Haemodynamic and hormonal responses to oral enalapril in salt depleted normotensive man.

Rj, MacFadyen; Elliott, HL; Modesti, Pietro Amedeo; Reid, JL

doi:10.1111/j.1365-2125.1993.tb05697.x

Cited by 15 publications

(8 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In salt-depleted subjects, acute ACE inhibition elicits a small but reproducible fall in BP. 35 The similar magnitude of BP fall with oral captopril seen in normal volunteers and in hypertensive subjects in the study of Gainer et al 34 is surprising. We deliberately avoided using a protocol of either salt repletion or depletion because of the possible confounding effects on the activity of the renin-angiotensin system.…”

Section: Discussionmentioning

confidence: 90%

See 1 more Smart Citation

Bradykinin B ₂ Receptor Antagonism Attenuates Blood Pressure Response to Acute Angiotensin-Converting Enzyme Inhibition in Normal Men

et al. 2000

View full text Add to dashboard Cite

Abstract-The physiological effects of angiotensin-converting enzyme (ACE) inhibition may be in part mediated by bradykinin. We investigated the effect of coadministration of the specific bradykinin B 2 receptor antagonist icatibant on hemodynamic and neurohormonal responses to acute intravenous ACE inhibition in normal men on a normal sodium diet. We performed a 4-phase, double-blind, double-dummy, placebo-controlled study in 12 male volunteers. The bradykinin antagonist icatibant (10 mg IV) was coadministered over the first 15 minutes of a 2-hour infusion of the ACE inhibitor perindoprilat (1.5 mg IV). Perindoprilat inhibited ACE activity and elicited the expected changes in active renin concentration and angiotensin peptides. Over the 3 hours after the start of drug infusion, perindoprilat lowered and icatibant increased mean arterial blood pressure (each PϽ0.0005 versus placebo). Coadministration of icatibant attenuated the mean arterial blood pressure response to perindoprilat (PϽ0.0005) but had no effect on neurohormonal responses to perindoprilat. Our study indicates that the bradykinin B 2 receptor antagonist icatibant attenuates the short-term blood pressure-lowering effect of acute ACE inhibition in normal men on a normal sodium diet. Bradykinin B 2 receptor antagonism alone increases resting blood pressure. Bradykinin may be involved in the control of blood pressure in the resting state in humans. (Hypertension. 2000;36:132-136.)Key Words: blood pressure Ⅲ angiotensin-converting enzyme Ⅲ bradykinin Ⅲ icatibant A ngiotensin-converting enzyme (ACE) catalyzes the conversion of angiotensin I (Ang I) to angiotensin II (Ang II) and the breakdown of bradykinin (BK), a potent vasodilator. 1,2 The pharmacological effects of ACE inhibitors may be in part mediated via BK accumulation rather than reduced Ang II formation. 3 There are at least 2 BK receptor subtypes, B 1 and B 2 ; the known biological effect of BK is mediated via the B 2 receptor, 4 the stimulation of which leads to the formation of NO 5 and vasodilator prostaglandins. 6 Icatibant (Hoe140) is a specific B 2 receptor antagonist that inhibits with high potency a variety of B 2 -mediated effects. 7 Icatibant attenuates the hypotensive response to ACE inhibition in the dog 8 and rat 9,10 and inhibits BK-induced vasodilation in a dose-dependent manner in human vascular beds in vivo. 11 The drug has a long duration of action: its half-life of protection against BK-induced hypotension in rats is Ͼ5 hours. 7,10 A possible noncompetitive component to the action of the drug is suggested by flattening of the BK log-dose response curve at high doses. 11,12 The purpose of the present study was to investigate the effect of coadministration of icatibant on the hemodynamic and neurohormonal responses to acute ACE inhibition in normal men. We also sought to assess the possible role of BK in basal blood pressure (BP) control in this situation. We used a protocol of constant-rate intravenous infusion of ACE inhibitor previously used by our group. [13][14][15] By so d...

show abstract

Section: Discussionmentioning

confidence: 90%

“…Our finding of an increase in heart rate after acute ACE inhibition is at odds with findings from previous studies in our unit in patients with heart failure 13,15 and in salt-depleted volunteers. 35 There is no clear explanation for this observation.…”

Section: Discussionmentioning

confidence: 98%

Bradykinin B ₂ Receptor Antagonism Attenuates Blood Pressure Response to Acute Angiotensin-Converting Enzyme Inhibition in Normal Men

et al. 2000

View full text Add to dashboard Cite

show abstract

“…This dose was chosen from data suggesting that it would achieve significant inhibition of serum ACE activity (26,27), with steady-state plasma concentrations reached by 3 to 4 d (28). With this dosing regimen, the maximal effect of enalapril occurs 2 to 3 h after administration and persists for 5 to 7 h (27,29).…”

Section: Drugsmentioning

confidence: 99%

Endothelin A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition Are Synergistic via an Endothelin B Receptor–Mediated and Nitric Oxide–Dependent Mechanism

Goddard¹,

Eckhart²,

Johnston³

et al. 2004

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Abstract. Animal studies suggest that endothelin A (ETA) receptor antagonism and angiotensin-converting enzyme (ACE) inhibition may be synergistic. This interaction and the role of ETB receptors and endothelial mediators were investigated in terms of systemic and renal effects in humans in two studies. In one study, six subjects received placebo, the ETA receptor antagonist BQ-123 alone, and BQ-123 in combination with the ETB receptor antagonist BQ-788 after pretreatment with the ACE inhibitor enalapril (E) or placebo. In the other, six subjects who were pretreated with E received placebo, BQ-123, and BQ-123 with concomitant inhibition of nitric oxide (NO) synthase or cyclo-oxygenase (COX). Both were randomized, double-blind, crossover studies. Mean arterial pressure was reduced by BQ-123, an effect that was doubled during ACE inhibition (mean area under curve Ϯ SEM; BQ-123, Ϫ2.3 Ϯ 1.8%; BQ-123ϩE, Ϫ5.1 Ϯ 1.1%; P Ͻ 0.05 versus placebo). BQ-123 increased effective renal blood flow (BQ-123, Ϫ0.1 Ϯ 2.4%; BQ-123ϩE, 10.9 Ϯ 4.2%; P Ͻ 0.01 versus BQ-123), reduced effective renal vascular resistance (BQ-123, Ϫ1.2 Ϯ 3.1%; BQ-123ϩE, Ϫ12.8 Ϯ 3.0%; P Ͻ 0.01 versus placebo and versus BQ-123), and increased urinary sodium excretion markedly (BQ-123, 2.6 Ϯ 12.8%; BQ-123ϩE, 25.2 Ϯ 12.6%; P Ͻ 0.05 versus BQ-123, P Ͻ 0.01 versus placebo and versus E) only during ACE inhibition. These effects were abolished by both ETB receptor blockade and NO synthase inhibition, whereas COX inhibition had no effect. In conclusion, the combination of ETA receptor antagonism and ACE inhibition is synergistic via an ETB receptormediated, NO-dependent, COX-independent mechanism. The reduction of BP and renal vascular resistance and associated substantial natriuresis make this a potentially attractive therapeutic combination in renal disease.Endothelin-1 (ET-1) is a vasoactive peptide that is produced by the vascular endothelium (1) and acts through two receptors to regulate vascular tone. Vascular smooth muscle ETA and ETB receptors (2,3) mediate vasoconstriction, whereas endothelial ETB receptors mediate vasodilation through generation of nitric oxide (NO) and prostanoids (3). Angiotensin II (Ang II) is another powerful vasoconstrictor involved in the regulation of vascular tone, and there is considerable evidence for an interaction between the endothelin and renin-angiotensin systems (4). Ang II increases ET-1 transcription and secretion in vitro in a variety of cell types, including endothelial and vascular smooth muscle cells (5,6), and ET receptor antagonists attenuate the acute hemodynamic effects of Ang II in rats in vivo (7,8). However, this is by no means a uniform finding (9) and has not been replicated in dogs (10) or humans (11). Data in animals suggest that concomitant ET blockade and angiotensin-converting enzyme (ACE) inhibition produce changes greater than those seen with blockade of either system alone (12-15). In addition, clinical studies that demonstrated major hemodynamic effects of ET receptor antagonists have generally been per...

show abstract

“…R enin release into plasma has been used to investigate the drug dose-dependence of renin-angiotensin system (RAS) inhibition [1][2][3] because the decrease in angiotensin II (Ang II) production at the level of juxtaglomerular cells induced by angiotensin I-converting enzyme (ACE) or renin inhibitors or the displacement of Ang II from Ang II type-1 (AT 1 ) receptors by antagonists interrupts the permanent feedback inhibition of renin release mediated by Ang II. 4 The use of renin release as a sensitive plasma biomarker of an acute RAS blockade has several advantages: (1) it can be used for all class of inhibitors, including the ACE inhibitor-AT 1 receptor antagonist combination 5 and renin inhibitors, 3 provided that renin concentration is measured by immunoradiometric assay; (2) the range of variation for this factor is large, at Ϸ2 orders of magnitude; and (3) it is a more precise measurement than blood pressure (BP), another marker used to quantify the intensity of RAS blockade, especially in sodium-depleted subjects.…”

mentioning

confidence: 99%

Integrating Drug Pharmacokinetics for Phenotyping Individual Renin Response to Angiotensin II Blockade in Humans

et al. 2004

View full text Add to dashboard Cite

Abstract-Renin release into plasma has been used to investigate the drug dose-dependence of renin-angiotensin system inhibition because it is proportional to the interruption of the permanent negative feedback loop of angiotensin II on renin secretion. We investigated the 24-hour between-subject differences in renin profiles by analyzing the time-dependence of individual renin responses in 16 mildly sodium-depleted normotensive subjects exposed in a 4-period crossover study to single oral doses of 8-and 16-mg (C8 and C16) candesartan cilexetil and 80-and 160-mg (V80 and V160) valsartan. C8 had a similar effect to V160 in terms of the increase in active renin concentration and decrease in blood pressure. C16 had the strongest effect and V80 the weakest effect on renin release. Within-and between-subject variability was more marked for valsartan pharmacokinetics than for candesartan pharmacokinetics and influenced variability in renin response. To eliminate some of the variability caused by the pharmacokinetics of each drug, we corrected the area under time curve of plasma renin levels by that of plasma drug levels to obtain an individual normalized index of renin release or "renin/pharmacokinetic index". In these experimental conditions, this index was found to be a reproducible individual characteristic affecting renin response, in addition to the pharmacokinetics and pharmacological properties of angiotensin II type-1 receptor antagonists. The pharmacokinetic-pharmacodynamic model of renin release described here could be of value for the identification and investigation of renin release abnormalities in patients with hypertension and for the comparison of renin-angiotensin system blockers. Key Words: blood pressure Ⅲ renin Ⅲ angiotensin antagonist R enin release into plasma has been used to investigate the drug dose-dependence of renin-angiotensin system (RAS) inhibition 1-3 because the decrease in angiotensin II (Ang II) production at the level of juxtaglomerular cells induced by angiotensin I-converting enzyme (ACE) or renin inhibitors or the displacement of Ang II from Ang II type-1 (AT 1 ) receptors by antagonists interrupts the permanent feedback inhibition of renin release mediated by Ang II. 4 The use of renin release as a sensitive plasma biomarker of an acute RAS blockade has several advantages: (1) it can be used for all class of inhibitors, including the ACE inhibitor-AT 1 receptor antagonist combination 5 and renin inhibitors, 3 provided that renin concentration is measured by immunoradiometric assay; (2) the range of variation for this factor is large, at Ϸ2 orders of magnitude; and (3) it is a more precise measurement than blood pressure (BP), another marker used to quantify the intensity of RAS blockade, especially in sodium-depleted subjects. 5,6 In contrast to the increase in renin concentration observed after RAS blockade, the magnitude of the decrease in BP may be influenced by a placebo effect and offers a limited range of variation (5 to 15 mm Hg).We investigated in detail between-subject d...

show abstract

Haemodynamic and hormonal responses to oral enalapril in salt depleted normotensive man.

Cited by 15 publications

References 13 publications

Bradykinin B ₂ Receptor Antagonism Attenuates Blood Pressure Response to Acute Angiotensin-Converting Enzyme Inhibition in Normal Men

Bradykinin B ₂ Receptor Antagonism Attenuates Blood Pressure Response to Acute Angiotensin-Converting Enzyme Inhibition in Normal Men

Endothelin A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition Are Synergistic via an Endothelin B Receptor–Mediated and Nitric Oxide–Dependent Mechanism

Integrating Drug Pharmacokinetics for Phenotyping Individual Renin Response to Angiotensin II Blockade in Humans

Contact Info

Product

Resources

About

Haemodynamic and hormonal responses to oral enalapril in salt depleted normotensive man.

Cited by 15 publications

References 13 publications

Bradykinin B 2 Receptor Antagonism Attenuates Blood Pressure Response to Acute Angiotensin-Converting Enzyme Inhibition in Normal Men

Bradykinin B 2 Receptor Antagonism Attenuates Blood Pressure Response to Acute Angiotensin-Converting Enzyme Inhibition in Normal Men

Endothelin A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition Are Synergistic via an Endothelin B Receptor–Mediated and Nitric Oxide–Dependent Mechanism

Integrating Drug Pharmacokinetics for Phenotyping Individual Renin Response to Angiotensin II Blockade in Humans

Contact Info

Product

Resources

About

Bradykinin B ₂ Receptor Antagonism Attenuates Blood Pressure Response to Acute Angiotensin-Converting Enzyme Inhibition in Normal Men

Bradykinin B ₂ Receptor Antagonism Attenuates Blood Pressure Response to Acute Angiotensin-Converting Enzyme Inhibition in Normal Men