Renal Hemodynamic Control by Endothelin and Nitric Oxide Under Angiotensin II Blockade in Man

Montanari, Alberto; Carra, Nicoletta; Perinotto, P; Iori, Veronica; Fasoli, Elena; A, Biggi; Novarini, A

doi:10.1161/hy0202.104399

Cited by 15 publications

(17 citation statements)

References 53 publications

(79 reference statements)

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“…11 This same group also provided evidence for ET A -dependent increases in renal vascular resistance in human subjects during AT 1 receptor blockade. 12 Together, these data indicate that regulation of the renal ET system by Ang II may be an important factor in mediating the renal and hypertensive effects of Ang II via stimulation of the ET A receptor. A similar relationship between the renin-angiotensin system and ET in postmenopausal hypertension has recently been reviewed elsewhere.…”

Section: Et-1 In Ang II Hypertensionmentioning

confidence: 79%

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

Pollock

2005

Hypertension

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E ndothelin (ET)-1 is a potent vasoconstrictor and mitogen, and because of these properties, it is thought to play a role in the development of hypertension. 1,2 The vascular endothelium is a major source of ET-1 production, although a variety of other cell types also have been shown to synthesize and release ET-1. ET-1 is believed to act in a paracrine manner on ET A and ET B receptors on smooth muscle, which mediate contraction, cell proliferation, and hypertrophy. Activation of ET B receptors on endothelial cells stimulates the production of prostacyclin and nitric oxide to induce vasorelaxation and inhibition of sodium transport in renal tubules. Given these properties, considerable attention has been paid to the mechanisms of ET-1 action as it relates to the renal control of blood pressure and the pathogenesis of salt-dependent hypertension. Renal ET synthesis is increased in experimental animals maintained on a high-salt diet and ET A receptor antagonists lower arterial pressure primarily in salt-dependent models of hypertension. 1,2 For the past 30 to 40 years, the actions of angiotensin (Ang) II has been arguably the most widely investigated factor in hypertension research. Although physiology textbooks agree on the major actions of Ang II, eg, vasoconstriction and release of aldosterone, recent attention has focused on its ability to stimulate the synthesis of ET-1, 3-5 as well as reactive oxygen species. 6 There are many reactive oxygen species such as superoxide, hydroxyl radical, and hydrogen peroxide that are produced by all cell types and can have profound effects on the vascular system to impact blood pressure regulation. Most recent attention has been paid to the role of superoxide. There are many enzymatic sources of superoxide including NADPH oxidase, xanthine oxidase, nitric oxide synthase, and cytochrome P450. The focus of the current review, however, is be on the interaction between the 2 peptide systems, ET-1 and Ang II, as they relate to oxidative stress. ET-1 in Ang II Hypertension ET-1 and Oxidative StressThe clinical significance of oxidative stress and its role in hypertension was recently reviewed by Touyz, 18 and so the current discussion is limited to the interaction between ET-1, Ang II, and superoxide.Studies from Ortiz et al have shown that the slow pressor response to Ang II is associated with increases in ET, as well as isoprostanes, a marker of lipid oxidation and an index of oxidative stress. 9 These effects could be prevented with bosentan, suggesting a role for ET in mediating the increase in oxidative stress in this model. They went on to demonstrate that antioxidant treatment with the superoxide dismutase mimetic, tempol, or the combination of vitamins C and E reduced Ang II-induced changes in ET expression. 14 Acute administration of tempol also has antihypertensive effects in rats chronically infused with Ang II. 15 Long-term treatment with tempol will lower arterial pressure in several models of hypertension associated with increases in ET production, including chroni...

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Section: Et-1 In Ang II Hypertensionmentioning

confidence: 79%

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

Pollock

2005

Hypertension

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“…The ET and renin-angiotensin systems are known to interact (4), and an in vivo synergistic effect between ETA receptor antagonism and ACE inhibition has been demonstrated in animals (12) and between ET receptor antagonism and angiotensin AT1 receptor antagonism in humans (37). We have shown, in healthy men who were subjected to systemic ACE inhibition with a clinically relevant dose of enalapril, that the effects of ETA receptor blockade on systemic hemodynamics are enhanced.…”

Section: Discussionmentioning

confidence: 91%

“…Montanari et al (37) demonstrated that ETA receptor antagonism can produce renal hemodynamic changes under conditions of angiotensin AT1 receptor blockade and that this action is inhibited by NO synthase inhibition. We demonstrated a similar synergy between ETA receptor antagonism and ACE inhibition, again dependent on NO, but extended this work by showing that this synergistic effect is abolished, for all indices studied, when the ETB receptor is blocked, suggesting that the ETB receptor is crucial to the mechanism of this interaction.…”

Section: Discussionmentioning

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

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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...

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“…[27][28][29] Furthermore, we have shown recently that acute ET A receptor antagonism can reduce proteinuria by an additional Ϸ30% on top of that achieved with optimal treatment with inhibitors of the renin-angiotensin system in subjects with proteinuric CKD. 14 The current study suggests that these effects are maintained longer term and are of a similar magnitude.…”

Section: Discussionmentioning

confidence: 99%

Selective Endothelin-A Receptor Antagonism Reduces Proteinuria, Blood Pressure, and Arterial Stiffness in Chronic Proteinuric Kidney Disease

et al. 2011

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Abstract-Proteinuria is associated with adverse cardiovascular and renal outcomes that are not prevented by current treatments.Endothelin 1 promotes the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism in proteinuric chronic kidney disease patients, assessing proteinuria, blood pressure (BP), and arterial stiffness, key independent, surrogate markers of chronic kidney disease progression and cardiovascular disease risk. In a randomized, double-blind, 3-way crossover study, 27 subjects on recommended renoprotective treatment received 6 weeks of placebo, 100 mg once daily of sitaxsentan, and 30 mg once daily of nifedipine long acting. Twenty-four-hour proteinuria, protein:creatinine ratio, 24-hour ambulatory BP, and pulse wave velocity (as a measure of arterial stiffness) were measured at baseline and week 6 of each treatment. In 13 subjects, renal blood flow and glomerular filtration rate were assessed at baseline and week 6 of each period.

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Renal Hemodynamic Control by Endothelin and Nitric Oxide Under Angiotensin II Blockade in Man

Cited by 15 publications

References 53 publications

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

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

Selective Endothelin-A Receptor Antagonism Reduces Proteinuria, Blood Pressure, and Arterial Stiffness in Chronic Proteinuric Kidney Disease

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