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Biomedical subjects

B Waeber

Publications and source records attributed to B Waeber.

At least 217 records · Page 12Linked to original sources
PubMed1989

Correlation between plasma concentration of cilazapril and haemodynamic and hormonal effects in healthy man.

1. The haemodynamic and humoral effects of cilazapril, a new angiotensin converting enzyme (ACE) inhibitor, were evaluated in normotensive healthy volunteers. 2. Single oral doses of 1.25, 2.5, 5 and 10 mg of cilazapril inhibited ACE by greater than or equal to 90% and induced the expected pattern of changes of the renin-angiotensin-aldosterone-system. 3. Cilazapril had a long duration of action, since some ACE inhibition was still present 72 h after drug intake. 4. Cilazapril administered intravenously at doses of 5 and 20 micrograms kg-1 for 24 h did not produce any significant effects. 5. During repeated administration of cilazapril for 8 days, no accumulation of cilazaprilat was observed and the clinical tolerance was excellent. 6. In normal volunteers, cilazapril administered orally acts as a potent inhibitor of converting enzyme.

Administration, Oral↗
PubMed1989

Atrial natriuretic peptide and urinary prostaglandins in man.

1. In order to assess the effects of atrial natriuretic factor on the renal biosynthesis of prostaglandins (PG), the urinary excretion of PGE2, PGF2 alpha, 6-keto-PGF1 alpha and thromboxane (Tx)B2 were followed in eight salt-loaded healthy volunteers infused for 2 h with a non hypotensive dose of human atrial natriuretic peptide (hANP, 0.7 nmol min-1). 2. Within 1 h, hANP, infusion produced a marked increase in the urinary PG output, especially of PGE2 and 6-keto-PGF1 alpha (188 +/- 21% and 202 +/- 24% of the pre-infusion values respectively), followed by a significant decrease during the recovery period. 3. No correlations could be uncovered between the urinary excretion of sodium and that of any of the PGs. In contrast, during the infusion of hANP, the urinary output of PGE2 and of 6-keto-PGF1 alpha was found positively related to the urinary flow rate (r = 0.42; P less than 0.05; n = 32 and r = 0.43; P less than 0.05; n = 32 respectively) as well as during the recovery period (r = 0.66, P less than 0.001; n = 32 and r = 0.55; P less than 0.01; n = 32 respectively). 4. It was concluded that, in man, infusion of a non hypotensive dose of hANP is followed by a rise in urinary PG excretion presumably reflecting enhanced renal PG biosynthesis. This increased urinary PG excretion does not seem to be involved in the natriuretic action of hANP but might participate to its diuretic effect.

Adult↗
PubMed1989

Pharmacokinetics of angiotensin converting enzyme inhibitors.

1. The pharmacokinetics of most ACE inhibitors have been evaluated indirectly by the measurements of plasma ACE activity and circulating levels of angiotensin I and II. 2. Although plasma ACE activity is very useful to study the degree and the time-course of ACE inhibition, one has to be aware that very different results can be obtained depending on the substrate employed in the assay. It is therefore impossible to compare the results of different inhibitors unless an identical methodology is used. 3. A clear dissociation between plasma angiotensin II levels and the antihypertensive effects of ACE inhibitors has been reported. This observation is in part linked to problems with the measurement of angiotensin II. New methods of determination of plasma angiotensin II have now allowed demonstration of the complete disappearance of plasma angiotensin II following acute ACE inhibition. During chronic treatment, however, angiotensin II generation is effectively blocked only during part of the day, but blood pressure remains controlled permanently. 4. Among the different pharmacokinetic characteristics of ACE inhibitors presently available, the route of excretion and to a lesser degree the half-life appear to be the most clinically relevant. However, the importance of the ability of ACE inhibitors to inhibit tissue renin-angiotensin systems remains to be defined.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Measurement of sympathetic nerve activity in the unanesthetized rat.

A new system was developed in our laboratory to continuously monitor intra-arterial pressure, heart rate, and sympathetic nerve activity in unanesthetized rats. The animals were prepared 24 h before the start of the experiments. Sympathoneural traffic was measured at the level of splanchnic nerve. The amplitude of the spikes recorded at this level was utilized to express sympathetic nerve activity. The amplitude of the residual electroneurogram signal present 30 min after the rats were killed was 32 +/- 2 mV (mean +/- SE; n = 11). For analysis, these background values were subtracted from values determined in vivo. The nerve we studied contains postganglionic fibers, since electrical activity decreased in response to ganglionic blockade with pentolinium (1.25 mg/min iv for 4 min). The amplitude of spikes fell by 43 +/- 4% (n = 4). Sympathetic nerve activity was highly reproducible at a 24-h interval (104 +/- 26 vs. 111 +/- 27 mV for the amplitude of spikes; n = 11). Dose-response curves to the alpha 1-stimulant methoxamine and to bradykinin were established in four rats. The increase in blood pressure induced by methoxamine caused a dose-dependent fall in sympathetic nerve activity, whereas the blood pressure reduction resulting from bradykinin was associated with a dose-dependent activation of sympathetic drive. These data therefore indicate that it is possible with out system to accurately measure sympathetic nerve activity in the awake rat, together with intra-arterial pressure and heart rate.

Animals↗
PubMed1989

Clinical pharmacology of ACE inhibition.

The radioimmunological determinations of immunoreactive 'angiotensin II' do not truly reflect angiotensin-(1-8)octapeptide levels, and thus cannot provide an accurate reflection of the efficacy of angiotensin-converting enzyme (ACE) inhibition. Elaborate methods are necessary to measure specifically the octapeptide angiotensin II. This methodology confirms that ACE inhibitors reduce circulating angiotensin II and that tolerance to the angiotensin II-lowering effect of ACE inhibitors does not develop, even after prolonged administration. Furthermore, a marked reduction of angiotensin II levels can be shown even in patients with primary aldosteronism. At peak blockade of ACE, the level of plasma angiotensin II is still related to circulating active renin and angiotensin I. The possible independent role of tissue renin-angiotensin systems in determining vasomotor tone is an interesting hypothesis. However, any discussion of whether tissue or plasma renin determines the pharmacologic effect of ACE inhibitors should be based on the simultaneous measurement of angiotensin-(1-8)octapeptide under steady-state conditions in tissue and plasma.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Hemodynamic and humoral effects of the new renin inhibitor enalkiren in normal humans.

The effect of the renin inhibitor enalkiren (Abbott-64662) was evaluated in eight normal volunteer subjects on a standardized sodium diet (100 mmol/day) by measurement of various components of the renin-angiotensin system and drug levels in plasma. On day 1, vehicle and doses of 0.001, 0.003, and 0.01 mg/kg i.v. were administered within 2 minutes at 90-minute intervals. On day 2, vehicle and doses of 0.01, 0.03, and 0.1 mg/kg i.v. were given. With the higher doses, blood pressure tended to decrease slightly with no change in heart rate. Plasma renin activity and plasma angiotensin-(1-8)octapeptide (angiotensin II) fell markedly in a dose-dependent manner. Inhibition of plasma renin activity was maximal 5 minutes after administration of the drug and persisted 90 minutes after the doses of 0.03 and 0.1 mg/kg. Not surprisingly, there was a close correlation between plasma renin activity and plasma angiotensin II levels (r = 0.81, n = 28, p less than 0.001). In contrast, active and total renin measured directly by monoclonal antibodies rose in dose-related fashion in response to renin inhibition. Pharmacokinetic parameters were calculated using the plasma drug concentrations obtained up to 6 hours after the 0.1 mg/kg dose. By means of a two-compartment model, plasma mean half-life of the drug was estimated at 1.60 +/- 0.43 hours.

Adult↗
PubMed1989

Hemodynamic and biochemical consequences of renin inhibition by infusion of CGP 38560A in normal volunteers.

Hemodynamic and biochemical effects of the new renin inhibitor CGP 38560A (molecular weight 826) were tested in 15 healthy volunteers after a single-blind, randomized, placebo-controlled protocol. At a 2-week interval, groups of five subjects received a 30-minute infusion of either 5% dextrose or CGP 38560A 50, 125, or 250 micrograms/kg. Blood pressure, heart rate, plasma renin activity, active and total renin, angiotensin-(1-8)octapeptide (angiotensin II), and aldosterone were sequentially measured up to 3 hours from the onset of the infusion. There was no consistent change in blood pressure or heart rate. Plasma renin activity and angiotensin II decreased dose dependently, and peak suppression was observed at the end of the infusion of CGP 38560A and after the 250-micrograms/kg dose. Plasma renin activity fell from 1.0 +/- 0.19 (mean +/- SEM) to less than 0.05 ng/ml/hr in all five subjects (p less than 0.001), and angiotensin II fell from 7.7 +/- 1.2 to 2.6 +/- 0.9 femtomole/ml (p less than 0.01). Active renin rose fourfold from 24 +/- 1.9 to 98 +/- 14 pg/ml (p less than 0.001) at the end of the infusion of the high dose. Plasma angiotensin II returned toward its initial values much faster than plasma renin activity and active renin. In conclusion, CGP 38560A was well tolerated. It induced a dose-dependent decrease in angiotensin II and plasma renin activity and a long-lasting and dose-dependent rise in active renin. The doses used did not reduce plasma angiotensin II maximally despite reduction of plasma renin activity to unmeasurable levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Effects of intranasal administration of synthetic (4-28)human atrial natriuretic peptide to normal volunteers.

The effects of intranasal administration of increasing doses of synthetic human natriuretic peptide (4-28 hANP) were studied in six healthy volunteers. The peptide was administered as a nasal spray at doses of 50, 100, 200, and 500 micrograms in ascending order at 48-h intervals. Vehicle was administered by the same route randomly between any two of the doses. Intranasal hANP administration had no effect on either blood pressure, heart rate (HR), or hematocrit. Diuresis did not change consistently, whereas natriuresis tended to rise with vehicle as well as with hANP administration. This was attributed to the infusion of isotonic saline during the experiment. There was no significant increase in plasma ANP levels after intranasal administration of any of the different doses. Thus, no evidence that the atrial natriuretic peptide tested (4-28 hANP) can cross the nasal mucosal barrier was found.

Administration, Intranasal↗
PubMed1989

Bolus injections of synthetic atrial natriuretic peptide in patients with chronic renal failure or nephrotic syndrome.

The diuretic and natriuretic responses to exogenous synthetic atrial natriuretic peptide (ANP) were evaluated in patients with chronic renal failure (CRF) or nephrotic syndrome (NS). Patients were studied after an oral water load (8 ml/kg in CRF and 20 ml/kg in NS patients). A short intravenous bolus of either a placebo or ANP was administered when urine output was stable. In each group of patients, three doses of ANP were injected at 24 h intervals, i.e., 1.0, 1.5, and 2.0 micrograms/kg in the CRF and 1.0, 1.5, and 3.0 micrograms/kg in the NS group. Blood pressure and heart rate were monitored throughout the study and urinary volume and electrolyte excretion were measured every 20 min up to 3 h after the bolus. An acute and transient fall in blood pressure was observed immediately after the ANP injection. It was more pronounced in CRF than in NS patients. In CRF patients, ANP caused only a slight increase in urinary volume (13.5-44% over baseline) but a significant increase in urinary sodium excretion (45-114% over baseline). In NS patients, significant increases in both urine volume (60-105%) and sodium excretion (149-248%) were also found. In these latter patients, the renal response to ANP appeared to be better preserved. The hemodynamic and renal changes induced by ANP occurred mainly during the first 20 min following the ANP administration, when the peak plasma ANP levels were obtained. However, no clear dose-response effect could be evidenced in either group with the three doses of ANP chosen in this study.

Adult↗
PubMed1989

Angiotensin converting enzyme inhibition: discrepancy between antihypertensive effect and suppression of enzyme activity.

With chronic angiotensin converting enzyme (ACE) inhibition, blood pressure remains controlled throughout the day despite intermittent recovery of normal function of the renin-angiotensin system. This has been taken as evidence to suggest that the disappearance of angiotensin II (Ang II) from the circulation is not the main mechanism involved in the blood pressure-lowering action of ACE inhibitors. However, the degree of ACE inhibition is often not reliably estimated by the commonly used measurements of plasma ACE activity in vitro or plasma immunoreactive Ang II levels. The most appropriate method to assess ACE activity seems to be the measurement of the ratio between circulating angiotensin-(1-8)octapeptide and angiotensin I (Ang I) concentrations. The octapeptide and angiotensin I (Ang I) concentrations. The octapeptide Ang II can be measured precisely using high pressure liquid chromatography followed by a radioimmunoassay. Even using such improved methods, with long-term ACE inhibition, there exists a clear dissociation between the time course of ACE inhibition and that of the antihypertensive effect. Although it is attractive to speculate on this basis that other pathways such as blockade of tissue renin or enhanced vasodilator activity are responsible for the antihypertensive effect of ACE inhibitors, it is important to remember that the dissociation between the pharmacokinetic profile and the time course of the antihypertensive effect is not specific for ACE inhibitors and is well known with other agents. Since intermittent reduction of circulating Ang II is still an omnipresent feature of ACE inhibition, it seems at present that ACE inhibitors reduce blood pressure predominantly by this mechanism.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Experience with perindopril in normal volunteers.

The new orally active angiotensin converting enzyme (ACE) inhibitor perindopril was evaluated in normotensive men. Doses of 2 to 16 mg were given once a day for up to one week. Single oral doses of perindopril were found to blunt the pressor response to exogenous angiotensin I in a dose-dependent manner. The drug-induced ACE inhibition, as estimated by the measurement of plasma ACE activity, was maximal 4 to 8 hours post drug intake. ACE activity was still importantly reduced 24 hours after dosing. Plasma levels of angiotensin II and aldosterone decreased significantly whereas plasma renin activity and blood angiotensin I levels rose during peak ACE inhibition induced by the 4 and 8 mg doses. However, circulating levels of angiotensin II returned to baseline 24 hours after dosing, both on the first day of treatment and after one week of administration. ACE inhibition with perindopril did not affect blood pressure and heart rate in any consistent manner. There was no evidence for drug accumulation during repeated administration. The novel ACE inhibitor was well tolerated and produced no change in routine laboratory tests. The long-acting ACE inhibitor perindopril appears therefore to be effective when given orally in a dose range of 4 to 16 mg.

Angiotensin I↗
PubMed1989

Experience with perindopril in normal volunteers.

The new orally active angiotensin converting enzyme (ACE) inhibitor perindopril was evaluated in normotensive men. Doses of 2 to 16 mg were given once a day for up to one week. Single oral doses of perindopril were found to blunt the pressor response to exogenous angiotensin I in a dose-dependent manner. The drug-induced ACE inhibition, as estimated by the measurement of plasma ACE activity, was maximal 4 to 8 hours post drug intake. ACE activity was still markedly reduced 24 hours after dosing. Plasma levels of angiotensin II and aldosterone decreased significantly, whereas plasma renin activity and blood angiotensin I levels rose during peak ACE inhibition induced by the 4 and 8 mg doses. However, circulating levels of angiotensin II returned to baseline values 24 hours after dosing, both on the first day of treatment and after one week of administration. ACE inhibition with perindopril did not consistently affect blood pressure and heart rate. There was no evidence for drug accumulation during repeated administration. The novel ACE inhibitor was well tolerated and produced no change in routine laboratory tests. The long-acting ACE inhibitor perindopril therefore appears to be effective when given orally in a dose range of 4 to 16 mg.

Acetylcholinesterase↗
PubMed1989

Ambulatory blood pressure measurement and antihypertensive therapy.

The traditional basis for assessing the effect of antihypertensive therapy is the blood pressure reading taken by a physician. However, several recent trials have been designed to evaluate the blood pressure lowering effect of various therapeutic agents during the patients' normal daytime activities, using a portable, semi-automatic blood pressure recorder. The results have shown that in a given patient, blood pressure measured at the physician's office often differs greatly from that prevailing during the rest of the day. This is true both in treated and untreated hypertensive patients. The difference between office and ambulatory recorded pressures cannot be predicted from blood pressure levels measured by the physician. Therefore, a prospective study was carried out in patients with diastolic blood pressures that were uncontrolled at the physician's office despite antihypertensive therapy. The purpose was to evaluate the response of recorded ambulatory blood pressure to treatment adjustments aimed at reducing office blood pressure below a pre-set target level. Only patients with high ambulatory blood pressures at the outset appeared to benefit from further changes in therapy. Thus, ambulatory blood pressure monitoring can be used to identify those patients who remain hypertensive only when facing the physician, despite antihypertensive therapy. Ambulatory monitoring could thus help to evaluate the efficacy of antihypertensive therapy and allow individual treatment.

Antihypertensive Agents↗
PubMed1989

Effects of smoking and physical exercise on platelet free cytosolic calcium in healthy normotensive volunteers.

Platelet free cytosolic calcium (PFCC) was measured in 21 healthy volunteers before and after cigarette smoking or physical exercise. The aim was to investigate whether acute blood pressure changes and increases in circulating levels of catecholamines and vasopressin modify PFCC. PFCC was determined using the Quin-2 method. Following cigarette smoking, significant increases in blood pressure, heart rate, plasma epinephrine (35 +/- 18 pg/ml before versus 51 +/- 31 pg/ml after smoking, P less than 0.05, mean +/- s.d.) and vasopressin levels (0.8 +/- 0.3 pg/ml before and 4.2 +/- 4.1 pg/ml after smoking, P less than 0.001) were observed. However, despite these acute hormonal and hemodynamic changes, PFCC remained stable at 156 +/- 55 nmol/l prior to the study and 157 +/- 29 nmol/l and 156 +/- 38 nmol/l at 20 and 80 min post-smoking, respectively. Acute physical exercise led to an increase in heart rate and systolic blood pressure but to a decrease in diastolic pressure. Moreover, a marked increase in plasma norepinephrine levels was observed after exercise (213 +/- 71 pg/ml before versus 747 +/- 501 pg/ml after exercise, P +/- 0.001). Again, PFCC was stable at 185 +/- 56 nmol/l at baseline versus 188 +/- 51 nmol/l at 20 min and 155 +/- 26 nmol/l at 80 min after exercise. These results therefore demonstrate that PFCC is not influenced acutely either by blood pressure increases, or by elevations in circulating catecholamine and vasopressin concentrations.

Adult↗