Inhibition of Endothelin ET<sub>B</sub>Receptor System Aggravates Neointimal Hyperplasia after Balloon Injury of Rat Carotid Artery

Kitada, Kento; Yui, Nozomi; Matsumoto, Chika; Mori, Tatsuhiko; Ohkita, Mamoru; Matsumura, Yasuo

doi:10.1124/jpet.109.157065

Cited by 22 publications

(31 citation statements)

References 37 publications

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“…On the contrary, our results suggest that ET-A/B blocker therapy significantly diminished the beneficial effects of PTRAS or ET-A receptor blockade on the stented kidney, implying that ET-B receptors are necessary to protect the kidney 28 It is possible that addition of ET-B receptor antagonism after PTRAS might have triggered AKI 29 or exacerbated eventual reperfusion injury 30 that was minimized in this model by single ET-A blockade, suggesting a potential interaction between both receptors in controlling renal damage. 9 Another possibility is that the addition of ET-B blockade exacerbated MV remodeling 31 and thus, intrarenal MV resistance in the poststenotic kidney, which may have also played a role later in the minimal or even negative changes in RBF or GFR 4 weeks after PTRAS. A prolonged and possibly exacerbated vasoconstriction 29 after ET-B antagonism may have also helped to aggravate MV rarefaction, which may have contributed to the persistence of renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Endothelin-A Receptor Antagonism after Renal Angioplasty Enhances Renal Recovery in Renovascular Disease

Chade¹,

Tullos²,

Stewart³

et al. 2015

Journal of the American Society of Nephrology

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Percutaneous transluminal renal angioplasty/stenting (PTRAS) is frequently used to treat renal artery stenosis and renovascular disease (RVD); however, renal function is restored in less than one half of the cases. This study was designed to test a novel intervention that could refine PTRAS and enhance renal recovery in RVD. Renal function was quantified in pigs after 6 weeks of chronic RVD (induced by unilateral renal artery stenosis), established renal damage, and hypertension. Pigs with RVD then underwent PTRAS and were randomized into three groups: placebo (RVD+PTRAS), chronic endothelin-A receptor (ET-A) blockade (RVD+PTRAS+ET-A), and chronic dual ET-A/B blockade (RVD+PTRAS+ET-A/B) for 4 weeks. Renal function was again evaluated after treatments, and then, ex vivo studies were performed on the stented kidney. PTRAS resolved renal stenosis, attenuated hypertension, and improved renal function but did not resolve renal microvascular rarefaction, remodeling, or renal fibrosis. ET-A blocker therapy after PTRAS significantly improved hypertension, microvascular rarefaction, and renal injury and led to greater recovery of renal function. Conversely, combined ET-A/B blockade therapy blunted the therapeutic effects of PTRAS alone or PTRAS followed by ET-A blockade. These data suggest that ET-A receptor blockade therapy could serve as a coadjuvant intervention to enhance the outcomes of PTRAS in RVD. These results also suggest that ET-B receptors are important for renal function in RVD and may contribute to recovery after PTRAS. Using clinically available compounds and techniques, our results could contribute to both refinement and design of new therapeutic strategies in chronic RVD. Chronic renovascular disease (RVD) increases the risk of cardiovascular morbidity and mortality and may progressively induce renal injury, leading to ESRD. 1 Percutaneous transluminal renal angioplasty/stenting (PTRAS) is a frequently used therapeutic strategy to treat patients with chronic RVD. Targeting the renal stenosis is a logical choice for treating RVD, because the resolution of the vascular obstruction followed by restoration of blood flow to the site of injured tissues should play an important role to initiate successful repairing responses. The use of PTRAS in RVD grew significantly during the past 20 years, 2 with tremendous progress in successfully resolving renal stenosis and restoring blood flow (.95% of the cases). 3 However, despite the high technical success of PTRAS, improvement in renal function is still observed in a relatively small portion of the cases. 4 The reasons for the persistent poor outcomes after PTRAS in RVD are still unclear. Furthermore, the dissociation between the technical success of PTRAS and renal outcomes underscores a pressing need to identify more effective therapeutic strategies in RVD.Endothelin-1 (ET-1) is a powerful renal vasoconstrictor and mitogenic peptide that plays important roles in controlling BP and renal function.

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Section: Discussionmentioning

confidence: 99%

Endothelin-A Receptor Antagonism after Renal Angioplasty Enhances Renal Recovery in Renovascular Disease

Chade¹,

Tullos²,

Stewart³

et al. 2015

Journal of the American Society of Nephrology

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“…Both selective ET A receptor and ET A /ET B dual receptor antagonists have been indicated to suppress the development of neointimal formation after vascular injury (McKenna et al, 1998;Sanmartin et al, 2003;Kitada et al, 2009). Therefore, there is general agreement that the ET-1/ET A system plays an important role in the development of neointimal formation, although it is disputed which type of antagonist is more effective for the treatment of neointimal formation.…”

Section: Introductionmentioning

confidence: 98%

“…The rats were then gavaged with vehicle, A-192621, ABT-627, or J-104132 for 2 weeks, starting 12 h after the balloon injury. These doses of A-192621, ABT-627, and J-104132 previously have been shown to almost abolish endogenous ET-1-induced neointimal formation (Kitada et al, 2009). In all animals, 2 weeks after the balloon injury, systolic blood pressure (SBP) was measured by the tail-cuff method using a pneumatic pulse transducer (BP-98A; Softron, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…In addition, these changes and values of plasma ET-1 levels by ET receptor antagonists were similar to those observed in male rats. Plasma ET-1 levels of male rats and the effects of ET receptor antagonists were reported in our previous study (Kitada et al, 2009 …”

Section: Downloaded Frommentioning

confidence: 99%

“…Therefore, there is general agreement that the ET-1/ET A system plays an important role in the development of neointimal formation, although it is disputed which type of antagonist is more effective for the treatment of neointimal formation. Most recently, we have demonstrated that the inhibition of ET B receptor-mediated actions by its pharmacological blockade or its genetic deficiency leads to an aggravation of neointimal formation after balloon injury (Kitada et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Endothelin ET_B Receptor Is Involved in Sex Differences in the Development of Balloon Injury-Induced Neointimal Formation

Kitada

Yui²,

Koyama³

et al. 2010

J Pharmacol Exp Ther

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The purpose of this study was to evaluate the involvement of endothelin (ET) B receptor-mediated action in the sex differences in balloon injury-induced neointimal formation using the spotting-lethal rat, which carries a naturally occurring deletion in its ET B receptor gene. Male and female ET B -deficient and wild-type rats underwent balloon injury of the carotid artery. In the wild-type rats, the neointima/media ratio was significantly lower in females than in males, but this sex difference was attenuated by ovariectomy and restored by treatment with 17␤-estradiol (20 g/kg/day). In the ET B -deficient rats, the neointima/media ratio of the male and female rats was markedly increased to the same level, and this increase was not affected by ovariectomy or 17␤-estradiol treatment. Treatment with (ϩ)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl] -5-(3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic acid (J-104132) (10 mg/kg/day), an ET A /ET B dual receptor antagonist, markedly decreased the neointima/media ratio of the male wild-type rats and the male and female ET Bdeficient rats, but not the female wild-type rats. In addition, 2R-(4-propoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N-(2,6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (A-192621) (30 mg/kg/day), a selective ET B receptor antagonist, abolished the sex difference of balloon injuryinduced neointimal formation. 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT-627) (10 mg/kg/day), a selective ET A receptor antagonist, and J-104132 (10 mg/kg/ day) markedly decreased the neointima/media ratio to the same extent in males but not intact females. These results indicate that the sex difference in balloon injury-induced neointimal formation was abolished by genetic ET B receptor deficiency or its pharmacological blockade. The lack of a vasoprotective effect of estrogen and the augmentation of ET A receptormediated action seem to be responsible for the abolition of sex differences in the ET B receptor-inhibited condition.

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The Role of Endothelin-1 and Endothelin Receptor Antagonists in Inflammatory Response and Sepsis

Kowalczyk

Kleniewska

Kołodziejczyk

et al. 2014

Arch. Immunol. Ther. Exp.

229

150

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Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor, mainly secreted by endothelial cells. It acts through two types of receptors: ETA and ETB. Apart from a vasoconstrictive action, ET-1 causes fibrosis of the vascular cells and stimulates production of reactive oxygen species. It is claimed that ET-1 induces proinflammatory mechanisms, increasing superoxide anion production and cytokine secretion. A recent study has shown that ET-1 is involved in the activation of transcription factors such as NF-jB and expression of proinflammatory cytokines including TNF-a, IL-1, and IL-6. It has been also indicated that during endotoxaemia, the plasma level of ET-1 is increased in various animal species. Some authors indicate a clear correlation between endothelin plasma level and morbidity/mortality rate in septic patients. These pathological effects of ET-1 may be abrogated at least partly by endothelin receptor blockade. ET-1 receptor antagonists may be useful for prevention of various vascular diseases. This review summarises the current knowledge regarding endothelin receptor antagonists and the role of ET-1 in sepsis and inflammation.

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Inhibition of Endothelin ET_BReceptor System Aggravates Neointimal Hyperplasia after Balloon Injury of Rat Carotid Artery

Cited by 22 publications

References 37 publications

Endothelin-A Receptor Antagonism after Renal Angioplasty Enhances Renal Recovery in Renovascular Disease

Endothelin-A Receptor Antagonism after Renal Angioplasty Enhances Renal Recovery in Renovascular Disease

Endothelin ET_B Receptor Is Involved in Sex Differences in the Development of Balloon Injury-Induced Neointimal Formation

The Role of Endothelin-1 and Endothelin Receptor Antagonists in Inflammatory Response and Sepsis

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Inhibition of Endothelin ETBReceptor System Aggravates Neointimal Hyperplasia after Balloon Injury of Rat Carotid Artery

Cited by 22 publications

References 37 publications

Endothelin-A Receptor Antagonism after Renal Angioplasty Enhances Renal Recovery in Renovascular Disease

Endothelin-A Receptor Antagonism after Renal Angioplasty Enhances Renal Recovery in Renovascular Disease

Endothelin ETB Receptor Is Involved in Sex Differences in the Development of Balloon Injury-Induced Neointimal Formation

The Role of Endothelin-1 and Endothelin Receptor Antagonists in Inflammatory Response and Sepsis

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Inhibition of Endothelin ET_BReceptor System Aggravates Neointimal Hyperplasia after Balloon Injury of Rat Carotid Artery

Endothelin ET_B Receptor Is Involved in Sex Differences in the Development of Balloon Injury-Induced Neointimal Formation