Biomedical subjects

H R Brunner

Publications and source records attributed to H R Brunner.

At least 235 records · Page 13Linked to original sources

PubMed1990

Reactive hyperreninemia is a major determinant of plasma angiotensin II during ACE inhibition.

The new ACE inhibitor trandolapril was administered to normal volunteers at daily doses of 0.5, 2, and 8 mg for 10 days. Twenty-one volunteers, aged 21-30 years, were included in the study. To randomly selected groups of seven subjects, each dose was administered in a single-blind fashion. None of the doses induced a consistent fall in blood pressure. Angiotensin-converting enzyme activity (ACE) was measured in vitro using three different synthetic substrates (i.e., Hip-Gly-Gly, Z-Phe-His-Leu, or angiotensin I). Although the degree of ACE inhibition assessed with the three methods varied widely, all methods clearly indicated dose-dependent ACE inhibition. These in vitro results were confirmed by measuring ACE inhibition in vivo using the ratio of plasma angiotensin II (ANG II) to blood angiotensin I (ANG I). The dose-dependent ACE inhibition was paralleled by a dose-dependent rise in active renin and blood angiotensin I levels, most evident on day 10. In contrast, plasma ANG II levels on day 10 were not different whether the volunteers received 0.5 or 8 mg trandolapril. Thus, whereas increasing doses of this new ACE inhibitor progressively enhanced the blockade of ACE activity, this was not reflected by additional reductions of plasma ANG II levels. The progressive enhancement of ACE inhibition seemed to be offset by the accentuation of the compensatory rise in renin and ANG I, which was still partially converted to ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1990

Caffeine-induced diuresis and atrial natriuretic peptides.

After a single-blind, randomized, cross-over protocol using decaffeinated coffee in a control experiment, the effect of an oral 250-mg caffeine dose on plasma immunoreactive atrial natriuretic peptide (ANF) was assessed in eight healthy students who had been on a methylxanthine-free diet for 1 week. One to 2 h after caffeine ingestion, both systolic blood pressure (SBP) and diastolic BP (DBP) increased by 12 mm Hg while heart rate (HR) also tended to increase. An increase in diuresis and in urinary sodium, potassium, and osmol excretion was observed within 1 h. Decaffeinated coffee induced no change in any of these parameters. Plasma epinephrine (EPI) increased gradually from 16.6 +/- 3.2 pg/ml (mean +/- SEM) to 45.1 +/- 7.9 pg/ml within 2 h after caffeine ingestion, but did not change after decaffeinated coffee (p less than 0.001). Plasma norepinephrine (NE), renin activity (PRA), aldosterone, and vasopressin remained unchanged. Plasma ANF was measured by radioimmunoassay (RIA) using an extremely sensitive antiserum (Kd = 10(-12) M) after rapid and virtually complete (90-103%) extraction from plasma. In 0.2 ml plasma, the theoretical detection limit is 1.1 fmol/ml. Normal plasma ANF concentrations in supine subjects were 17.9 +/- 8.1 fmol/ml (mean +/- SD) and 11.0 +/- 3.3 fmol/ml in subjects in the upright position. Plasma ANF levels were not affected by coffee drinking. In conclusion, by using a new and sensitive assay for plasma ANF, we did not find that caffeine-induced diuresis is mediated by ANF.

Adult↗

PubMed1990

Effects of dextronatrin on blood pressure, hematocrit, urinary sodium excretion and sympathetic nerve activity of rats.

The purpose of this investigation was to study in unanesthetized rats the blood pressure, renal and hematocrit responses to dextronatrin, a structural analogue of atrial natriuretic peptides (ANP). The peptide was infused intravenously for 20 min at doses of either 1 or 20 micrograms/min in binephrectomized rats as well as in rats with intact kidneys. The experiments were started 2 h after preparation of the rats under ether anesthesia. In binephrectomized rats, the small dose of dextronatrin lowered blood pressure and raised hematocrit. In those rats, the larger dose of the investigational peptide had no blood pressure lowering effect, but still increased hematocrit. Dextronatrin had no effect on heart rate, both in rats with and without kidneys. Dextronatrin given at the 1 microgram/min dose to normal rats caused a significant increase in urinary Na excretion. The large dose, however, did not modify this parameter. The effect of dextronatrin (1 microgram/min for 20 min) on splanchnic nerve activity was evaluated in other normal rats after a recovery period of 24 h from surgical procedure. Integrated nerve activity was found to significantly increase in parallel with heart rate while blood pressure was reduced. Taken together, these results show that a low dose of dextronatrin lowers blood pressure and induces an increase in urinary Na excretion and hematocrit. They also indicate that the blood pressure and renal effects of the peptide are abolished when a high dose is administered. In addition, it appears that the shift of fluid from the intra- to the extravascular compartment, reflected in binephrectomized rats by an increase in hematocrit, does not depend on the level of systemic blood pressure. Finally, the present observations suggest that the blood pressure lowering effect of dextronatrin is accompanied in the conscious rat by a stimulation of the sympathetic nervous system.

Amino Acid Sequence↗

PubMed1990

Effect of metoclopramide on angiotensins, aldosterone, and atrial peptide during hypoxia.

The coupling of aldosterone with renin is altered during acute hypoxemia. We measured the various components of the renin-angiotensin system and the plasma levels of immunoreactive atrial natriuretic factor (iANF) during room air and hypoxic gas-mixture breathing before and after administration of metoclopramide, a competitive antagonist of dopamine. Seven resting volunteers were studied 1 wk apart under room air and hypoxic conditions (inspired O2 fraction 0.12). During hypoxemia, the release of aldosterone induced by metoclopramide was significantly smaller. This change was associated with a slight increase in iANF and with a decrease in plasma angiotensin II levels, without any change in immunoreactive blood angiotensin I concentrations. Plasma electrolytes and blood acid-base status did not show relevant changes, nor did blood pressure and heart rate. We conclude that the decreased aldosterone concentrations seen under hypoxemia are related to decreased angiotensin II levels. Other influences, such as elevated ANF, may also mediate this effect.

Adult↗

PubMed1990

Role of atrial natriuretic peptides and neuropeptide Y in blood pressure regulation.

Atrial natriuretic peptides (ANP) are released into the circulation in response to enhanced atrial stretching. These peptides not only have diuretic and natriuretic properties, but also exert a relaxing effect on the vasculature. Moreover, they antagonize the contractions induced by norepinephrine and angiotensin II. Neuropeptide Y (NPY) is also a vasoactive peptide. It is widely distributed throughout the central and peripheral nervous systems. NPY is coreleased with norepinephrine by perivascular nerve endings. At high concentrations, this peptide has a direct vasoconstrictor effect. In addition, it enhances the vascular effect of various agonists, including norepinephrine and angiotensin II. Both ANP and NPY have an inhibitory effect on renin secretion. This effect may have important implications for the role of these peptides in cardiovascular regulation.

Aldosterone↗

PubMed1990

Determinants of angiotensin II generation during converting enzyme inhibition.

The reaction of the renin-angiotensin system to acute angiotensin converting enzyme inhibition was investigated in a single-blind, crossover study in nine normal volunteers receiving two out of three regimens in random order: the new converting enzyme inhibitor benazepril (20 mg once or 5 mg four times at 6-hour intervals) or enalapril (20 mg). Plasma converting enzyme activity, drug levels, angiotensin I and angiotensin II, active renin, and aldosterone were measured before and 1-4 hours and 14-30 hours after drug intake. Baseline in vitro plasma converting enzyme activity was 97 +/- 15 nmol/ml/min (mean +/- SD) when Hip-Gly-Gly was used as substrate, but with carbobenzoxy-Phe-His-Leu (Z-Phe-His-Leu) or angiotensin I as substrate it was only 20 +/- 4 and 1.7 +/- 0.3 nmol/ml/min, respectively. Discriminating power at peak converting enzyme inhibition was enhanced with the two latter substrates. In vivo converting enzyme activity was estimated by the plasma angiotensin II/angiotensin I ratio, which correlated well with in vitro converting enzyme activity using Z-Phe-His-Leu as substrate (r = 0.76, n = 252). Angiotensin II levels returned to baseline less than 24 hours after drug administration, whereas in vitro and in vivo converting enzyme activity remained considerably inhibited and active renin together with angiotensin I levels were still elevated. A close linear relation was found between plasma angiotensin II and the angiotensin I/drug level ratio (r = 0.91 for benazeprilat and r = 0.88 for enalaprilat, p less than 0.001). Thus, plasma angiotensin II truly reflects the resetting of the renin-angiotensin system at any degree of converting enzyme inhibition. The ratio of plasma angiotensin II to angiotensin I represents converting enzyme inhibition more accurately than in vitro assays, which vary considerably depending on substrates and assay conditions used.

Angiotensin I↗

PubMed1990

Comparative cardiovascular effects of drugs used for hypertension.

Currently 4 classes of antihypertensive drugs - diuretics, beta-blockers, calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors - are most commonly used to treat hypertensive patients. Each class of drug has a distinctive cardiovascular pharmacodynamic profile and even within classes there exist agents with slightly different properties. The effects of the various drug classes on the heart and peripheral circulation, on the kidney and electrolyte metabolism, on the brain and on the renin-angiotensin system are now reasonably well described. Knowledge and understanding of these different cardiovascular effects are extremely important in order to adapt treatment to the needs of an individual patient. Furthermore, when combination therapy becomes necessary, the different cardiovascular aspects of the various drugs can be used to enhance antihypertensive efficacy and to attenuate adverse effects of separate compounds.

Adrenergic beta-Antagonists↗

PubMed1990

Hemodynamic effects of a kinin antagonist.

The present study was undertaken to assess in unanesthetized rats the effect of a kinin antagonist (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg-trifluoroacetic acid) on blood pressure, heart rate, and splanchnic nerve activity. The antagonist infused intra-arterially (50 micrograms/min) for 10 min had no blood pressure effect in control rats. It did, however, cause a significant increase in blood pressure in animals preinfused with a nonpressor dose of angiotensin II (1 ng/min i.v.) for 70 min. The antagonist-induced blood pressure rise was not associated with an increase in splanchnic nerve activity. Acute angiotensin-converting enzyme (ACE) inhibition with captopril (2.5 mg i.v.) had no influence on the pressor response to the kinin antagonist in angiotensin II-treated rats. These results obtained in conscious normotensive rats suggest that endogenous kinins participate in the control of blood pressure by attenuating the vasoconstrictor effect of angiotensin II. The involvement of kinin does not seem to be enhanced by acute ACE inhibition.

Amino Acid Sequence↗

PubMed1990

Use of non-invasive ambulatory blood pressure monitoring to screen for high-risk hypertensive patients.

Blood pressures measured casually by a doctor often differ considerably from those recorded during everyday activities away from the medical environment. In the present study, we compared office and ambulatory recorded pressures in 475 consecutive untreated patients diagnosed hypertensive by physicians. Blood pressure monitored non-invasively during the day was, on average 15/7 mmHg lower than the corresponding office pressures. The difference between office and ambulatory recorded pressure tended to be greatest in those patients with the highest office blood pressure levels, although the relationship between the two types of measurement was too weak (r = 0.50 and 0.38 for systolic and diastolic pressure, respectively) to have any predictive value in the individual patient. Office blood pressures were at least 10 mmHg higher than ambulatory pressures in 62% of patients for systolic and 42% for diastolic pressure. Blood pressure levels recorded during ambulatory monitoring were higher than in the doctor's office for 18% of patients for systolic and 22% for diastolic pressure. Among patients with systolic pressures of between 161 and 180 mmHg or diastolic pressures between 96 and 105 mmHg when facing a doctor, 27 and 37% respectively, showed markedly lower systolic (less than 140 mmHg) or diastolic (less than 90 mmHg) ambulatory recorded pressures. These data therefore indicate that ambulatory blood pressure monitoring may help to identify those truly hypertensive patients who are most likely to benefit from antihypertensive therapy.

Blood Pressure Determination↗

PubMed1990

Various approaches to blockade of the renin-angiotensin system: persistent renin response.

The first compounds used to block the renin-angiotensin system were polypeptide antagonists of angiotensin II, administered parenterally. Subsequently, orally active angiotensin converting enzyme inhibitors were developed which were generally well tolerated, and were effective in the treatment of hypertension and congestive heart failure. Today they are well established as therapeutic agents. Nevertheless, the search continues for more specific therapeutic agents such as orally active renin inhibitors and angiotensin II antagonists, and accurate biochemical methods must be available to assess their efficacy. All approaches trigger a considerable compensatory rise in renin secretion which tends to counteract the blocking effect of these compounds. Hence all agents, but particularly the renin inhibitors, must have a good bioavailability and a high affinity in order to overcome the effect of the compensatory renin secretory response. As yet, it is too early to predict whether the potentially more specific renin inhibitors or angiotensin II antagonists will replace the present widely used angiotensin converting enzyme inhibitors.

Angiotensin II↗

PubMed1990

Trials using a crossover design and ambulatory blood pressure recordings to determine the efficacy of antihypertensive agents in individual patients.

The antihypertensive effects of the beta-blocking agent betaxolol and the calcium entry blocker verapamil were compared in a crossover single-blind trial. Seventeen patients with uncomplicated essential hypertension took either betaxolol or a slow-release formulation of verapamil for two consecutive 6-week periods. The sequence of treatment phases was randomly allocated and a 2-week washout period preceded each treatment. The antihypertensive effect of the test drugs was assessed both at the physician's office and during everyday activities using a portable blood pressure recorder. The crossover design of the trial made it possible to evaluate the antihypertensive efficacy of betaxolol and verapamil both in the group as a whole and in the individual patient. The individual patient response to one of these agents was not a reliable indicator of the same patient's response to the alternative agent. Betaxolol brought both office and ambulatory recorded blood pressures under control in a larger fraction of patients than verapamil, although the magnitude of the blood pressure fall in the responders was equal for each drug. These observations stress the need for an individualized approach to the evaluation of antihypertensive therapy. The present results also demonstrate that optimal antihypertensive therapy is still a matter of trial and error. The precise methodology that ought to characterize crossover trials may make it possible to improve the therapeutic approach to hypertensive patients.

Ambulatory Care↗

PubMed1989

Angiotensin-converting enzyme inhibition versus blockade of the renin-angiotensin system.

Angiotensin-converting enzyme (ACE) inhibitors have been designed to reduce the generation of angiotensin II, i.e., to block the renin-angiotensin system. Interestingly, there exists a considerable dissociation between the time course of ACE inhibition and that of blockade of the renin-angiotensin system. Due to the greatly improved methodology used to estimate the degree of ACE inhibition in vitro and in vivo, it has become evident that the compensatory increase in renin levels in response to ACE inhibition is the key factor determining the degree and duration of blockade of the renin-angiotensin system resulting from ACE inhibition. A better understanding of these relationships would seem to be useful in determining duration of action and particularly the optimal dose of any ACE inhibitor.

Angiotensin II↗

PubMed1989

[Blood pressure lowering action and tolerance of ketanserin in mono- or combination therapy].

The antihypertensive efficacy and tolerability of the 5HT2-receptor antagonist ketanserin was investigated in 188 patients aged 41 to 82 years with mild to moderate essential hypertension. Ketanserin was given as monotherapy (n = 107) as well as in combination with either the diuretic hydrochlorothiazide/amiloride (n = 42) or the betablocker atenolol (n = 39) for 12 weeks. Compared to placebo, ketanserin lowered systolic blood pressure by 11 +/- 16 (SD), 9 +/- 13 and 9 +/- 11 mm Hg (p less than 0.01 for all) and diastolic blood pressure by 9 +/- 10, 10 +/- 9 and 7 +/- 9 mm Hg (p less than 0.001 for all), in the three treatment groups; body weight, serum sodium, potassium, uric acid, cholesterol and triglycerides remained unchanged. The incidence of withdrawals due to unwanted effects was 4% on ketanserin monotherapy, and 12% and 10% on the diuretic/ketanserin and the betablocker/ketanserin combination respectively. Well-being during ketanserin therapy was improved in the older patients in particular; sleep disturbances, daytime fatigue and overall weakness decreased. Ketanserin was well tolerated in combination with the diuretic, whereas in combination with the betablocker the occurrence of dry mouth and stuffy nose was slightly higher. - Ketanserin proved to be an effective antihypertensive drug comparable to other blood pressure lowering agents. It can be combined advantageously with a potassium sparing diuretic or a betablocker. The greater efficacy and tolerability in patients greater than or equal to 60 years qualify ketanserin primarily as an antihypertensive agent for older patients.

Adult↗

PubMed1989

Effects of prolonged administration of the angiotensin converting enzyme inhibitor CGS 16617 in normotensive volunteers.

A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 16617, has been evaluated in normotensive subjects during acute and prolonged administration. Single ascending doses of CGS 16617 20 to 100 mg were given to 9 normotensive volunteers at one week intervals and the changes in blood pressure, plasma ACE and renin activity were examined up to 72 h after drug intake. Also, CGS 16617 50 mg/day or placebo were given for 30 days to 8 and 6 normotensive subjects, respectively, maintained on an unrestricted salt diet. Blood pressure was measured daily in the office and ambulatory blood pressure profiles were also obtained before, during and after therapy, using the Remler M 2000 blood pressure recording system. CGS 16617 was an effective and long lasting ACE inhibitor. It did not induce a consistent change in blood pressure, but, the individual responses were very variable and several subjects experienced a clear decrease in the average of the blood pressures recorded during the daytime.

Administration, Oral↗

PubMed1989

Plasma angiotensins, renin, and blood pressure during acute renin inhibition by CGP 38 560A in hypertensive patients.

The new renin inhibitor CGP 38560A has been shown to block angiotensin (ANG) production in healthy volunteers. In order to determine its potential antihypertensive effect, the compound was administered in a 30-min infusion, in 12 hypertensive patients (mean blood pressure (BP): 112.8 +/- 3.5 mm Hg). These patients were selected for their sensitivity to captopril: a single oral dose of 50 mg captopril lowered their mean BP by 8.8 +/- 2.2 mm Hg after 30 min and by 15.3 +/- 1.5 mm Hg after 90 min. At the end of the renin inhibitor infusion, mean blood pressure decreased by 5.7 +/- 2.2 mm Hg in the six patients infused with the dose of 0.125 mg/kg and by 6.0 +/- 1.8 mm Hg in the six patients infused with 0.250 mg/kg. The fall in blood pressure was correlated to the initial plasma renin activity (PRA) (r = 0.61, P less than .05). A dose-dependent effect was observed on plasma ANG I which fell by 74% with 0.125 mg/kg and by 94% with 0.250 mg/kg. Identical falls were found for plasma ANG II (72% and 94%, respectively) and ANG I and ANG II were well correlated (r = 0.91, P less than .001). The fall in BP was correlated to the fall in plasma ANG I (r = 0.77, P less than .01). The time-course of the BP changes was parallel to the changes in plasma angiotensins, as were the slightly delayed rise and fall in active renin measured by a direct immunoradiometric assay. When measured by the conventional ANG I radioimmunoassay, PRA values indicated a long-lasting inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

Plasma angiotensin II and the antihypertensive action of angiotensin-converting enzyme inhibition.

The measurement of immunoreactive "angiotensin II" in plasma cannot provide an accurate reflection of the efficacy of angiotensin-converting enzyme (ACE) inhibition because different angiotensin fragments interfere in all radioimmunoassays available so far. More complex methods are necessary in order to measure specifically angiotensin-(1-8)octapeptide. With such methodology it can be shown that no tolerance develops to the angiotensin II-reducing effect of ACE inhibitors after prolonged administration. Marked reduction of angiotensin II levels can be shown even in patients with primary aldosteronism. At peak blockade, the level of plasma angiotensin II is still related to circulating active renin and angiotensin I. Accordingly, because ACE inhibitors raise circulating angiotensin I in a dose-dependent fashion, this should be taken into account when dosing ACE inhibitors. The hypothesis that tissue renin-angiotensin systems play an important independent role in determining vasomotor tone is very interesting. However, any discussion on whether tissue or plasma renin determines the pharmacological effect of ACE inhibitors should be based on the simultaneous measurement of true angiotensin II in tissue and plasma under steady-state conditions.

Angiotensin II↗

PubMed1989

Effect of cold pressor test on the internal diameter of the radial artery.

The aim of this study was to investigate in normal subjects the effect of a cold pressor test on the caliber of the radial artery, a muscular artery of medium size. The internal diameter of this artery was measured continuously using a recently developed ultrasonic device. Immersion of one hand in ice water for two minutes increased blood pressure from 115/75 +/- 3/2 (Mean +/- SEM) to 136/90 +/- 6/2 mm Hg (P less than .001) and decreased the internal diameter of the radial artery from 2.82 +/- 0.12 to 2.60 +/- 0.09 mm (P less than .01). These data therefore indicate that the vasoconstriction induced by the cold pressor test involves not only arterioles, but also medium-size arteries.

Adolescent↗

PubMed1989

Angiotensin converting enzyme inhibition and renin inhibition.

Over a period of several years, methods of measuring circulating angiotensin II have been progressively improved and it has now become possible to measure circulating angiotensin II with a high degree of accuracy. The main ingredients in this new methodology are bonded-phase silica for quantitative angiotensin extraction from biological fluids and antibodies with a high affinity to angiotensin II to provide for the sensitivity of the radio-immunoassay, high performance liquid chromatography to guarantee the specificity for the angiotensin-(1-8)octapeptide, and a renin inhibitor in the blood sampling tube to prevent any in vitro angiotensin II generation. With this new methodology it can be demonstrated that after the first administration of a full dose of an angiotensin converting enzyme (ACE) inhibitor, plasma angiotensin II virtually disappears from the circulation, whereas with chronic administration which induces a marked increase in renin secretion and thereby in angiotensin I levels, angiotensin II clearly remains present in plasma at peak inhibition, though at a much lower level than before ACE inhibition. Plasma angiotensin II levels were decreased equally and dose-dependently by the administration of two renin inhibitors, CGP 38560A and A64662. However, in man these compounds have so far only been tested with single administration. In conclusion, the measurement of plasma angiotensin II equally reflects the degree of ACE and renin inhibition, and is therefore the only logical approach to evaluation of the efficacy and potency of ACE inhibitors and renin antagonists.

Angiotensin I↗