New Clues Towards Solving the Mystery of Endothelin and Blood Pressure Regulation

Speed, Joshua S.; Pollock, David M.

doi:10.1161/hypertensionaha.115.05277

Cited by 5 publications

(8 citation statements)

References 10 publications

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“…The endothelin (ET) class of peptides has been described as comprising the most potent vasoactive peptides known. Aberrations in ET signaling have been correlated with numerous cardiovascular diseases such as hypertension (Pollock ; Speed and Pollock , ), heart failure (Schneider et al. ; Zucker et al.…”

Section: Introductionmentioning

confidence: 99%

Activation of neuronal endothelin B receptors mediates pressor response through alpha-1 adrenergic receptors

et al. 2017

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Abnormalities in activity of the endothelin (ET) system have been widely reported in a number of cardiovascular disease states such as hypertension and heart failure. Although the vascular responses to ET are well established, the interaction between ET and other important modulators of blood pressure, such as the sympathetic nervous system, are less understood. Previous reports implicate ET signaling through ET type B (ETB) receptors in increasing neuronal activity. Therefore, we hypothesized that activation of ETB receptors on sympathetic nerves would increase blood pressure through an adrenergic‐mediated mechanism. Thus, we used anesthetized ETB‐deficient rats, which only express functional ETB receptors on adrenergic neurons, and genetic controls, which express functional ETB receptors in vascular tissue and kidney epithelium. We determined the pressor response to the selective ETB receptor agonist sarafotoxin c (S6c). Separate groups of rats were treated with the α 1‐adrenergic receptor antagonist prazosin or the β‐adrenergic receptor antagonist propranolol to elucidate the role of adrenergic signaling in mediating the blood pressure response. We observed a dose‐dependent pressor response to S6c in ETB‐deficient rats that was reversed by prazosin treatment and augmented by propranolol. In genetic control rats, the effects of S6c on sympathetic neurons were mostly masked by the direct activity of ETB receptor activation on the vasculature. Heart rate was mostly unaffected by S6c across all groups and treatments. These results suggest that ETB activation on sympathetic neurons causes an increase in blood pressure mediated through α 1‐adrenergic receptor signaling.

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Section: Introductionmentioning

confidence: 99%

Activation of neuronal endothelin B receptors mediates pressor response through alpha-1 adrenergic receptors

et al. 2017

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“…For example, Kurihara et al reported that Edn1 +/− heterozygotes expressing 50% normal level of ET-1 are hypertensive 34 . On the other hand, both endothelial cell specific ET-1-KO mice as well as mice overexpressing EDN1 specifically in endothelial cells have near normal BP 35 . Presence of a complex feedback and/or developmental adjustment of the ET-1 system have been postulated and is supported by the finding that animals developed hypertension when endothelial cell specific overproduction of ET-1 was induced in adults 36 .…”

Section: Discussionmentioning

confidence: 99%

Causative Effects of Genetically Determined High Maternal/Fetal Endothelin-1 on Preeclampsia-Like Conditions in Mice

Kakoki

Smid

et al. 2018

Hypertension

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Endothelin-1 (ET-1) is implicated in the pathophysiology of preeclampsia. An association between an gene polymorphism with high ET-1 and preeclampsia was reported in humans, but their cause and effect relationships have not been defined. We examined the pregnancy effects in mice with a modified allele that increases mRNA stability and thus ET-1 production. Heterozygous females showed no obvious abnormalities before pregnancy, but when mated with wild-type (WT) males developed a full spectrum of preeclampsia-like phenotypes, including increased systolic blood pressure, proteinuria, glomerular endotheliosis, and intrauterine fetal growth restriction. At 7.5 days post-coitus, the embryos from dams, regardless of their genotype, lagged 12 hours in development compared with embryos from WT dams, had disoriented ectoplacental cones, and retained high E-cadherin expression. In contrast, WT females mated with males, which also carried half of the fetuses with genotype, showed a mild systolic blood pressure increase only. These WT dams had 2× higher plasma soluble fms-like tyrosine kinase-1 than WT dams mated with WT males. In human first trimester trophoblast cells, pharmacological doses of ET-1 increased the cellular transcripts and protein secretion via both type A and B ET-1 receptors. Our data demonstrate that high maternal ET-1 production causes preeclampsia-like phenotypes during pregnancy, affecting both initial stage of trophoblast differentiation/invasion and maternal peripheral vasculature during late gestation. High fetal ET-1 production, however, could cause increased soluble fms-like tyrosine kinase-1 in the maternal circulation and contribute to blood pressure elevation.

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“…Our data demonstrated that maternal overexpression of ET-1 is sufficient to cause the end organ damage of PE, confirming that it is the operational status of the entire ET-1 system that predisposes mothers to PE. [27]. Accordingly, EDNRA antagonists, such as ambrisentan, blunt its actions and greatly decrease the severity of the PE-like phenotype induced by increased sFlt-1 [21,22].…”

Section: Aggarwal Et Al Reported An Association Between Edn1mentioning

confidence: 99%

“…On the other hand, ET-1 transgenic mice with higher than normal ET-1 level have normal BP [ 25 ]. The complex of ET-1 system is elegantly reviewed by Speed et al [ 27 ].…”

Section: Endothelin-1 and Preeclampsiamentioning

confidence: 99%

Beneficial effects of nicotinamide on the mouse model of preeclampsia

Huynh

Takahashi

Maeda-Smithies

et al. 2018

OAJ Pregnancy and Childcare

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Preeclampsia (PE) is a pregnancy related disorder that is characterized by hypertension and proteinuria in the mother. It is associated with impaired coagulation and liver function, and a variety of other detrimental effects. In severe cases without treatment, PE can progress to eclampsia and result in seizures, a life-threatening condition. Although the etiology of PE is largely unknown, sFlt-1 (soluble vascular endothelial growth factor receptor 1) released by the impaired placenta resulting from insufficient perfusion plays a critical role in PE, and phenotypes of PE can be induced by experimentally increasing sFlt-1. We and other investigators have proposed that endothelin-1 (ET-1) system is the mediator of the pathological effects of excess sFlt-1, and antagonists of ET-1 receptor block the effects of sFlt-1. Unfortunately, this class of drugs is teratogenic and unsuitable for treating pregnant women. Nicotinamide is a naturally occurring derivative of vitamin B3 in the body and inhibits ADP-ribosyl cyclase, which is activated by the ET-1 receptor. Therefore, if utilized, it would be expected to play a beneficial role in PE. In mouse models of PE, a high dose of nicotinamide shows great success in lowering blood pressure, correcting renal function and structure, prolonging pregnancy as well as increasing fetal weight/number. Nicotinamide, being generally regarded as safe, could be a promising substance to further investigate for use in clinical trials. Keywords: Preeclampsia, Nicotinamide.

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New Clues Towards Solving the Mystery of Endothelin and Blood Pressure Regulation

Cited by 5 publications

References 10 publications

Activation of neuronal endothelin B receptors mediates pressor response through alpha-1 adrenergic receptors

Activation of neuronal endothelin B receptors mediates pressor response through alpha-1 adrenergic receptors

Causative Effects of Genetically Determined High Maternal/Fetal Endothelin-1 on Preeclampsia-Like Conditions in Mice

Beneficial effects of nicotinamide on the mouse model of preeclampsia

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