Ambrisentan, an endothelin receptor type A-selective endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension

Kingman, Martha; Ruggiero, Rosechelle; Torres, Fernando

doi:10.1517/14656560903061275

Cited by 39 publications

(34 citation statements)

References 27 publications

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“…The clinical relevance of this potential therapeutic approach is tempered by work showing that genetic knockout of the ET A receptor leads to birth defects and eventual embryonic lethality in mice [66]. As a result, administration of ET receptor antagonists is contraindicated in pregnancy [67]. However, specific windows during early to mid-gestation have been identified in animal studies, where pharmacological antagonism of ET A caused phenotypes similar to that seen in the knockout.…”

Section: Targeting Eta Receptor Signalingas a Potential Therapeutic Tmentioning

confidence: 99%

The Endothelin System: A Critical Player in the Pathophysiology of Preeclampsia

2018

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Purpose of Review Preeclampsia (PE) is a disorder of pregnancy typically characterized by new-onset hypertension and proteinuria after gestational week 20. Although preeclampsia is one of the leading causes of maternal and perinatal morbidity and death worldwide, the mechanisms of the pathogenesis of the disorder remain unclear and treatment options are limited. Placental ischemic events and the release of placental factors appear to play a critical role in the pathophysiology. These factors contribute to a generalized systemic vascular endothelial dysfunction and result in increased systemic vascular resistance and hypertension. Recent Findings There is increasing evidence to suggest that endothelin-1 (ET-1) in the maternal vascular endothelium is a critical final common pathway, whereby placental ischemic factors cause cardiovascular and renal dysfunction in the mother. Multiple studies report increased levels of ET-1 in PE. A number of experimental models of PE are also associated with elevated tissue levels of prepro-ET-1 mRNA. Moreover, experimental models of PE (placental ischemia, sFlt-1 excess, TNF-α excess, and AT1-AA infusion) have proven to be responsive to ET type A receptor antagonism. Recent studies also suggest that abnormalities in ET type B receptor signaling may also play a role in PE. Summary Although numerous studies highlight the importance of the ET system in the pathogenesis of PE, further work is needed to determine whether ET receptor antagonists could provide an effective therapy for the management of this disease.

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Section: Targeting Eta Receptor Signalingas a Potential Therapeutic Tmentioning

confidence: 99%

The Endothelin System: A Critical Player in the Pathophysiology of Preeclampsia

2018

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“…Endothelin-1 (EDN1) is the most powerful naturally occurring prohypertensive peptide, and antagonists of the endothelin type A receptor (EDNRA) greatly ameliorate the PE-like condition that develops in the kidneys of rodents with excess sFLT1 (2,3). Unfortunately, these antagonists are teratogenic (4) and consequently unacceptable for use in treating PE.…”

mentioning

confidence: 99%

Nicotinamide benefits both mothers and pups in two contrasting mouse models of preeclampsia

Fushima

Oyanagi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Preeclampsia (PE) complicates ∼5% of human pregnancies and is one of the leading causes of pregnancy-related maternal deaths. The only definitive treatment, induced delivery, invariably results in prematurity, and in severe early-onset cases may lead to fetal death. Many currently available antihypertensive drugs are teratogenic and therefore precluded from use. Nonteratogenic antihypertensives help control maternal blood pressure in PE, but results in preventing preterm delivery and correcting fetal growth restriction (FGR) that also occurs in PE have been disappointing. Here we show that dietary nicotinamide, a nonteratogenic amide of vitamin B 3 , improves the maternal condition, prolongs pregnancies, and prevents FGR in two contrasting mouse models of PE. The first is caused by endotheliosis due to excess levels in the mothers of a soluble form of the receptor for vascular endothelial growth factor (VEGF), which binds to and inactivates VEGF. The second is caused by genetic absence of Ankiryn-repeat-and-SOCS-box-containingprotein 4, a factor that contributes to the differentiation of trophoblast stem cells into the giant trophoblast cells necessary for embryo implantation in mice; its absence leads to impaired placental development. In both models, fetal production of ATP is impaired and FGR is observed. We show here that nicotinamide decreases blood pressure and endotheliosis in the mothers, probably by inhibiting ADP ribosyl cyclase (ADPRC), and prevents FGR, probably by normalizing fetal ATP synthesis via the nucleotide salvage pathway. Because nicotinamide benefits both dams and pups, it merits evaluation for preventing or treating PE in humans.he maternal hypertension and proteinuria characterizing preeclampsia (PE) are primarily consequences of an imbalance between proangiogenic growth factors that promote vascular well-being (such as VEGF), and antiangiogenic factors that sequester the growth factors (such as the soluble form of VEGF receptor-1, now referred to as sFLT1) (1). Both the hypertension and the proteinuria of PE are caused by abnormally high amounts of antiangiogenic factors derived from the placenta. Fetal growth restriction (FGR), an additional feature of PE, is a consequence of reduced placental blood flow resulting from damage to the placental vasculature caused by antiangiogenic factors and/or to impaired development of the placenta. Endothelin-1 (EDN1) is the most powerful naturally occurring prohypertensive peptide, and antagonists of the endothelin type A receptor (EDNRA) greatly ameliorate the PE-like condition that develops in the kidneys of rodents with excess sFLT1 (2, 3). Unfortunately, these antagonists are teratogenic (4) and consequently unacceptable for use in treating PE.Nicotinamide is a potential nonteratogenic alternative because it relaxes blood vessels constricted with EDN1 (5) and because it has been extensively tested at high oral doses in men and (nonpregnant) women and found safe (6). Results and DiscussionNicotinamide Ameliorates the Hypertension, Albuminuria, an...

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“…Effects of antagonistic and agonistic binding to the endothelin-1 type-A receptor (ET A R)/ endothelin-1 type-B receptor (ET B R) on CAR expression in endothelial cells HUVEC were incubated with Ambrisentan and BQ-788, two selective antagonists for either the ET A R or ET B R (Kingman et al, 2009;Okada & Nishikibe, 2002). Exposure to BQ-788 resulted in a dose-dependent reduction of CAR expression by 26.3 (±15.0) % (100 nmol l 21 ) and 43.8 (±22.1) % (200 nmol l 21 ), respectively.…”

Section: Viral Infection Of Endothelial Cellsmentioning

confidence: 99%

Antiviral effect of Bosentan and Valsartan during coxsackievirus B3 infection of human endothelial cells

Funke

Farr

Werner

et al. 2010

Journal of General Virology

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In viral myocarditis, adeno- and enteroviruses have most commonly been implicated as causes of infection. Both viruses require the human coxsackie-adenovirus receptor (CAR) to infect the myocardium. Due to its crucial role for viral entry, CAR-downregulation may lead to novel approaches for treatment for viral myocarditis. In this study, we report on pharmaceutical drug influences on CAR levels in human umbilical vein endothelial cells (HUVEC) and cervical carcinoma cells (HeLa) detected by immunoblotting, quantitative real time-PCR and cellular susceptibility to the cardiotropic coxsackie-B3 virus strain Nancy (CVB3). Our results indicate, for the first time, a dose-dependent CAR mRNA and protein downregulation upon Valsartan and Bosentan treatment. Most interestingly, drug-induced CAR diminution significantly reduced the viral load in CVB3-infected HUVEC. In order to assess the regulatory effects of both drugs in detail, we knocked down their protein targets, the G-protein coupled receptors angiotensin-II type-1 receptor (AT1R) and endothelin-1 type-A and -B receptors (ETAR/ETBR) in HUVEC. Receptor-specific gene silencing indicates that CAR gene expression is regulated by agonistic and antagonistic binding to ETBR, but not ETAR. In addition, neither stimulation nor inhibition of AT1R seemed to be involved in CAR gene regulatory processes. Our study indicates that Valsartan and Bosentan protected human endothelial cells from CVB3-infection. Therefore, besides their well-known anti-hypertensive effects these drugs may also protect the myocardium and other tissues from coxsackie- and adenoviral infection.

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Ambrisentan, an endothelin receptor type A-selective endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension

Cited by 39 publications

References 27 publications

The Endothelin System: A Critical Player in the Pathophysiology of Preeclampsia

The Endothelin System: A Critical Player in the Pathophysiology of Preeclampsia

Nicotinamide benefits both mothers and pups in two contrasting mouse models of preeclampsia

Antiviral effect of Bosentan and Valsartan during coxsackievirus B3 infection of human endothelial cells

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