Effect of human atrial natriuretic factor on renal plasma flow.
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Adult↗
Biomedical subjects
B Waeber
Publications and source records attributed to B Waeber.
Protection by recombinant alpha 1-antitrypsin Ala357 Arg358 against arterial hypotension induced by factor XII fragment.
The specificity of serpin superfamily protease inhibitors such as alpha 1-antitrypsin or C1 inhibitor is determined by the amino acid residues of the inhibitor reactive center. To obtain an inhibitor that would be specific for the plasma kallikrein-kinin system enzymes, we have constructed an antitrypsin mutant having Arg at the reactive center P1 residue (position 358) and Ala at residue P2 (position 357). These modifications were made because C1 inhibitor, the major natural inhibitor of kallikrein and Factor XIIa, contains Arg at P1 and Ala at P2. In vitro, the novel inhibitor, alpha 1-antitrypsin Ala357 Arg358, was more efficient than C1 inhibitor for inhibiting kallikrein. Furthermore, Wistar rats pretreated with alpha 1-antitrypsin Ala357 Arg358 were partially protected from the circulatory collapse caused by the administration of beta-Factor XIIa.
Animals↗
Rapid measurement of total and active renin: plasma concentrations during acute and sustained converting enzyme inhibition with CGS 14824A.
Total and active renin were measured in plasma of 6 normal volunteers before and after acute and sustained angiotensin converting enzyme (ACE) inhibition with CGS 14824A (2 mg and 10 mg p.o. q.d.) or placebo treatment. The same sandwich technique was used for the measurement of both total and active renin using a polyacrylamide-iron-oxide linked monoclonal antibody to trap renin and 125I-labelled second monoclonal antirenin antibodies without or with specificity for active renin. Normal values for supine subjects ranged for active renin between less than 3 pg/ml and 28 pg/ml and for total renin between 73 and 263 pg/ml. Plasma ACE activity was clearly suppressed during 24 hours following both 2 mg and 10 mg CGS 14824A. Active plasma renin reached 6- and 12-fold normal values on days 1 and 7 of treatment with the 10 mg dose. Total renin rose to 150% and 228% respectively at the same time. Inactive renin continued rising during the first day of 10 mg CGS treatment to a final 141% at 24 hours post-drug and didn't change on day 7. Plasma renin activity correlated well with active renin levels (r = 0.92). We conclude that both total and active plasma renin concentrations can now be directly measured with great accuracy within 6 hours.
Adult↗
Pharmacology of converting enzyme inhibitors.
Angiotensin converting enzyme inhibitors were developed to prevent the in vivo generation of angiotensin II and thereby to reduce peripheral vasoconstriction. However, these compounds exert some additional effects that may or may not be angiotensin dependent. These include potential sodium diuresis, bradykinin accumulation, prostaglandin release, blunting of sympathetic activity, parasympathomimetic actions, central effects, redistribution of blood flow toward some particularly important organs. Only the comprehensive assessment of the many complex interactions that exist between the renin-angiotensin and several other regulatory systems reveals the complete therapeutic profile of this class of pharmacologic agents.
Angiotensin-Converting Enzyme Inhibitors↗
Pharmacodynamic and humoral effects of single intravenous doses of captopril in normal subjects.
The blood pressure, heart rate and humoral responses to single intravenous doses of the angiotensin converting enzyme inhibitor captopril were evaluated in 5 volunteers on a free salt intake. Each subject was given at one-week intervals a 1, 5 and 25 mg intravenous dose of captopril as well as the vehicle of captopril. The study was conducted in a single-blind fashion and the order of treatment phases was randomized. Captopril was found to inhibit the renin-angiotensin system in a dose-dependent fashion. A fall in circulating angiotensin II was observed with doses of 1 and 5 mg. Plasma angiotensin II was not detectable 15 min after the 25 mg dose. Acute inhibition of angiotensin converting enzyme with intravenous captopril had no effect on blood pressure and heart rate.
Adult↗
Effect of prolonged angiotensin converting enzyme inhibition on ambulatory blood pressure of normotensive volunteers.
The blood pressure effect of 8-day angiotensin converting enzyme (ACE) inhibition was studied in normotensive healthy volunteers maintained on an unrestricted salt intake. Six volunteers received cilazapril (5 mg/day), 5 perindopril (8 mg/day) and 5 CGS14824A (10 mg/day). The 3 investigational inhibitors were found to have no consistent effect on blood pressure monitored during day-time outside the clinic using a semi-automatic blood pressure recorder (Remler M2000).
Adult↗
Effects of single doses of the converting enzyme inhibitor cilazapril in normal volunteers.
The new converting enzyme inhibitor cilazapril, or RO 31-2848, was evaluated in 14 healthy male volunteers. In a pilot study in two subjects, the inhibiting capacity of single oral doses of 5 and 10 mg on the pressure and heart rate response to exogenous angiotensin I was assessed. Both doses reduced the blood pressure response to angiotensin I to 10% of control within 45 min and for the 4 h tested. In the main study, 12 volunteers each received two single oral doses of cilazapril at a 2-week interval, and plasma converting enzyme and renin activity, blood angiotensin I, plasma immunoreactive angiotensin II and aldosterone were measured serially. Single doses of 1.25, 2.5, 5, and 10 mg of cilazapril were tested in groups of six subjects each. All doses inhibited plasma converting enzyme activity by 90% for at least 8 h and induced the expected pattern of changes of the renin-angiotensin-aldosterone system. Only slight dose-dependent variations in the effect were observed. Basic heart rate and blood pressure were not altered by any of the doses, which all were well tolerated. These data suggest that cilazapril is a very potent and long-acting new converting enzyme inhibitor.
Angiotensin I↗
Pharmacokinetics of the converting enzyme inhibitor cilazapril in normal volunteers and the relationship to enzyme inhibition: development of a mathematical model.
The pharmacokinetics of the new converting enzyme inhibitor cilazapril were investigated in 12 healthy male volunteers. Single oral doses of 1.25, 2.5, 5, and 10 mg of cilazapril were tested in groups of six subjects, each of whom received two different doses. A 2-week interval was allowed between treatments. Plasma levels of cilazaprilat, the active form of cilazapril, were measured for up to 3 days after drug administration. Peak plasma levels and 24-h areas under the curve (AUCs) were almost directly proportional to dose, and the elimination half-life (t1/2) during the first 8 h after dosing was 1.5 h. From 24 h on, there was a prolonged terminal phase with a t1/2 of approximately 50 h, and there was only slight dose-dependency during this phase. These data suggest that the pharmacokinetics of cilazapril are nonlinear. A physiologically realistic model based on saturable binding to converting enzyme was developed to account both for the drug kinetics and for the relationship of the kinetics to the dynamics of plasma converting enzyme inhibition. A number of conclusions relevant to the therapeutic application of cilazapril in hypertension are drawn from the data and from the pharmacokinetic-pharmacodynamic model.
Angiotensin-Converting Enzyme Inhibitors↗
Repeated administration of the converting enzyme inhibitor cilazapril to normal volunteers.
Cilazapril 1.25 and 5.0 mg p.o. q.d. was administered in double-blind fashion to two groups of six normal volunteers on 8 consecutive days. Blood pressure, heart rate, and plasma converting enzyme activity were measured each day prior to drug administration and up to 72 h after the last dose. Plasma renin activity, blood angiotensin I, plasma angiotensin II, and aldosterone as well as plasma cilazaprilat levels were determined on the first and the last day of active treatment at times 0, 4, and 24 h. The drug was very well tolerated by all volunteers. At 4 h postdrug, plasma converting enzyme activity was reduced in dose-dependent fashion on the first and the eighth day; plasma cilazaprilat levels were also clearly dose dependent. Nevertheless, 24 h postdrug cilazaprilat levels were similar on the first and last day of drug administration, and plasma converting enzyme activity was also stable throughout the 8 days. The various components of the renin-angiotensin system responded in the usual fashion. These results provide strong evidence that cilazapril is a very potent and highly effective converting enzyme inhibitor. Doses well below 5 mg/day will probably suffice for therapeutic efficacy. These data also confirm the hypothesis formulated in the preceding article, i.e., that there is no accumulation of the drug with repeated administration despite its long pharmacological half-life (t1/2).
Adult↗
Endotoxin-induced hypotension in rats is not mediated by prekallikrein activation.
To test whether endotoxin decreases blood pressure acutely in rats by activating the plasma kinin-forming system, plasma kallikrein activity was determined in different experimental settings of endotoxemia. Conscious normotensive rats were infused for 45 min with endotoxin (LPS E. coli 0111:B4) at a dose (0.01 mg/min) which had no effect on blood pressure. Additional rats were infused with the vehicle of endotoxin. Plasma prekallikrein activity was measured at the end of the 45 min infusions. In other rats, a bolus intravenous injection of endotoxin (2 mg) was administered following the 45 min infusion of endotoxin or its vehicle. In these two latter groups of rats, plasma prekallikrein activity was determined 15 min after administration of the bolus dose of endotoxin. In rats pretreated with the endotoxin infusion, the bolus dose of endotoxin had no significant effect on blood pressure, whereas rats infused with the vehicle became and remained hypotensive up to the end of the experiment. There was however no significant difference in plasma prekallikrein activity within the different groups of rats. In another group of rats, dextran sulfate (0.25 mg i.v.), which activates factor XII and thereby the conversion of prekallikrein to kallikrein, induced a short-lasting fall in blood pressure. 15 min after administration of dextran sulfate, plasma prekallikrein activity was almost completely suppressed. These results obtained in unanesthetized rats strongly suggest that the blood pressure fall induced by E. coli endotoxin is not due to activation of prekallikrein and consequently of the kinin-forming system.
Animals↗
Acute antihypertensive effect of angiotensin converting enzyme inhibition and calcium entry blockade.
The acute blood pressure response to an angiotensin converting enzyme inhibitor (enalaprilat) was compared in patients with uncomplicated essential hypertension with that obtained under similar conditions with a calcium entry blocker (nifedipine). The patients were studied after a 3 week washout period. At a 48 h interval, each patient received in randomized order either enalaprilat (5 mg i.v.) or nifedipine (10 mg p.o.). Enalaprilat and nifedipine were equally effective in acutely lowering blood pressure. However, good responders to one agent were not necessarily good responders to the other.
Adult↗
Kalemia during combined therapy with an angiotensin converting enzyme inhibitor and a potassium-sparing diuretic.
Both angiotensin converting enzyme (ACE) inhibitors and potassium-sparing diuretics tend to increase serum potassium levels. This retrospective study was undertaken to assess whether these two types of agents can nevertheless be combined safely. Twelve hypertensive patients were treated for 1-70 months (mean = 17) with an ACE inhibitor together with a potassium-sparing diuretic (spironolactone, n = 10; amiloride, n = 2). In addition, eight patients also took a thiazide or a loop diuretic. Nine patients had a normal and three a slightly impaired renal function. No clinically relevant hyperkalemia was observed during the course of the study. These data suggest that it is not impossible to combine an ACE inhibitor with a potassium-sparing diuretic, as long as renal function is normal and serum potassium concentration is monitored closely.
Adult↗
[Extrarenal effects of the atrial natriuretic factor].
The synthesis of peptides which have the natriuretic and vasodilator properties of the atrial natriuretic factor has made it possible to study the physiological role of this recently discovered hormonal system. In addition to renal effects, atrial natriuretic peptides exert vascular, hemodynamic and endocrine actions which may participate in the regulation of plasma and interstitial volume as well as arterial blood pressure. Its acute hypotensive effect, which was observed in normal volunteers and in patients with cardiac failure or hypertension, is not entirely explained by its direct vasodilator effect. The complexity of its role is demonstrated by its inhibiting action on the synthesis and/or the activity of other vasoactive hormones. The observed increase in hematocrit suggests that vascular permeability may be enhanced; the resulting consequences, e.g. on blood viscosity, still need to be elucidated. When infusing atrial natriuretic peptides, there exists a clear delay between the moment steady-state plasma levels are achieved and peak effect occurs. This renders the interpretation of the results very difficult. At this moment, the physiological role of atrial natriuretic peptides as well as their potential future use as therapeutic agents cannot yet be fully appreciated.
Atrial Natriuretic Factor↗
Effect of eight-day converting enzyme inhibition on ambulatory blood pressure recordings in normotensive volunteers.
The three angiotensin converting enzyme (ACE) inhibitors cilazapril, perindopril and CGS 14824A were administered for 8 days to, respectively, 6, 5 and 5 normotensive healthy volunteers maintained on an unrestricted salt intake. Before starting treatment, as well as on the last day of therapy, an ambulatory blood pressure profile was obtained with a semi-automatic blood pressure recorder (Remler M2000). An additional blood pressure recording was performed 1 month after the end of the 8-day course of treatment with cilazapril and CGS 14824A. Eight day ACE inhibition with any of the 3 drugs did not result in a consistent decrease of ambulatory blood pressure recordings. This suggests that in normotensive subjects on a free salt intake the renin-angiotensin system may not be a key determinant of blood pressure.
Adult↗
Angiotensin converting enzyme inhibition and the normal kidney.
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Angiotensin-Converting Enzyme Inhibitors↗
[Attenuation of the vasopressor effect of angiotensin II, vasopressin and alpha 1-adrenergic stimulation by bradykinin].
The role of circulating bradykinin in the regulation of cardiovascular homeostasis was studied in the normotensive conscious rat using a competitive antagonist of bradykinin at the receptor level. This antagonist (B4162) was administered intravenously as a bolus dose of 400 micrograms. This dose was shown to effectively block the hypotensive effect of exogenous bradykinin (2.5 micrograms) for at least 5 min. The bradykinin antagonist was administered at the end of an infusion of angiotensin II (1 ng/min, n = 5, or 12.5 ng/min, n = 6), of methoxamine (0.5 micrograms/min, n = 5, or 4 micrograms/min, n = 6), of lysine vasopressin (0.25 mUI/min, n = 11) or of saline (10 microliter/min, n = 7). The bradykinin antagonist did not change the mean arterial pressure of the control rats. The low doses of angiotensin II and of methoxamine did not have an effect on mean blood pressure. The bradykinin antagonist however increased mean blood pressure of these rats within 1 min by 10 +/- 2 (p less than 0.01, mean +/- SEM) and by 12 +/- 3 (p less than 0.01) mmHg, respectively. The large dose of angiotensin II raised mean blood pressure from 127 +/- 3.6 to 142 +/- 4.9 mmHg and that of methoxamine from 130 +/- 2 to 146 +/- 5 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
[Abdominal pain and hypertension].
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Abdomen, Acute↗
[New data on experimental endotoxic shock].
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Animals↗