The assessment of ACE activity in man following angiotensin I challenges: a comparison of cilazapril, captopril and enalapril.

Essig, J.; Belz, G. G.; Wellstein, Anton

doi:10.1111/j.1365-2125.1989.tb03485.x

Cited by 21 publications

(8 citation statements)

References 13 publications

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“…However, ACE inhibitors substantially decrease blood pressure and total peripheral vascular resistance in normal subjects who are Na+ depleted andlor hypovolemic because their renin-angiotensin system is activated (Atlas et al, 1983). Inhibition of ACE activity by ACE inhibitors dose-dependently suppresses angiotensin I-induced increases in blood pressure in normal subjects, and the extent of the suppression is highly correlated with suppression of plasma ACE activity; in normal subjects a concentration of ACE inhibitor that decreased plasma ACE activity by 75% decreased the blood pressure response to angiotensin I infusion by =60%, thus demonstrating equivalent suppressive effects of ACE inhibitors on plasma and vascular ACE activities (Essig et al, 1989;Massarella et al, 1989;Waterfall, 1989). Since septic shock with endotoxemia decreases renal perfusion pressure and elevates renin and angiotensin I production, inhibition by LPS of vascular ACE activity by 75% should decrease angiotensin I1 production by a similar amount and thus could contribute to the hypotension associated with sepsis.…”

Section: Discussionmentioning

confidence: 95%

Lipopolysaccharides decrease angiotensin converting enzyme activity expressed by cultured human endothelial cells

Watanabe

Lam

Keresztes

et al. 1992

Journal Cellular Physiology

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Angiotensin converting enzyme (ACE) is present on endothelial cells and plays a role in regulating blood pressure in vivo by converting angiotensin I to angiotensin II and metabolizing bradykinin. Since ACE activity is decreased in vivo in sepsis, the ability of lipopolysaccharide (LPS) to suppress endothelial cell ACE activity was tested by culturing human umbilical vein endothelial cells (HUVEC) for 0-72 hr with or without LPS and then measuring ACE activity. ACE activity in intact HUVEC monolayers incubated with LPS (10 micrograms/ml) decreased markedly with time and was inhibited by 33%, 71%, and 76% after 24 hr, 48 hr, and 72 hr, respectively, when compared with control, untreated cells. The inhibitory effect of LPS was partially reversible upon removal of the LPS and further incubation in the absence of LPS. The LPS-induced decrease in ACE activity was dependent on the concentrations of LPS (IC50 = 15 ng/ml at 24 hr) and was detectable at LPS concentrations as low as 1 ng/ml. That LPS decreased the Vmax of ACE in the absence of cytotoxicity and without a change in Km suggests that LPS decreased the amount of ACE present on the HUVEC cell membrane. While some LPS serotypes (Escherichia coli 0111:B4 and 055:B5, S. minnesota) were more potent inhibitors of ACE activity than others (E. coli 026:B6 and S. marcescens), all LPS serotypes tested were inhibitory. These finding suggest that LPS decreases endothelial ACE activity in septic patients; in turn, this decrease in ACE activity may decrease angiotensin II production and bradykinin catabolism and thus play a role in the pathogenesis of septic shock.

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Section: Discussionmentioning

confidence: 95%

Lipopolysaccharides decrease angiotensin converting enzyme activity expressed by cultured human endothelial cells

Watanabe

Lam

Keresztes

et al. 1992

Journal Cellular Physiology

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“…Before dosing and at 3 h, 6 h, 9 h, 12 h and 24 h after administration of study drug exogenous angiotensin II diluted with physiological saline solution was continuously infused in increasing dose steps at 3 min intervals (0.17 up to 20 μg min −1 ) as described in detail previously [15, 17–19]. Three min after dose increase a steady state in blood pressure increase was achieved, as shown even for angiotensin I by Essig et al [19]. The dosage of angiotensin II infusion was discontinued when systolic (SBP) and/or diastolic blood pressure (DBP) had exceeded the baseline value by +25 mmHg or the maximum infusion rate of 20 μg min −1 had been reached.…”

Section: Methodsmentioning

confidence: 99%

Angiotensin II antagonism and plasma radioreceptor‐kinetics of candesartan in man

Malerczyk¹,

Fuchs

Belz³

et al. 1998

Brit J Clinical Pharma

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AimsThe pharmacodynamic properties of the angiotensin II antagonist candesartan in humans were assessed from the rightward shifts of angiotensin II dose-effect curves (Schild regression technique). The pharmacokinetic characteristics were determined by radioreceptor assay (r.r.a.) and h.p. ]-angiotensin II). Before and up to 24 h post dosing angiotensin II was infused in ascending dose steps until blood pressure (systolic and/or diastolic) increased by +25 mmHg. Individual angiotensin II dose-effect curves were fitted according to an E max model and dose ratios (DR) calculated from the antagonist induced rightward shifts. Results Candesartan, the active metabolite of candesartan cilexetil, declined from peak concentrations at about 4 h with a t 1/2 of about 6 h. A linear relation (slope 1) between h.p.l.c. and r.r.a. data revealed that there is no other active metabolite. DR at 6-9 h post dosing reached a maximum of about 30 and at 24 h still amounted to 4-7, indicating the persistence of a relevant antagonistic effect in vivo. The apparent K i -doses (derived from Schild regression plots) indicated a high potency (1.9 mg at 24 h) and slow decline of effect. Between plasma concentrations and antagonistic effect a counterclockwise hysteresis was visible. Conclusions A longer persistence of the antagonistic effect at the receptor site than expected by the presence in plasma indicates a slow off-rate of candesartan cilexetil from in vivo receptors. This provides an additional rationale for the observed 24 h therapeutic activity of candesartan cilexetil.

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“…A single blood pressure measurement was made during the final 2 min of each infusion using a Datascope Accutorr 2A monitor (Datascope, Montvak, NJ, USA). This methodology is based on that of Erb et al [40] and Essig et al [41].…”

Section: Study D: In Vivo Angiotensin Pressor Testingmentioning

confidence: 99%

Evaluation of two carrier protein–angiotensin I conjugate vaccines to assess their future potential to control high blood pressure (hypertension) in man

Downham

Auton

Rosul

et al. 2003

Brit J Clinical Pharma

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Aims We aim to modulate the renin-angiotensin system (RAS) by active immunization against angiotensin I hormone (AI), potentially providing a novel conjugate vaccine treatment for hypertension in man. Methods Immunization studies in rat and human subjects compare the effectiveness of tetanus toxoid (TT) and keyhole limpet haemocyanin (KLH) vaccines for immunotherapy following conjugation with an AI peptide analogue ( AI ). Cardiovascular responses were assessed in immunized rats and human subjects (two-dose trial only), following increasing i.v. infusions of either AI or angiotensin II hormone (AII). Results The AI -TT and AI -KLH conjugate vaccines induced an equivalent immune response, and inhibition of the pressor effects to exogenous AI in rats. Single-dose clinical trials with both conjugate vaccines only resulted in an immune response to the KLH carrier protein. A two-dose clinical trial of AI -KLH conjugate vaccine resulted in a significant immune response to AI . A shift in diastolic blood pressure (DBP) dose-response was demonstrated following challenge with AI and AII for the study volunteer showing the largest anti-AI IgG induction. Conclusion KLH was shown to be a suitable alternative to TT as a carrier protein for AI , thus supporting continued evaluation of our AI -KLH conjugate vaccine for treatment of hypertension in man.

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The assessment of ACE activity in man following angiotensin I challenges: a comparison of cilazapril, captopril and enalapril.

Cited by 21 publications

References 13 publications

Lipopolysaccharides decrease angiotensin converting enzyme activity expressed by cultured human endothelial cells

Lipopolysaccharides decrease angiotensin converting enzyme activity expressed by cultured human endothelial cells

Angiotensin II antagonism and plasma radioreceptor‐kinetics of candesartan in man

Evaluation of two carrier protein–angiotensin I conjugate vaccines to assess their future potential to control high blood pressure (hypertension) in man

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