Increased expression of endothelin-1 gene in blood vessels of deoxycorticosterone acetate-salt hypertensive rats.

Lariviere, Richard W.; Day, Robert; Schiffrin, Ernesto L.

doi:10.1161/01.hyp.21.6.916

Cited by 162 publications

(77 citation statements)

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“…Besides Ang II, vasopressin, endothelin (28,29), and the sympathoadrenal system may also contribute to the development and maintenance of DOCA-salt hypertension in rats. Central pathways involving AT1 receptor stimulation may contribute to increases in arginine vasopressin (AVP) and sympathetic activity, which contribute to the increases in BP in DOCA-salt rats (25,40).…”

Section: Discussionmentioning

confidence: 99%

Effects of Centrally Administered Losartan on Deoxycorticosterone-salt Hypertension Rats

Park

Leenen

2001

J Korean Med Sci

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INTRODUCTIONIn deoxycorticosterone acetate (DOCA)-salt hypertensive rats the development and maintenance of hypertension is considered to be independent of the renin-angiotensin system, because plasma renin in this model is low (1), and peripheral administration of angiotensin converting enzyme (ACE) inhibitors (2) or angiotensin (Ang) II receptor antagonists (3) has no effect on blood pressure (BP). However, there is some evidence for a role of the brain renin-angiotensin system in the pathogenesis of DOCA-salt hypertension in rats.DOCA-salt-treated rats show higher Ang II receptor density in brain areas involved in cardiovascular regulation, such as the nucleus of solitary tract, area postrema, median preoptic nucleus, subfornical organ, and solitary vagal area (4-6), and have elevated levels of renin and Ang II in hypothalamus and brain stem nuclei (7,8). Acute intracerebroventricular (icv) administration of captopril decreases the blood pressure of DOCA-salt hypertensive rats (9). Chronic icv administration of captopril attenuates the development of hypertension in DOCA-salt hypertensive rats (10). However, the interpretation of these findings is complicated because ACE is involved in the metabolism of various peptides that may participate in regulating BP, including bradykinin, enkephalin and substance P (11).Three studies assessed the effects of icv Ang II receptor antagonists on BP in DOCA-salt hypertensive rats. Acute icv administration of salarasin did not lower BP during 30 min of follow-up (12). In contrast, injection of losartan icv or into the rostral part of the third ventricle did lower BP for more than 1 hr in 4 weeks DOCA-salt hypertensive rats (13). Moreover, continuous icv infusion of CV-11974 (active metabolite of candesartan) for 7 days lowered BP from the fourth day after infusion (14). However, because hemodynamic measurements in these studies were done under anesthesia in 4 weeks and 6 weeks DOCA-salt hypertensive rats, the role of brain Ang II in the development of the hypertension in the DOCA-salt hypertensive rat model is not known yet.The aim of the present study was to determine the acute central effects of the type 1 Ang II (AT1) receptor antagonist losartan in conscious DOCA-salt hypertensive rats, at either 2 weeks during the development of the hypertension or at 4 weeks in the maintenance phase of the hypertension. MATERIALS AND METHODS AnimalsMale Wistar rats aged 5 weeks, weighing 140-170 g, were J Korean Med Sci 2001; 16: 553-7 ISSN 1011-8934 Copyright � The Korean Academy of Medical Sciences 553 Effects of Centrally Administered Losartan on Deoxycorticosteronesalt Hypertension RatsTo investigate whether brain AT1 receptor stimulation contributes as a hypertensive mechanism to deoxycorticosterone acetate (DOCA)-salt hypertension, losartan (1 mg/4 L) or artificial cerebrospinal fluid (aCSF) was injected into the lateral cerebral ventricle in conscious control uninephrectomized Wistar rats or rats with DOCA-salt for 2 or 4 weeks, and mean arterial pressure (MAP) and heart r...

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Section: Discussionmentioning

confidence: 99%

Effects of Centrally Administered Losartan on Deoxycorticosterone-salt Hypertension Rats

Park

Leenen

2001

J Korean Med Sci

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“…176,177 The ET system is activated in several but not all animal models of arterial hypertension. 171,[178][179][180][181][182][183][184][185][186][187] Correspondingly, ET plasma levels have been reported to be elevated in certain patients with essential hypertension, 188 but this is a subject to controversy. 60,189 The causal role of ET-1 in the pathogenesis of hypertension thus remains unclear.…”

Section: Endothelin and Endothelin Antagonists In Hypertensionmentioning

confidence: 99%

Working under pressure: the vascular endothelium in arterial hypertension

et al. 2000

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The vascular endothelium synthesizes and releases a spectrum of vasoactive substances like nitric oxide (NO) and endothelin (ET). In hypertension, the delicate balance of endothelium-derived factors is disturbed. ET acts as the natural counterpart to endothelium-derived NO, which exerts vasodilating, antithrombotic, and antiproliferative effects, and inhibits leukocyte-adhesion to the vascular wall. Besides its blood pressure rising effect also in man, ET induces vascular and myocardial hypertrophy, which are independent risk factors for cardiovascular morbidity and mortality. The derangement of endothelial function in hypertension is likely to be caused in part by genetic factors, but also due to elevated blood pressure itself. Due to its position between blood pressure and smooth muscle cells responsible for peripheral resistance, the endothelium is thought to be both target and mediator of arterial hypertension. Oxi-

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“…Specifically, salt-sensitive models and those with severe hypertension appear to be the ones in which ET-1 plays a role. One model of salt-dependent hypertension is the deoxycorticosterone acetate-salt hypertensive rat, which has enhanced expression of ET-1, hypertrophic remodeling of blood vessels, vascular reactive oxygen species (ROS) accumulation and endothelial dysfunction (6,25,26,50).The generation of transgenic mice overexpressing the human preproET-1 selectively in the endothelium (eET-1) has allowed a greater understanding of the direct vascular effects of ET-1, since this mouse model is normotensive and therefore there is no confounding effect of BP elevation on vascular changes (3). The study of 10 wk old male mice revealed vascular hypertrophic remodeling, endothelial dysfunction, and ROS accumulation (3).…”

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confidence: 99%

Vascular gene expression in mice overexpressing human endothelin-1 targeted to the endothelium

Simeone

Li²,

Paradis³

et al. 2011

Physiological Genomics

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Simeone SM, Li MW, Paradis P, Schiffrin EL. Vascular gene expression in mice overexpressing human endothelin-1 targeted to the endothelium. Physiol Genomics 43: 148 -160, 2011. First published November 2, 2010; doi:10.1152/physiolgenomics.00218.2009.-Endothelin (ET)-1 plays an important pathophysiological role in several vascular diseases including hypertension and atherosclerosis. Transgenic mice overexpressing human preproET-1 selectively in the endothelium (eET-1) exhibit vascular injury in the absence of blood pressure elevation. ET-1 overexpression may induce vascular injury by inducing changes in gene expression. To understand mechanisms whereby ET-1 induces vascular damage, vascular gene expression profiling was performed using DNA microarrays. RNA from mesenteric arteries of male and female young (6 -7 wk) and mature (6 -8 mo) eET-1 and wild-type (WT) mice was isolated, and changes in gene expression were determined by genome-wide expression profiling using Illumina microarray and FlexArray software. Data were analyzed using a relaxed and a stringent statistical approach. The gene lists were compared and analyzed as well with Ingenuity Pathway Analysis. The most common change was an increase in the expression of lipid metabolism genes. Four of these genes were validated by qPCR, cyp51, dgat2, and scd1 genes in young and elovl6 in both young and mature male mice, supporting a role of ET-1 in atherosclerosis. To test the hypothesis that ET-1 participates in mechanisms leading to atherosclerosis, we crossed eET-1 with atherosclerosisprone apoE Ϫ/Ϫ mice to determine whether ET-1 overexpression exacerbates high-fat diet (HFD)-induced atherosclerosis using oil red O staining of descending thoracic aorta. HFD increased lipid plaques by 3-, 27-, and 86-fold in eET-1, apoE Ϫ/Ϫ , and crossed mice, respectively, vs. WT. This suggests that increased endothelial ET-1 expression results in early changes in gene expression in the vascular wall that enhance lipid biosynthesis and accelerate progression of atherosclerosis. aorta; artery; lipid biosynthesis; vascular remodeling; inflammation; atherosclerosis ESSENTIAL HYPERTENSION IS characterized by increased peripheral resistance to blood flow (48). The vasoconstrictor peptide endothelin-1 (ET-1) (58), which has a critical role in normal development and probably in regulation of blood flow in normal physiology (24), has been associated with increased blood pressure (BP) in human and experimental animal studies (1, 47). ET-1 has also been implicated in other pathophysiological conditions such as pulmonary hypertension (16), atherosclerosis (4, 22, 56), heart failure (17,19,35,46,52), myocardial infarction (8, 34), and chronic renal failure (1, 11, 37), among others (49). ET-1 is produced predominantly by endothelial cells but also by many other cells and tissues such as vascular smooth muscle cells, fibroblasts, macrophages/ monocytes and cardiomyocytes, as well as noncardiovascular cells and tissues such as renal tubular epithelial cells, glial cells, and pituitary cell...

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Increased expression of endothelin-1 gene in blood vessels of deoxycorticosterone acetate-salt hypertensive rats.

Cited by 162 publications

References 24 publications

Effects of Centrally Administered Losartan on Deoxycorticosterone-salt Hypertension Rats

Effects of Centrally Administered Losartan on Deoxycorticosterone-salt Hypertension Rats

Working under pressure: the vascular endothelium in arterial hypertension

Vascular gene expression in mice overexpressing human endothelin-1 targeted to the endothelium

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