174, and angiotensin II blockade. Six healthy subjects received single oral doses of 40, 80, or 120 mg losartan and placebo at 1-week intervals in a crossover study. Angiotensin II blockade was assessed by the blood pressure response to exogenous angiotensin II before and after losartan administration. EXP3174 reached higher plasma concentrations and was eliminated more slowly than its parent compound; its levels paralleled the profile of angiotensin II blockade closer than losartan. Inhibition of the pressure response was dose dependent. The Hill-shaped relationship between response and EXP3174 concentration (or time-integrated variables) approached a plateau with 80 mg. The dose-dependent increase in plasma renin and angiotensin II exhibited a considerable individual scatter. We conclude that losartan produces a dose-dependent, effective angiotensin II blockade that is largely determined by the active metabolite EXP3174.

Administration, Oral↗
PubMed1992

Effects of aging and hypertension on plasma angiotensin II and platelet angiotensin II receptor density.

Plasma renin activity (PRA) declines with age in normal individuals, but the effect of age on plasma angiotensin II (ANG II) is less clear. A decline in plasma ANG II with age could result in altered platelet ANG II receptor density since plasma hormone levels influence their target organ receptors. To investigate this possibility, PRA, plasma ANG II, and platelet ANG II receptor density were examined in 17 young, 12 middle-aged, and 14 elderly healthy normotensive volunteers. To assess whether hypertension altered receptor density, these variables were also examined in 23 hypertensive patients. In normotensives, there was a negative correlation between age and PRA (r = -0.43, P < .05), no significant change in basal plasma ANG II with age, and a weak positive correlation between age and ANG II receptor density (r = 0.34, P < .05). Multiple regression analysis revealed that the relationship between age and ANG II receptor density was independent of the associated rise in mean arterial pressure with age (P < .05). Platelet ANG II receptor density was not significantly related to PRA or plasma ANG II. ANG II receptor affinity did not change with age. Neither PRA nor ANG II receptor density or affinity differed between hypertensives and normotensives of similar mean age, but plasma ANG II was significantly lower in hypertensives compared with normotensives. We concluded that aging is associated with a decline in supine PRA. The small decrease in plasma ANG II was not significant. Platelet ANG II receptor density increased with age primarily due to a small group of elderly subjects with elevated receptor density. There was no change in ANG II receptor density or affinity in hypertensives despite apparently lower plasma ANG II in these patients.

Adult↗
PubMed1992

Clinical experience with angiotensin II receptor antagonists.

This series of studies was designed to assess in normal volunteers the relationships between various doses (5, 10, 20, 40, 80, and 120 mg) of the orally active angiotensin II antagonist losartan (DuP 753, MK-954) and their inhibitory effect on the pressure response to a given bolus of angiotensin I or II. It was found that the maximal inhibitory effect was reached with a dose of 80 mg. The minimal dose necessary for maximal efficacy would therefore be expected to be between 40 and 80 mg. The effect lasted for more than 24 h and was related almost exclusively to the circulating levels of the active metabolite EXP3174. It remains to be demonstrated in hypertensive patients that the same dose relationship holds for the antihypertensive effect, but preliminary data already suggest that this is the case.

Administration, Oral↗
PubMed1992

Measurement of converting enzyme activity by antibody-trapping of generated angiotensin II. Comparison with two other methods.

Activity of the angiotensin converting enzyme (ACE) is usually measured in vitro by estimation of products cleaved by the enzyme from synthetic substrates. These substrates have affinities for ACE different from the natural substrate angiotensin I, and insensitive detection systems necessitate millimolar substrate concentrations while physiological angiotensin I concentrations are in the picomolar range. A new assay for ACE activity measurement was developed which reliably quantitates femtomoles of generated angiotensin II in plasma from angiotensin I added at a 17 pmol/mL concentration. The production of high affinity monoclonal antibodies against angiotensin II (Kd = 7 x 10(-11) mol/L) allowed a quantitative trapping (and thus protection from degrading enzymes) of angiotensin II generated during the incubation step and subsequent radioimmunoassay by simple dilution with labelled angiotensin II. Using 40 microL plasma, the detection limit was 20 fmol/mL/min. Normal human plasma has an ACE activity of 335 +/- 83 fmol/mL/min (mean +/- SD). Precision was characterized by coefficients of variation of less than or equal to 11% both within-assay and between-assays. Accuracy of the new method was established by comparing ACE activity with the ratio of plasma angiotensin II/angiotensin I in plasma obtained from normal volunteers 0.5 to 24 h after oral administration of 20 mg enalapril. The percentage of ACE inhibition indicated by both methods was almost identical (r = 0.93, n = 60, P less than .001). Since the latter ratio appears to reflect in vivo ACE activity, these results indicate that accurate measurement in vitro of ACE activity in vivo has been achieved.

Administration, Oral↗