Endothelin System–Dependent Cardiac Remodeling in Renovascular Hypertension

Hocher, Berthold; George, Ines; Rebstock, Johannes; Bauch, Alexandra; Schwarz, Anja; Neumayer, Hans‐H.; Bauer, Christian

doi:10.1161/01.hyp.33.3.816

Cited by 120 publications

(89 citation statements)

References 43 publications

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“…21 Cardiac fibrosis is also a consequence of endothelin action resulting from fibroblast stimulation, as demonstrated in the hearts of rats with renal hypertension. 43 Activation of the cardiac endothelin system may initially contribute to improved heart function, but later it may participate in the progression of cardiac failure. 59 In malignant hypertension, endothelin-antagonist treatment was renoprotective.…”

Section: Role Of Et-1 In Target Organ Damage In Experimental Hypertenmentioning

confidence: 99%

“…These results contrast with the lack of effect of endothelin antagonists in renin-dependent 2-kidney 1-clip Goldblatt hypertensive rats, which do not exhibit generalized vascular overexpression of ET-1 24 or respond to endothelin antagonists with blood-pressure lowering. 42,43 Other models that respond to angiotensin antagonism, such as SHR 30 -32 and long-term N -nitro-L-arginine methyl ester (L-NAME)-treated rats, 44 do not seem to have a significant endothelin contribution. Thus, the endothelin system is activated in low-renin, salt-sensitive, and moderate to severe forms of hypertension.…”

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confidence: 99%

“…21 Cardiac fibrosis is also a consequence of endothelin action resulting from fibroblast stimulation, as demonstrated in the hearts of rats with renal hypertension. 43 …”

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confidence: 99%

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Role of endothelin-1 in hypertension

Iglarz

Schiffrin

2003

Current Science Inc

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Abstract-Endothelin-1 (ET-1) is overexpressed in the vascular wall in certain models of experimental hypertension:deoxycorticosterone acetate salt-treated rats, deoxycorticosterone acetate salt-treated spontaneously hypertensive rats (SHR), stroke-prone SHR, Dahl salt-sensitive rats, angiotensin II-infused rats, and 1-kidney 1 clip Goldblatt rats; it is not overexpressed in SHR, 2-kidney 1-clip hypertensive rats, or L-NAME-treated rats. In hypertensive rats without generalized vascular overexpression, however, expression of ET-1 was often enhanced in intramyocardial coronary arteries, suggesting a role of endothelin in myocardial ischemia in hypertension. In rats overexpressing ET-1, ET A/B and ET A -selective receptor antagonists lowered blood pressure and reduced vascular growth, particularly in small arteries, beyond what could be attributed to blood pressure lowering, suggesting a direct effect of ET-1 on growth. Hypertensive rats treated with endothelin antagonists are protected from stroke and renal injury. The ET A/B antagonist bosentan induced blood-pressure reductions in mildly hypertensive patients similar to those achieved with an angiotensinconverting enzyme inhibitor. Moderately to severely hypertensive patients presented with enhanced expression of prepro-ET-1 mRNA in the endothelium of subcutaneous resistance arteries, suggesting that these stages of hypertension may respond particularly well to endothelin antagonism. Hypertensive patients with coronary artery disease have increased arterial expression of ET-1, and increased plasma levels of immunoreactive endothelin have been described in black patients. ET-1 plays an important role in atherosclerosis, for which hypertension is an important risk factor. T he endothelins are potent 21-amino acid vasoconstrictor peptides encoded by 3 genes and produced in many different tissues, particularly the endothelium of blood vessels. 1,2 Endothelin-1 (ET-1), the main endothelin generated in the endothelium, acts in a paracrine or autocrine manner on ET A and ET B receptors on adjacent endothelial or smoothmuscle cells. The genes for ET A and ET B receptors have been cloned. 3,4 ET A and ET B receptors on smooth muscle induce contraction and stimulate proliferation and cell hypertrophy. 5 Endothelial ET B receptors stimulate the production of nitric oxide and prostacyclin and, accordingly, elicit vasorelaxation. 6 It is unclear whether the vasoconstrictor or vasorelaxant action of ET-1 is the predominant physiological effect. This may vary in different vascular beds.Mice in which the ET-1 gene has been inactivated exhibit a slight elevation of blood pressure, 7 which may result from hypoxemia resulting from the craniofacial developmental abnormalities that occur in this experimental paradigm or it may be an expression of a predominant vasodilator action of ET-1. A recent study evaluated this by using crosses of mice heterozygous for targeted disruption of the ET B receptor (Ϫ/ϩ) with mice homozygous for the piebald mutation of the ET B gene (s/s). 8 The prog...

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Section: Role Of Et-1 In Target Organ Damage In Experimental Hypertenmentioning

confidence: 99%

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confidence: 99%

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Role of endothelin-1 in hypertension

Iglarz

Schiffrin

2003

Current Science Inc

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“…ET-1 has been considered to play an important role in several animal models of hypertension (12,14,15) The normalization of BP by ET receptor agonists in various forms of experimental hypertension (14,17) as well as in human essential hypertension (18) demonstrates its impact on the regulation of vascular tone. However, two independent ET-1 transgenic mouse models do not support the concept that the ET system might play an important role in the pathogenesis of hypertension, because these ET-1-overproducing mice are not hypertensive (19,20).…”

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confidence: 99%

Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension

Quaschning

Voß

Relle

et al. 2007

Journal of the American Society of Nephrology

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Endothelin-1 (ET-1) is one of the most potent biologic vasoconstrictors. Nevertheless, transgenic mice that overexpress ET-1 exhibit normal BP. It was hypothesized that vascular effects of ET-1 may be antagonized by an increase of the endothelial counterpart of ET-1, nitric oxide (NO), which is produced by the endothelial NO synthase (eNOS). Therefore, cross-bred animals of ET transgenic mice (ET؉/؉) and eNOS knockout (eNOS؊/؊) mice and were generated, and BP and endothelial function were evaluated in these animals. Endothelium-dependent and -independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings. The tissue ET and NO system was determined in aortic rings by quantitative real-time PCR and Western blotting. Systolic BP was similar in ET؉/؉ and wild-type (WT) mice but was significantly elevated in eNOS؊/؊ mice (117 ؎ 4 mmHg versus 94 ؎ 6 mmHg in WT mice; P < 0.001) and even more elevated in ET؉/؉ eNOS؊/؊ cross-bred mice (130 ؎ 4 mmHg; P < 0.05 versus eNOS؊/؊). Maximum endothelium-dependent relaxation was enhanced in ET؉/؉ mice (103 ؎ 6 versus 87 ؎ 4% of preconstriction in WT littermates; P < 0.05) and was completely blunted in eNOS؊/؊ (؊3 ؎ 4%) and ET؉/؉ eNOS؊/؊ mice (؊4 ؎ 4%), respectively. Endothelium-independent relaxation was comparable among all groups. T he intact endothelium produces a variety of vasoactive substances, such as nitric oxide (NO), thromboxane, and the 21-amino acid peptide endothelin-1 (ET-1). ET-1 is a potent vasoconstrictor (1) and mitogen in vivo and in vitro and exerts its biologic effects via activation of specific receptors: Whereas on vascular smooth muscle cells the predominant ET receptor is the ET A receptor (ET A R) subtype (2,3), contributing to long-lasting vasoconstriction, endothelial cells express the ET B receptor (ET B R), mediating the formation of NO (4) and prostacyclin (5) and featuring the pulmonary clearance of circulating ET-1 (6) as well as the reuptake of ET-1 by endothelial cells (7).Correspondingly, intravenous administration of ET-1 causes a rapid and transient vasodilation followed by a sustained increase in BP (8). In addition to the negative feedback loop via ET B R, ET-1 production in the vascular wall is inhibited by NO (9) and prostacyclin (10) via cGMP-dependent mechanisms. Therefore, the NO system may be considered as the functional counterpart of the ET system (11-16), thus warranting the sub-

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“…53 Experimental data demonstrate that angiotensin II is not only a potent vasoconstrictor but also stimulates cell hypertrophy and proliferation. 9,27,31,33 Thus, high levels of angiotensin II may contribute to vascular hypertrophy, proliferation associated with atherosclerosis, and progressive glomerular sclerosis. Finally, in the poststenotic kidney, one animal study suggests that renal blood flow and GFR may be better preserved with ARBs than ACEI.…”

Section: Antihypertensive Therapymentioning

confidence: 99%

Controversial Treatment of Atherosclerotic Renal Vascular Disease

Dworkin

2006

Hypertension

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A therosclerotic renal artery stenosis (RAS) is a relatively common problem, affecting from 1% to 5% of patients with hypertension. 1,2 Given the high prevalence of hypertension, it follows that there are from 2 million to 4 million individuals with RAS in the United States alone. Autopsy data demonstrate that the incidence of RAS increases with age affecting 18% of individuals between the ages 65 to 74 years and Ͼ40% of those more than age 75. 3 RAS is also common in individuals with vascular disease in other beds and is present in Յ40% of those with overt coronary artery disease, aortoiliac disease, or peripheral vascular disease. 4 -6 At present, the best treatment for RAS is unknown, and, in particular, whether or not revascularization, typically accomplished by angioplasty and stenting, improves clinical outcomes for patients with RAS is unclear. Nevertheless, it is estimated that Ϸ40 000 renal artery angioplasties procedures are performed in the United States each year, which, depending on whether or not the procedure is beneficial, is either far too many or far too few. The purpose of this article is to review current knowledge about atherosclerotic RAS and to discuss the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial, which is examining the best treatment for this disease.

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Endothelin System–Dependent Cardiac Remodeling in Renovascular Hypertension

Cited by 120 publications

References 43 publications

Role of endothelin-1 in hypertension

Role of endothelin-1 in hypertension

Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension

Controversial Treatment of Atherosclerotic Renal Vascular Disease

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