scholarly journals HYPOTENSIVE EFFECTIVENESS OF THE INTRARENAL MEDULLARY ENDOTHELIN ETA RECEPTOR BLOCKADE IN THE TWO ANIMAL MODELS OF HYPERTENSION

2021 ◽  
Vol 39 (Supplement 1) ◽  
pp. e16
Author(s):  
Bozena Badzynska ◽  
Janusz Sadowski ◽  
Ivana Vaneckova ◽  
Elzbieta Kompanowska-Jezierska
Keyword(s):  
Animal Models ◽  
Receptor Blockade ◽  
Eta Receptor

scholarly journals End-organ damage in hypertensive transgenic Ren-2 rats: influence of early and late endothelin receptor blockade

2009 ◽  
pp. S69-S78
Author(s):  
Z Vernerová ◽  
P Kujal ◽  
HJ Kramer ◽  
A Bäcker ◽  
L Červenka ◽  
...  
Keyword(s):  
Survival Rate ◽  
Late Onset ◽  
Severe Hypertension ◽  
Organ Damage ◽  
Renal Parenchyma ◽  
Suitable Model ◽  
Receptor Blockade ◽  
End Organ Damage ◽  
Selective Blockade ◽  
Eta Receptor

The rat strain transgenic for the murine Ren-2 renin gene (TGR) is defined as a monogenic model of angiotensin II-dependent hypertension with endogenous activation of the renin-angiotensin system. Homozygous males TGR develop malignant hypertension with a strong salt-sensitive component. These animals show severe hypertension, proteinuria and high mortality. Morphological changes of renal parenchyma correspond to chronic ischemic glomerular changes. Heterozygous TGR develop only mild hypertension and thus provide a more suitable model of hypertension regarding to clinical studies. Within the renal parenchyma, secondary focal segmental glomerulosclerosis (FSGS) predominates. High-salt diet in heterozygous animals induces transition from benign to malignant phase of hypertension. In this case, ischemic glomerular changes are superimposed on preexisting secondary FSGS. In the regression model of hypertension (late-onset treatment) the effect of salt intake is attenuated. In homozygous TGR, early selective ETA receptor blockade decreased blood pressure and ameliorated end-organ damage. Late selective ETA receptor blockade reduced podocyte injury despite final severe hypertension. Survival rate was markedly improved in both regimens with ETA selective blockade, while there was only partial improvement with early non-selective blockade. Both bosentan and atrasentan decreased ET-1 levels in both regimens. In heterozygous TGR, early and late ETA treatment substantially while ETA/ETB treatment partially improved survival rate. Significant effect on BP was found with early and late ETA blockade, while ETA/ETB blockade had no effect. Bosentan and atrasentan similarly decreased ET-1 levels on both regimens. In conclusion, selective ETA receptor blockade is superior to nonselective ETA/ETB receptor blockade in attenuating hypertension and end-organ damage. Its effect is more pronounced when applied early in the life.

Selective ETA vs. dual ETA/B receptor blockade for the prevention of sunitinib-induced hypertension and albuminuria in WKY rats

2019 ◽  
Vol 116 (10) ◽  
pp. 1779-1790 ◽  
Author(s):  
Katrina M Mirabito Colafella ◽  
Karla B Neves ◽  
Augusto C Montezano ◽  
Ingrid M Garrelds ◽  
Richard van Veghel ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Renal Injury ◽  
Angiogenesis Inhibitor ◽  
Receptor Blockade ◽  
Receptor Antagonism ◽  
Sunitinib Treatment ◽  
Wky Rats ◽  
Induced Hypertension ◽  
Eta Receptor ◽  
Stimulation Of

Abstract Aims Although effective in preventing tumour growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin (ET)-1 up-regulation. ET-1 via stimulation of the ETA receptor has pro-hypertensive actions whereas stimulation of the ETB receptor can elicit both pro- or anti-hypertensive effects. In this study, our aim was to determine the efficacy of selective ETA vs. dual ETA/B receptor blockade for the prevention of angiogenesis inhibitor-induced hypertension and albuminuria. Methods and results Male Wistar Kyoto (WKY) rats were treated with vehicle, sunitinib (angiogenesis inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ETA/B receptor antagonist; 30 mg/kg/day) or sitaxentan (selective ETA receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Compared with vehicle, sunitinib treatment caused a rapid and sustained increase in mean arterial pressure of ∼25 mmHg. Co-treatment with macitentan or sitaxentan abolished the pressor response to sunitinib. Sunitinib did not induce endothelial dysfunction. However, it was associated with increased aortic, mesenteric, and renal oxidative stress, an effect that was absent in mesenteric arteries of the macitentan and sitaxentan co-treated groups. Albuminuria was greater in the sunitinib- than vehicle-treated group. Co-treatment with sitaxentan, but not macitentan, prevented this increase in albuminuria. Sunitinib treatment increased circulating and urinary prostacyclin levels and had no effect on thromboxane levels. These increases in prostacyclin were blunted by co-treatment with sitaxentan. Conclusions Our results demonstrate that both selective ETA and dual ETA/B receptor antagonism prevents sunitinib-induced hypertension, whereas sunitinib-induced albuminuria was only prevented by selective ETA receptor antagonism. In addition, our results uncover a role for prostacyclin in the development of these effects. In conclusion, selective ETA receptor antagonism is sufficient for the prevention of sunitinib-induced hypertension and renal injury.

Effects of obesity on endothelium-dependent reactivity during acute nitric oxide synthase inhibition: modulatory role of endothelin

2002 ◽  
Vol 103 (s2002) ◽  
pp. 13S-15S ◽  
Author(s):  
Tobias TRAUPE ◽  
Livius V. D'USCIO ◽  
Klaus MUENTER ◽  
Henning MORAWIETZ ◽  
Wilhelm VETTER ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Carotid Artery ◽  
Vascular Reactivity ◽  
Receptor Blockade ◽  
Obese Mice ◽  
Vascular Rings ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
Oxide Synthase

This study investigated vascular reactivity in response to acetylcholine, in the presence of acute inhibition of nitric oxide synthase, in the carotid artery and aorta of obese C57Bl6/J mice fed on a high-fat diet for 30 weeks, and of control mice. A subgroup of obese animals was also treated with the ETA receptor antagonist darusentan (50mg·kg-1·day-1). In vascular rings from control animals, acetylcholine caused endothelium-dependent contractions in the carotid artery, but not in the aorta. In vascular rings from obese mice, contractility to acetylcholine was also evident in the aorta, and that in the carotid artery was increased compared with control mice. ETA receptor blockade by darusentan treatment of the obese mice prevented enhanced vasoconstriction to acetylcholine, resulting in mild vasodilatation. Thus obesity increases endothelium-dependent vasoconstriction in the absence of endothelial nitric oxide. This effect can be completely prevented by chronic ETA receptor blockade, suggesting that endothelin modulates increased endothelium-dependent vasoconstriction in obesity.

scholarly journals Addition of ETA receptor blockade increases renoprotection provided by renin–angiotensin system blockade in 5/6 nephrectomized Ren-2 transgenic rats

Life Sciences ◽  
2014 ◽  
Vol 118 (2) ◽  
pp. 297-305 ◽  
Author(s):  
Věra Čertíková Chábová ◽  
Zdenka Vernerová ◽  
Petr Kujal ◽  
Zuzana Husková ◽  
Petra Škaroupková ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Receptor Blockade ◽  
Transgenic Rats ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Eta Receptor

Endothelin-1 inhibits endothelium-dependent vasodilatation in the human forearm: reversal by ETA receptor blockade in patients with atherosclerosis

2002 ◽  
Vol 102 (3) ◽  
pp. 321-327 ◽  
Author(s):  
Felix BÖHM ◽  
Gunvor AHLBORG ◽  
John PERNOW
Keyword(s):  
Endothelial Dysfunction ◽  
Venous Occlusion ◽  
Similar Degree ◽  
Receptor Blockade ◽  
Arterial Infusion ◽  
Endothelin 1 ◽  
Enhanced Expression ◽  
Eta Receptor ◽  
Eta Receptor Antagonist

Several cardiovascular disorders, including atherosclerosis, are associated with endothelial dysfunction and enhanced expression of endothelin-1 (ET-1). The role of ET-1 in the development of endothelial dysfunction in vivo remains unclear. The objective of the present study was to investigate the effect of elevated circulating levels of ET-1 on endothelium-dependent vasodilatation (EDV), and to test the hypothesis that ETA receptor antagonism improves EDV in patients with atherosclerosis. EDV and endothelium-independent vasodilatation were determined by brachial artery infusion of acetylcholine and sodium nitroprusside respectively during measurement of forearm blood flow (FBF) with venous occlusion plethysmography. A 60min intra-arterial infusion of ET-1 (n = 10) significantly blunted EDV in young healthy males (33±13% compared with 271±74% increase in FBF induced by 10μg/min acetylcholine; P < 0.01). Noradrenaline, which evoked a similar degree of vasoconstriction, did not attenuate EDV. In a separate set of experiments, a 60min intra-arterial infusion of the selective ETA receptor antagonist BQ123 evoked a significant increase in EDV in patients with atherosclerosis (n = 10; 109±45% compared with 255±101% increase in FBF induced by 10μg/min acetylcholine; P < 0.01), whereas no significant change was observed in healthy age-matched controls (n = 9). Endothelium-independent vasodilatation was not affected by ET-1 or BQ123. These observations demonstrate that elevated levels of ET-1 impair EDV in healthy control subjects. Furthermore, ETA receptor blockade improves EDV in patients with atherosclerosis, indicating that ET-1 attenuates EDV via an ETA-receptor-mediated mechanism.

scholarly journals ETA receptor blockade attenuates the hypertension but not renal dysfunction in DOCA-salt rats

1998 ◽  
Vol 275 (1) ◽  
pp. R245-R252 ◽  
Author(s):  
Graham H. Allcock ◽  
Richard C. Venema ◽  
David M. Pollock
Keyword(s):  
Renal Function ◽  
Creatinine Clearance ◽  
Filtration Rate ◽  
Tap Water ◽  
Receptor Blockade ◽  
Salt Treatment ◽  
Excretory Function ◽  
Salt Hypertension ◽  
Eta Receptor ◽  
Food And Water Intake

Endothelin (ET)-1 has potent renal and systemic vasoconstrictor properties, and thus we investigated whether ET-1 plays a role in increasing blood pressure and decreasing renal function in DOCA-salt hypertension. After a right nephrectomy, rats had DOCA or placebo pellets implanted subcutaneously and were given saline or tap water to drink, respectively. Additional groups of rats were given the ETA receptor antagonist A-127722 in their water. Rats were maintained in metabolic cages for monitoring excretory function and food and water intake. Three weeks after surgery, mean arterial pressure (MAP) was recorded in the conscious rats via a carotid artery catheter. As expected, DOCA-salt rats had significantly higher MAP compared with uninephrectomized controls (197 ± 6 vs. 133 ± 3 mmHg). Creatinine clearance, used as an estimate of glomerular filtration rate, was significantly reduced in DOCA-salt rats (2.9 ± 0.4 vs. 6.8 ± 0.3 dl ⋅ day−1 ⋅ 100 g−1 body wt in controls). ETA receptor blockade with A-127722 significantly reduced MAP (156 ± 8 mmHg) but had no effect on creatinine clearance of DOCA-salt-treated rats (2.8 ± 0.3 dl ⋅ day−1 ⋅ 100 g−1 body wt). Plasma ET-1 levels were significantly raised after DOCA-salt treatment (1.4 ± 0.5 pg/ml vs. 0.4 ± 0.1 pg/ml in controls). A-127722 treatment increased circulating ET-1 levels in both placebo (2.3 ± 0.5 pg/ml) and DOCA-salt (5.6 ± 0.7 pg/ml) rats. However, ET-1 mRNA expression in renal cortical and medullary tissue was not affected by either A-127722 or DOCA-salt treatments. Thus ETA receptors appear to play a role in the maintenance and development of DOCA-salt hypertension but not in the accompanying reduction of renal function.

ETA-receptor blockade prevents matrix metalloproteinase activation late postmyocardial infarction in the rat

2001 ◽  
Vol 280 (3) ◽  
pp. H984-H991 ◽  
Author(s):  
Bruno K. Podesser ◽  
Deborah A. Siwik ◽  
Franz R. Eberli ◽  
Flora Sam ◽  
Soeun Ngoy ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Matrix Metalloproteinase ◽  
Ex Vivo ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Control Group ◽  
Receptor Blockade ◽  
Postmyocardial Infarction ◽  
Eta Receptor ◽  
Stimulation Of

Endothelin (ET) A (ETA) receptors activate matrix metalloproteinases (MMP). Since endothelin-1 (ET) is increased in myocardium late postmyocardial infarction (MI), we hypothesized that stimulation of ETA receptors contributes to activation of myocardial MMPs late post-MI. Three days post-MI, rats were randomized to treatment with the ETA-selective receptor antagonist sitaxsentan ( n = 12) or a control group ( n = 12). Six weeks later, there were rightward shifts of the left ventricular (LV) end-diastolic and end-systolic pressure-volume relationships, as measured ex vivo by the isovolumic Langendorff technique. Both shifts were markedly attenuated by sitaxsentan. In LV myocardium remote from the infarct, the activities of MMP-1, MMP-2, and MMP-9 were increased in the post-MI group, and the increases were prevented by sitaxsentan treatment. Expression of tissue inhibitor of MMP-1 was decreased post-MI, and the decrease was prevented by sitaxsentan treatment. Chronic post-MI remodeling is associated with activation of MMPs in myocardium remote from the infarct. Inhibition of ETAreceptors prevents MMP activation and LV dilation, suggesting that ET, acting via the ETA receptor, contributes to chronic post-MI remodeling by its effects on MMP activity.

Activation of the right ventricular endothelin (ET) system in the monocrotaline model of pulmonary hypertension: response to chronic ETA receptor blockade

2003 ◽  
Vol 105 (6) ◽  
pp. 647-653 ◽  
Author(s):  
Jean-François JASMIN ◽  
Peter CERNACEK ◽  
Jocelyn DUPUIS
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricle ◽  
Right Ventricular ◽  
Ventricular Hypertrophy ◽  
Right Ventricular Hypertrophy ◽  
Lower Percentage ◽  
Receptor Blockade ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
The Right

Although activation of the endothelin (ET) system contributes to pulmonary hypertension, modifications of the cardiopulmonary ET system and its responses to chronic ET receptor blockade are not well known. To investigate this, rats were injected with monocrotaline (60 mg/kg intraperitoneal) or saline, followed with treatment with the selective ETA receptor antagonist LU135252 (LU; 50 mg·kg-1·day-1) or with saline. After 3 weeks, haemodynamics, cardiac hypertrophy, ET-1 levels and cardiopulmonary ET-receptor-binding profile were evaluated. Monocrotaline (n=7) elicited marked pulmonary hypertension and right ventricular hypertrophy compared with controls (n=8). Both variables were substantially attenuated by LU therapy (n=8; P<0.05 for both). After monocrotaline, right ventricular ET-1 levels were more significantly increased than in the left ventricle (+198% compared with +127%; P<0.05). ETB receptor density was augmented (3-fold) in the right ventricle, whereas that of ETA receptors was not affected. LU treatment also significantly attenuated these alterations (P<0.05). In the lungs, ET-1 levels were not increased after monocrotaline, whereas the balance of ETB to ETA receptors was altered, with a trend toward a lower percentage of ETB than in the control rats. LU treatment did not affect these variables in the lungs. Therefore monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy are associated with the up-regulation of ET-1 and ETB receptors in the right ventricle. These alterations are attenuated with the reduction of pulmonary hypertension and right ventricular hypertrophy after chronic blockade of the ETA receptors, supporting the role of the ET system in right ventricular hypertrophy.

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