Endothelin-1 and -3 induce choleresis in the rat through ETB receptors coupled to nitric oxide and vagovagal reflexes

Abstract

We have reported previously that centrally applied ET (endothelin)-1 and ET-3 induce either choleresis or cholestasis depending on the dose. In the present study, we sought to establish the role of these endothelins in the short-term peripheral regulation of bile secretion in the rat. Intravenously infused endothelins induced significant choleresis in a dose-dependent fashion, ET-1 being more potent than ET-3. Endothelins (with the exception of a higher dose of ET-1) did not affect BP (blood pressure), portal venous pressure or portal blood flow. ET-1 and ET-3 augmented the biliary excretion of bile salts, glutathione and electrolytes, suggesting enhanced bile acid-dependent and -independent bile flows. ET-induced choleresis was mediated by ET(B) receptors coupled to NO and inhibited by truncal vagotomy, atropine administration and capsaicin perivagal application, supporting the participation of vagovagal reflexes. RT (reverse transcription)-PCR and Western blot analysis revealed ETA and ET(B) receptor expression in the vagus nerve. Endothelins, through ET(B) receptors, augmented the hepatocyte plasma membrane expression of Ntcp (Na⁺/taurocholate co-transporting polypeptide; Slc10a1), Bsep (bile-salt export pump; Abcb11), Mrp2 (multidrug resistance protein-2; Abcc2) and Aqp8 (aquaporin 8). Endothelins also increased the mRNAs of these transporters. ET-1 and ET-3 induced choleresis mediated by ET(B) receptors coupled to NO release and vagovagal reflexes without involving haemodynamic changes. Endothelin-induced choleresis seems to be caused by increased plasma membrane translocation and transcriptional expression of key bile transporters. These findings indicate that endothelins are able to elicit haemodynamic-independent biological effects in the liver and suggest that these peptides may play a beneficial role in pathophysiological situations where bile secretion is impaired.

Tissue-specific and time-dependent regulation of the endothelin axis by the circadian clock protein Per1

“…In normal liver function, ET-1 may act through an ET B -nitric oxide-dependent mechanism to increase expression of critical bile secretory genes and regulate choleresis, the secretion of bile into the gallbladder ( Rodriguez et al, 2013 ). Here liver ET-1 mRNA increased somewhat at midnight and was substantially elevated in the livers of Per1 het mice at both time points.…”

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

“… a Ehrenreich et al ( 1992 ), b Endo et al ( 1992 ), c Hynynen and Khalil ( 2006 ), d Lima et al ( 2011 ), e Liu et al ( 1997 ), f Motte et al ( 2006 ), g Ohkita et al ( 2012 ), h Rodriguez et al ( 2013 ) …”

“…So far, ETA and ETB receptors have been detected in many cell types other than blood vessels (Table 1 ), but predominantly in cardiovascular tissues (Hynynen and Khalil 2006 ). Endothelins, through their receptors, exert an influence on the function of many organs like the heart, the kidneys, the lungs and the liver (Lima et al 2011 ; Rodriguez et al 2013 ). Apart from participating in the regulation of vascular tone, endothelins take part in vascular, myocardial and bone remodelling, inhibition of apoptosis and salt-water retention.…”

“…Apart from participating in the regulation of vascular tone, endothelins take part in vascular, myocardial and bone remodelling, inhibition of apoptosis and salt-water retention. Furthermore, endothelins can contribute to bronchoconstriction, angiogenesis and neuropathic pain (Rodriguez et al 2013 ; Thakkar et al 2006 ).…”

Bile Synthesis Peculiarities following Changes in the Functional State of the Endothelin Receptors

“…Moreover, a wide variety of biochemical processes in liver, including glycogenolysis, gluconeogenesis and hemodynamic action, are all regulated by endothelin (Monti et al,2000).There are some investigations confirming an inhibitory effect of ET-1on bile secretion. According to Rodriguez et al (2013), ET-1induces a dose-dependent decrease in bile flow in isolated perfused rat liver, while Tanaka et al (1994), applying a similar experimental model, demonstrated that a low dose ET-1 increased bile acid-dependent bile secretion. However, these results do not give a clear view concerning endothelin receptors participation in regulation of qualitative and quantitative characteristics of liver secretory function.…”