B. Waeber - Academia.edu (original) (raw)
Papers by B. Waeber
Journal of Hypertension, 2008
Journal of Hypertension, 2013
Ambulatory blood pressure monitoring (ABPM) is being used increasingly in both clinical practice ... more Ambulatory blood pressure monitoring (ABPM) is being used increasingly in both clinical practice and hypertension research. Although there are many guidelines that emphasize the indications for ABPM, there is no comprehensive guideline dealing with all aspects of the technique. It was agreed at a consensus meeting on ABPM in Milan in 2011 that the 34 attendees should prepare a comprehensive position paper on the scientific evidence for ABPM.This position paper considers the historical background, the advantages and limitations of ABPM, the threshold levels for practice, and the cost-effectiveness of the technique. It examines the need for selecting an appropriate device, the accuracy of devices, the additional information and indices that ABPM devices may provide, and the software requirements.At a practical level, the paper details the requirements for using ABPM in clinical practice, editing considerations, the number of measurements required, and the circumstances, such as obesity and arrhythmias, when particular care needs to be taken when using ABPM.The clinical indications for ABPM, among which white-coat phenomena, masked hypertension, and nocturnal hypertension appear to be prominent, are outlined in detail along with special considerations that apply in certain clinical circumstances, such as childhood, the elderly and pregnancy, and in cardiovascular illness, examples being stroke and chronic renal disease, and the place of home measurement of blood pressure in relation to ABPM is appraised.The role of ABPM in research circumstances, such as pharmacological trials and in the prediction of outcome in epidemiological studies is examined and finally the implementation of ABPM in practice is considered in relation to the issue of reimbursement in different countries, the provision of the technique by primary care practices, hospital clinics and pharmacies, and the growing role of registries of ABPM in many countries.
Journal of Human Hypertension, 2010
Journal of Hypertension, 2008
Journal of Hypertension, 2013
Journal of Human Hypertension, 2010
Journal of Cardiovascular Pharmacology, 1982
We investigated in conscious normotensive rats the effect of SKF64139 (2 mg i.v.), a potent pheny... more We investigated in conscious normotensive rats the effect of SKF64139 (2 mg i.v.), a potent phenylethanolamine N-methyltransferase (PNMT) inhibitor, on blood pressure responses to norepinephrine (40, 80, and 160 ng i.v.); methoxamine (2.5, 5 and 10 micrograms i.v.), a directly active sympathomimetic agent that is not taken up by adrenergic nerves; and tyramine (20, 40, and 80 micrograms i.v.), an indirectly acting sympathomimetic amine. The pressor effect of norepinephrine was not changed by 2 mg of SKF64139, while those of methoxamine and tyramine were significantly reduced. The dose-response curve to exogenous norepinephrine was also evaluated following blockade of norepinephrine uptake in the nerve endings using 0.25 mg desipramine i.v. This dose of desipramine had no effect on blood pressure increase induced by methoxamine. In rats pretreated with the neuronal uptake inhibitor desipramine in a dose that did not affect alpha-adrenoceptors, SKF64139 significantly decreased the pressor responses to norepinephrine. Increasing the dose of SKF64139 to 8 mg i.v. resulted in a significant fall in base-line blood pressure and in a blunted blood pressure response to norepinephrine. These data demonstrate that in vivo the PNMT inhibitor SKF64139 blocks alpha-adrenoceptors and inhibits neuronal uptake. The alpha-adrenoceptor blocking properties of SKF65139 are masked by simultaneous blockade of norepinephrine uptake when agonists with affinity for the uptake system are used. These findings need to be taken into account when interpreting cardiovascular effects of the PNMT inhibitor SKF64139.
Journal of Cardiovascular Pharmacology, 1988
The present study was designed to assess in conscious normotensive rats the influence of various ... more The present study was designed to assess in conscious normotensive rats the influence of various pressor agents on the acute blood pressure response to a bradykinin antagonist (B4162). This antagonist was used at a dose (400 micrograms i.v.) which had been previously shown to block the blood pressure lowering effect of exogenous bradykinin for several minutes. In control rats, the bradykinin antagonist had no effect on blood pressure. However, in rats pretreated with nonpressor doses of angiotensin II or methoxamine or with pressor doses of vasopressin or methoxamine, the same antagonist significantly increased blood pressure by 10 +/- 2.2, 12 +/- 2.7, 9 +/- 1.7, and 16 +/- 3.4 mm Hg, respectively. It therefore appears that circulating bradykinin is not directly involved in blood pressure regulation of conscious normotensive rats. Endogenous bradykinin may however play an important role in blood pressure control by attenuating the pressor effect of angiotensin II, vasopressin, and alpha-adrenoceptor stimulation.
Journal of Cardiovascular Pharmacology, 1989
The diuretic and natriuretic responses to exogenous synthetic atrial natriuretic peptide (ANP) we... more 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.
Journal of Cardiovascular Pharmacology, 1987
Cilazapril 1.25 and 5.0 mg p.o. q.d. was administered in double-blind fashion to two groups of si... more 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).
Journal of Cardiovascular Pharmacology, 1987
The pharmacokinetics of the new converting enzyme inhibitor cilazapril were investigated in 12 he... more 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.
Journal of Cardiovascular Pharmacology, 1987
The new converting enzyme inhibitor cilazapril, or RO 31-2848, was evaluated in 14 healthy male v... more 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.
Hypertension, 1990
The reaction of the renin-angiotensin system to acute angiotensin converting enzyme inhibition wa... more 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 n/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< 0.001). Thus, plasma angiotensin II truly reflects the resetting of the reninangiotensin system at any degree of converting enzyme inhibition. The ratio of plasma angiotensin II to angietensin I represents converting enzyme inhibition more accurately than in vitro assays, which vary considerably depending on substrates and assay conditions used.
Hypertension, 1981
Sixteen patients with refractory hypertension were submitted to vigorous sodium depletion while c... more Sixteen patients with refractory hypertension were submitted to vigorous sodium depletion while cardiovascular homeostasis was monitored with measurements of hormonal and hemodynamic parameters and repeat saralasin tests. This regimen resulted in a negative sodium balance by an average of 300 mEq. The loss of sodium closely correlated to the decrease of body weight (r = 0.70, p less than 0.005). Blood pressure (BP) decreased from 176/166 +/- 8/3 to 155/109 +/-6/3 mm Hg. There was a significant correlation between percent increments in plasma renin activity (PRA) and the rise in plasma norepinephrine (r = 0.68, p less than 0.05) and a close negative correlation between percent increase in PRA and the ratio of fall in mean blood pressure (MAP) per unit of weight loss (r = -0.73, p less than 0.005). Thus, patients with the least percent increase in PRA demonstrated the greatest fall in BP per unit of weight loss, indicating that relative rather than absolute elevation of renin may be the factor limiting antihypertensive efficacy of sodium depletion. Sodium depletion induced increase in peripheral resistance and decrease in cardiac output, both mostly attributable to relative hyperreninemia. Indeed, the adverse hemodynamic changes were reversed by angiotensin inhibition, during which BP normalized. It is concluded that vigorous sodium depletion complemented by angiotensin blockade or suppression with sympatholytic agents improves management of otherwise refractory hypertension.
American Journal of Kidney Diseases, 1995
0 The acute renal tubular effects of two pharmacologically distinct angiotensin II receptor antag... more 0 The acute renal tubular effects of two pharmacologically distinct angiotensin II receptor antagonists have been evaluated in normotensive volunteers on various salt diets. In the first study, the renal response to a single oral dose of l~rtan (100 mg) was assessed in subjects on a low (50 mmol Na/d) and on a high (200 mmol NaAl) salt intake. In a second protocol, the renal effects of 50 mg irbesartan were investigated in subjects receiving a 100 mmol Na/d diet Both angiotensin II antagonists induced a significant increase in urinary sodium excretion. Wii losattan, a modest, transient increase in urinary potassium and a significant increase in uric acid excretion were found. In contrast, no change in potassium and uric acid excretions were observed with irbesartan, suggesting that the effects of losartan on potassium and uric acid are due to the intrinsic pharmacologic properties of losartan rather than to the specific blockade of renal angiotensin II receptors. Assessment of segmental sodium reabsorption using lithium as a marker of proximal tubular reabsorption demonstrated a decreased distal reabsotption of sodium with both antagonists. A direct proximal tubular natriuretic eftect of the angiotensin II antagonist could be demonstrated only with irbesartan. This apparent discrepancy allowed us to reveal the importance of acute water loading as a possible confounding factor in renal studies. The results of the present analysis show that acute water loading per se may enhance renal sodium excretion and hence modii the level of activity of the renin-angiotensin system expected from a given sodium diet. Since acute water loading is a common practice in clinical renal studies, this confounding factor should be taken into account when investigating the renal effects of vasoactive systems. 0 1995 by the National Kidney Foundation, Inc.
Assessment & Evaluation in Higher Education, 2004
... DOI: 10.1080/0260293032000158207 Catherine Krantz-girod a , Raphae¨l Bonvin a , Jacques Lanar... more ... DOI: 10.1080/0260293032000158207 Catherine Krantz-girod a , Raphae¨l Bonvin a , Jacques Lanares a , Seágoleine Cueánot a , Franc¸ois Feihl a , Fred Bosman a &amp; Bernard Waeber * a * pages 123-133. Available online ...
Journal of Hypertension, 2008
Journal of Hypertension, 2013
Ambulatory blood pressure monitoring (ABPM) is being used increasingly in both clinical practice ... more Ambulatory blood pressure monitoring (ABPM) is being used increasingly in both clinical practice and hypertension research. Although there are many guidelines that emphasize the indications for ABPM, there is no comprehensive guideline dealing with all aspects of the technique. It was agreed at a consensus meeting on ABPM in Milan in 2011 that the 34 attendees should prepare a comprehensive position paper on the scientific evidence for ABPM.This position paper considers the historical background, the advantages and limitations of ABPM, the threshold levels for practice, and the cost-effectiveness of the technique. It examines the need for selecting an appropriate device, the accuracy of devices, the additional information and indices that ABPM devices may provide, and the software requirements.At a practical level, the paper details the requirements for using ABPM in clinical practice, editing considerations, the number of measurements required, and the circumstances, such as obesity and arrhythmias, when particular care needs to be taken when using ABPM.The clinical indications for ABPM, among which white-coat phenomena, masked hypertension, and nocturnal hypertension appear to be prominent, are outlined in detail along with special considerations that apply in certain clinical circumstances, such as childhood, the elderly and pregnancy, and in cardiovascular illness, examples being stroke and chronic renal disease, and the place of home measurement of blood pressure in relation to ABPM is appraised.The role of ABPM in research circumstances, such as pharmacological trials and in the prediction of outcome in epidemiological studies is examined and finally the implementation of ABPM in practice is considered in relation to the issue of reimbursement in different countries, the provision of the technique by primary care practices, hospital clinics and pharmacies, and the growing role of registries of ABPM in many countries.
Journal of Human Hypertension, 2010
Journal of Hypertension, 2008
Journal of Hypertension, 2013
Journal of Human Hypertension, 2010
Journal of Cardiovascular Pharmacology, 1982
We investigated in conscious normotensive rats the effect of SKF64139 (2 mg i.v.), a potent pheny... more We investigated in conscious normotensive rats the effect of SKF64139 (2 mg i.v.), a potent phenylethanolamine N-methyltransferase (PNMT) inhibitor, on blood pressure responses to norepinephrine (40, 80, and 160 ng i.v.); methoxamine (2.5, 5 and 10 micrograms i.v.), a directly active sympathomimetic agent that is not taken up by adrenergic nerves; and tyramine (20, 40, and 80 micrograms i.v.), an indirectly acting sympathomimetic amine. The pressor effect of norepinephrine was not changed by 2 mg of SKF64139, while those of methoxamine and tyramine were significantly reduced. The dose-response curve to exogenous norepinephrine was also evaluated following blockade of norepinephrine uptake in the nerve endings using 0.25 mg desipramine i.v. This dose of desipramine had no effect on blood pressure increase induced by methoxamine. In rats pretreated with the neuronal uptake inhibitor desipramine in a dose that did not affect alpha-adrenoceptors, SKF64139 significantly decreased the pressor responses to norepinephrine. Increasing the dose of SKF64139 to 8 mg i.v. resulted in a significant fall in base-line blood pressure and in a blunted blood pressure response to norepinephrine. These data demonstrate that in vivo the PNMT inhibitor SKF64139 blocks alpha-adrenoceptors and inhibits neuronal uptake. The alpha-adrenoceptor blocking properties of SKF65139 are masked by simultaneous blockade of norepinephrine uptake when agonists with affinity for the uptake system are used. These findings need to be taken into account when interpreting cardiovascular effects of the PNMT inhibitor SKF64139.
Journal of Cardiovascular Pharmacology, 1988
The present study was designed to assess in conscious normotensive rats the influence of various ... more The present study was designed to assess in conscious normotensive rats the influence of various pressor agents on the acute blood pressure response to a bradykinin antagonist (B4162). This antagonist was used at a dose (400 micrograms i.v.) which had been previously shown to block the blood pressure lowering effect of exogenous bradykinin for several minutes. In control rats, the bradykinin antagonist had no effect on blood pressure. However, in rats pretreated with nonpressor doses of angiotensin II or methoxamine or with pressor doses of vasopressin or methoxamine, the same antagonist significantly increased blood pressure by 10 +/- 2.2, 12 +/- 2.7, 9 +/- 1.7, and 16 +/- 3.4 mm Hg, respectively. It therefore appears that circulating bradykinin is not directly involved in blood pressure regulation of conscious normotensive rats. Endogenous bradykinin may however play an important role in blood pressure control by attenuating the pressor effect of angiotensin II, vasopressin, and alpha-adrenoceptor stimulation.
Journal of Cardiovascular Pharmacology, 1989
The diuretic and natriuretic responses to exogenous synthetic atrial natriuretic peptide (ANP) we... more 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.
Journal of Cardiovascular Pharmacology, 1987
Cilazapril 1.25 and 5.0 mg p.o. q.d. was administered in double-blind fashion to two groups of si... more 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).
Journal of Cardiovascular Pharmacology, 1987
The pharmacokinetics of the new converting enzyme inhibitor cilazapril were investigated in 12 he... more 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.
Journal of Cardiovascular Pharmacology, 1987
The new converting enzyme inhibitor cilazapril, or RO 31-2848, was evaluated in 14 healthy male v... more 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.
Hypertension, 1990
The reaction of the renin-angiotensin system to acute angiotensin converting enzyme inhibition wa... more 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 n/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< 0.001). Thus, plasma angiotensin II truly reflects the resetting of the reninangiotensin system at any degree of converting enzyme inhibition. The ratio of plasma angiotensin II to angietensin I represents converting enzyme inhibition more accurately than in vitro assays, which vary considerably depending on substrates and assay conditions used.
Hypertension, 1981
Sixteen patients with refractory hypertension were submitted to vigorous sodium depletion while c... more Sixteen patients with refractory hypertension were submitted to vigorous sodium depletion while cardiovascular homeostasis was monitored with measurements of hormonal and hemodynamic parameters and repeat saralasin tests. This regimen resulted in a negative sodium balance by an average of 300 mEq. The loss of sodium closely correlated to the decrease of body weight (r = 0.70, p less than 0.005). Blood pressure (BP) decreased from 176/166 +/- 8/3 to 155/109 +/-6/3 mm Hg. There was a significant correlation between percent increments in plasma renin activity (PRA) and the rise in plasma norepinephrine (r = 0.68, p less than 0.05) and a close negative correlation between percent increase in PRA and the ratio of fall in mean blood pressure (MAP) per unit of weight loss (r = -0.73, p less than 0.005). Thus, patients with the least percent increase in PRA demonstrated the greatest fall in BP per unit of weight loss, indicating that relative rather than absolute elevation of renin may be the factor limiting antihypertensive efficacy of sodium depletion. Sodium depletion induced increase in peripheral resistance and decrease in cardiac output, both mostly attributable to relative hyperreninemia. Indeed, the adverse hemodynamic changes were reversed by angiotensin inhibition, during which BP normalized. It is concluded that vigorous sodium depletion complemented by angiotensin blockade or suppression with sympatholytic agents improves management of otherwise refractory hypertension.
American Journal of Kidney Diseases, 1995
0 The acute renal tubular effects of two pharmacologically distinct angiotensin II receptor antag... more 0 The acute renal tubular effects of two pharmacologically distinct angiotensin II receptor antagonists have been evaluated in normotensive volunteers on various salt diets. In the first study, the renal response to a single oral dose of l~rtan (100 mg) was assessed in subjects on a low (50 mmol Na/d) and on a high (200 mmol NaAl) salt intake. In a second protocol, the renal effects of 50 mg irbesartan were investigated in subjects receiving a 100 mmol Na/d diet Both angiotensin II antagonists induced a significant increase in urinary sodium excretion. Wii losattan, a modest, transient increase in urinary potassium and a significant increase in uric acid excretion were found. In contrast, no change in potassium and uric acid excretions were observed with irbesartan, suggesting that the effects of losartan on potassium and uric acid are due to the intrinsic pharmacologic properties of losartan rather than to the specific blockade of renal angiotensin II receptors. Assessment of segmental sodium reabsorption using lithium as a marker of proximal tubular reabsorption demonstrated a decreased distal reabsotption of sodium with both antagonists. A direct proximal tubular natriuretic eftect of the angiotensin II antagonist could be demonstrated only with irbesartan. This apparent discrepancy allowed us to reveal the importance of acute water loading as a possible confounding factor in renal studies. The results of the present analysis show that acute water loading per se may enhance renal sodium excretion and hence modii the level of activity of the renin-angiotensin system expected from a given sodium diet. Since acute water loading is a common practice in clinical renal studies, this confounding factor should be taken into account when investigating the renal effects of vasoactive systems. 0 1995 by the National Kidney Foundation, Inc.
Assessment & Evaluation in Higher Education, 2004
... DOI: 10.1080/0260293032000158207 Catherine Krantz-girod a , Raphae¨l Bonvin a , Jacques Lanar... more ... DOI: 10.1080/0260293032000158207 Catherine Krantz-girod a , Raphae¨l Bonvin a , Jacques Lanares a , Seágoleine Cueánot a , Franc¸ois Feihl a , Fred Bosman a &amp; Bernard Waeber * a * pages 123-133. Available online ...