Role of endothelin-1 receptor blockers on hemodynamic parameters and oxidative stress

doi:10.1016/S1734-1140(10)70240-1

Pharmacological Reports

Volume 62, Issue 1, January–February 2010, Pages 28-34

https://doi.org/10.1016/S1734-1140(10)70240-1 Get rights and content

Abstract

Endothelin (ET) was first isolated and described by Yanagisawa et al. and has since been described as one of the most potent known vasoconstrictor compounds. ET-1 mediates its effects via two types of receptors, ET_A and ET_B, which are expressed in the vascular smooth muscle cells, endothelial cells, intestines and brain. Secretion of ET-1 results in long-lasting vasoconstriction, increased blood pressure and, in turn, overproduction of free radicals. As dysregulation of the endothelin system is an important factor in the pathogenesis of several diseases including atherosclerosis, hypertension and endotoxic shock, the ET_A and ET_B receptors are attractive therapeutic targets for treatment of these disorders. The biosynthesis and release of ET-1 are regulated at the transcriptional level. Studies have shown that p38MAP kinase, nuclear factor κB (NF-κB), PKC/ERK and JNK/c-Jun all take part in the ROS-activated production of ET-1. Furthermore, administration of ET significantly reduces the generation of free radicals. However, treatment with ET_B receptor blockers does not elicit the same effect. Therefore, the effects of endothelin receptor blockers on blood pressure and the generation of free radicals remain debatable. This review summarizes recent investigations into the role of endothelin receptor blockers with respect to the modulation of hemodynamic parameters and the generation of free radicals.

Introduction

Endothelin-1 (ET-1) was first isolated from porcine aortic endothelial cells by Yanagisawa et al. [63]. Since its discovery, endothelin-1 has been demonstrated as one of the most potent known vasoconstrictors. Three structurally related isoforms of ET-1 have been identified: ET-1, ET-2 and ET-3. The physiological effects of ETs are mediated through two types of receptors, subtype A and subtype B. ET release causes massive vasoconstriction, increased blood pressure and, in turn, excessive production of reactive oxygen species (ROS). This review will focus on the role of ET-1 and blockers of the ET-1 receptor in hemody-namic changes and oxidative stress.

Section snippets

ET biochemistry

ETs are a family of 21-amino acid cysteine-rich pep-tides. They act as vasoconstrictors and are synthesized de novo, as opposed to being stored in cells. ET-1 is synthesized in bulk by endothelial cells and smooth muscle cells [38] as well as by macrophages [6], cadiomiocytes [49], neurons [13], and renal medulla [7] and Kupffer cells; ET-2 is primarily synthesized in the intestines, and ET-3 is synthesized in the brain, the lungs, and the intestines [41].

ET-1 synthesis begins with the

ET-1 receptors

The ET-1 receptors (ET-Rs) belong to the family of G-protein coupled receptors. Three types of ET-Rs have been characterized in humans, the ET_A, ET_B (subtypes 1 and 2) and ET_C receptors [8]. The ET_a-R and ET_B2-R, which are responsible for vasoconstric-tion, are predominately expressed in peripheral tissue such as vascular smooth muscle, airway smooth muscle, cardiomyocytes, hepatocytes, neurons [34, 40, 48]. In contrast, expression of the ET_b1-R is predominantly observed in the endothelium, the

ET-1 in oxidative stress

ROS take part in physiological reactions and signal transduction. However, excessive synthesis of ROS can generate deleterious effects, often resulting in the development of cardiovascular disorders. The most important oxygen reactive compounds are hydrogen radicals (OH^•), superoxide anions (O₂^•–), hydrogen peroxide (H₂O₂), and reactive nitrogen radicals such as NO and its derivate peroxynitrite (ONOO^-). O₂^•– is generated both enzymatically (e.g., NADPH oxidase, horseradish peroxidase, xantine

Influence of ET-1 receptor blockers on blood pressure

Endocrine secretion of ET-1 exerts two opposite and consecutive effects on vessel tension and heart rate (HR). First, secretion of NO and prostacycline triggers ET-1 to cause rapid and short-lived vasodilatation via the ET_B2-R. The duration of these effects is no longer than 5 min and only slight changes in HR are visible [63]. Next, ET-1 combines with the ET_A-R that is stored in cardiomiocytes and mobilizes calcium ions from the endoplasmic reticulum. This association causes long-lasting and

ET-1 receptor blockers and their influence on oxidative stress

The proinflammatory effect that ET-1 exerts on an organism is connected to the activation of inflammatory cells, such as neutrophils and mast cells, as well as the stimulation of oxygen radical production by macro-phages and the release of NO from endothelial cells [21].

Most studies agree that ET-1 augments ROS production via the ET_A-R [2, 3], as the inhibition of ET_A-R decreases ET-1-induced generation of ROS, while inhibition of ET_B receptors has no significant effect. This finding suggests

Conclusion

Our understanding of the role of ET-1 and blockers of its receptors in the generation of free radicals is far from complete. Many studies have indicated that ET-1 triggers hemodynamic changes through its receptors, leading to the excessive production of free oxygen and/or nitrogen species. However, the identity of the specific cellular pathways involved in this process remains unclear. Additional exploration of the biological role of endothelin-1 may aid in the development of new drugs as

Acknowledgment

This study was supported by grant 503-0079-3 from the Medica University of Lodz.

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MinireviewRole of endothelin-1 receptor blockers on hemodynamic parameters and oxidative stress

Abstract

Introduction

Section snippets

ET biochemistry

ET-1 receptors

ET-1 in oxidative stress

Influence of ET-1 receptor blockers on blood pressure

ET-1 receptor blockers and their influence on oxidative stress

Conclusion

Acknowledgment

Biochem Biophys Res Commun

Eur J Obstet Gynecol Reprod Biol

Food Chem Toxicol

Biochem Pharmacol

J Mol Cell Cardiol

Free Radic Biol Med

Jpn J Pharmacol

Peptides

Toxicology

J Mol Cell Cardiol

J Biol Chem

Trends Cardiovasc Med

Neurosci Lett

Biochem Biophys Res Commun

Neurosci Lett

Eur J Pharmacol

Eur J Pharmacol

Int J Cardiol

The importance of endothelin-1 for vascular dysfunction in cardiovascular disease

Cardio-vasc Res

ETa receptor blockade decreases vascular superoxide generation in DOCA-salt hypertension

Hypertension

Reactive oxygen species modulate endothelin-1-induced c-fos gene expression in cardiomyocytes

Cardiovasc Res

Role of mitogen-activated protein kinase pathway in reactive oxygen species-mediated endo-thelin-1-induced P-myosin heavy chain gene expression and cardiomyocyte hypertrophy

J Biomed Sci

Blood pressure-independent reduction in proteinuria and arterial stiffness after acute endothelin-A receptor antagonism in chronic kidney disease

Hypertension

Endothelins, peptides with potent vasoactive properties, are produced by human macrophages

J Exp Med

Role of endothelins in hypertension

Am J Ther

Endothelin receptor antagonist CPU0213 suppresses ventricular fibrillation in L-thyroxin induced cardiomyo-pathy

Pharmacol Rep

Endothelin-1 regulates astrocyte proliferation and reactive gliosis via a JNK/cJun signaling pathway

J Neurosci

Effects of an ET1-receptor antagonist, FR139317, on regional haemodynamic responses to endothelin-1 and [Ala11, 15] Ac-endothelin-1 (6–21) in conscious rats

Br J Pharmacol

Endothelin 1, an endo-thelium-derived peptide, is expressed in neurons of the human spinal cord and dorsal root ganglia

Proc Natl Acad Sci USA

Endothelin-1 plasma concentration in children and adolescents with atherogenic risk factors

Kardiol Pol

Effects of endothelin receptor antagonists on endothelin-1 and inducible nitric oxide syn-thase genes in a rat endotoxic shock model

Clin Sci

Endothelin antagonism suppresses plasma and cardiac endothelin-1 levels in SHRSPs at the typical hypertensive stage

Exp Biol Med (Maywood)

Minireview
Role of endothelin-1 receptor blockers on hemodynamic parameters and oxidative stress