Endothelin-1 inhibits secretin-stimulated ductal secretion by interacting with ETA receptors on large cholangiocytes.
We studied the expression of endothelin-1 (ET-1) receptors (ETA and ETB) and the effects of ET-1 on cholangiocyte secretion. The effects of ET-1 on cholangiocyte secretion were assessed in normal and bile duct-ligated (BDL) rats by measuring 1) basal and secretin-induced choleresis in vivo, 2) secretin receptor gene expression and cAMP levels in small and large cholangiocytes, and 3) luminal expansion in response to secretin in intrahepatic bile duct units (IBDU). ETA and ETB receptors were expressed by small and large cholangiocytes. ET-1 had no effect on basal bile flow or bicarbonate secretion in normal or BDL rats but decreased secretin-induced bicarbonate-rich choleresis in BDL rats. ET-1 decreased secretin receptor gene expression and secretin-stimulated cAMP synthesis in large cholangiocytes and secretin-induced luminal expansion in IBDU from normal or BDL rats. The inhibitory effects of ET-1 on secretin-induced cAMP synthesis and luminal duct expansion were blocked by specific inhibitors of the ETA (BQ-610) receptor. ET-1 inhibits secretin-induced ductal secretion by decreasing secretin receptor and cAMP synthesis, two important determinants of ductal secretion.
Department of Internal Medicine and Medical Physiology, Scott and White Hospital and Texas A&M University Health Science Center College of Medicine, Temple, Texas 76504, USA.
A
A
Caligiuri
S
S
Glaser
R E
RE
Rodgers
J L
JL
Phinizy
W
W
Robertson
E
E
Papa
M
M
Pinzani
G
G
Alpini
D000818:Animals; D001646:Bile / Q000378:metabolism*; D001652:Bile Ducts / Q000502:physiology; D001653:Bile Ducts, Intrahepatic / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017931:DNA Primers; D019332:Endothelin-1 / Q000494:pharmacology*; D005786:Gene Expression Regulation; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012633:Secretin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014158:Transcription, Genetic
D017931:DNA Primers; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D012633:Secretin; D000242:Cyclic AMP