The role of endothelin-1 and the endothelin B receptor in the pathogenesis of hepatopulmonary syndrome in the rat

Abstract

Endothelin-1 (ET-1T he endothelium plays a central role in the regulation of vascular tone both under normal circumstances and in cirrhosis by releasing endotheliumderived vasodilators and vasoconstrictors in response to a variety of biochemical and physical stimuli. 1 Nitric oxide (NO) and endothelin-1 (ET-1) are two important endothelial mediators that modulate vascular tone. Endothelial NO production is catalyzed predominately by the endothelial form of nitric oxide synthase (eNOS) and under normal circumstances is constitutively expressed and activated by calcium entry into cells. 2 ET-1 is a 21 amino acid peptide formed from a precursor, big ET-1, through the action of an endothelin-converting enzyme and is produced in a number of cell types in addition to endothelial cells, including hepatic stellate cells and biliary epithelium. 3-6 ET-1 is classically recognized as a potent paracrine vasoconstrictor, and its action is mediated by two G protein coupled receptors. 7,8 The endothelin A (ET A ) receptor mainly exists in vascular smooth muscle cells and mediates contraction and vasoconstriction. 9 Two endothelin B (ET B ) receptor types have been found: one in endothelial cells that upregulates eNOS and NO and the other in smooth muscle cells that functions similar to the ET A receptor. 10,11 Increased circulating ET-1, in part derived from increased hepatic production and

Intrapulmonary vascular dilatations are common in portopulmonary hypertension and may be associated with decreased survival

“…The endothelin-A receptor mediates vasoconstriction and is down-regulated in animal models of HPS, whereas expression of the endothelin-B receptor, which leads to vasodilatation via endothelial nitric oxide synthase, is increased. [35][36][37] Data from animal models of HPS suggest a central role for pulmonary intravascular macrophages through generation of inducible nitric oxide synthase, vascular endothelial growth factor, and platelet-derived growth factor. 35,38,39 Inhibition of nitric oxide synthase, the endothelin-B receptor, and vascular endothelial growth factor has mitigated HPS in animal models.…”

“…[35][36][37] Data from animal models of HPS suggest a central role for pulmonary intravascular macrophages through generation of inducible nitric oxide synthase, vascular endothelial growth factor, and platelet-derived growth factor. 35,38,39 Inhibition of nitric oxide synthase, the endothelin-B receptor, and vascular endothelial growth factor has mitigated HPS in animal models. [40][41][42] Notably, these same mediators have also been implicated in POPH and endothelin receptor antagonists (dual and selective), and phosphodiesterase-5 inhibitors are mainstays of therapy for PAH and POPH.…”

Alteration of the renal regulatory hormonal pattern during experimental obstructive jaundice

“…ET-1 is a peptide with a powerful vasoconstrictor action that is involved in the genesis of several diseases, mainly in the hepato-biliary area. Therefore, it has been suggested that ET-1 has a key function in serious complications of hepatic cirrhosis such as portal hypertension (17) and hepatopulmonary syndrome (18). It was recently shown that the blocking of ET-1 receptors improved microcirculation and sinusoidal perfusion in an experimental model of acute liver failure (19).…”

Molecular mechanisms of hepatopulmonary syndrome

“…Through the tight contact ET-1 enters the circulatory system, binds to ET-receptors in the endothelial cells of the lung vessels, causing increase in the expression and activity of eNOS, and vasodilation [60]. In addition, there is evidence that the introduction of ЕТ В receptor selective antagonist to animals after ligation of the common bile duct causes a reduction in pulmonary endothelial eNOS and improvement of HPS symptoms [61].…”