Cytokines induce increased endothelin ET(B) receptor-mediated contraction.
The effect of cytokines on the induction of contractile endothelin ET(B) receptors during organ culture was examined. Ring segments of rat superior mesenteric artery were used fresh or incubated for 24 h in Dulbecco's modified Eagle's medium alone, or with either interleukin-1beta, tumor necrosis factor-alpha (TNF-alpha) or interleukin-2. In fresh arterial segments there was no endothelin ET(B) receptor-induced contraction. After incubation, the selective endothelin ET(B) receptor agonist sarafotoxin 6c evoked a contraction of 22 +/- 6% relative to that induced by 60 mM K+. The endothelin ET(B) receptor-induced contraction was further increased to 125 +/- 25% and 157 +/- 29% by interleukin-1beta and TNF-alpha, respectively, while interleukin-2 did not alter the endothelin ET(B) receptor-induced contraction. The identity of the contractile receptor was confirmed as the endothelin ET(B) receptor by the use of an additional specific endothelin ET(B) receptor agonist, IRL 1620, and by antagonist experiments with FR 139317 and IRL 2500. The endothelin-1-induced contraction was not altered by either of the cytokines. Reverse transcriptase-polymerase chain reaction revealed increased levels of endothelin ET(B) mRNA, relative to endothelin ET(A) mRNA following organ culture, suggesting that contractile endothelin ET(B) receptors appear via de novo transcription. None of the cytokines changed the ratio of endothelin ET(A) and endothelin ET(B) receptor mRNA, indicating that the further increased sarafotoxin 6c-induced contraction is mediated through an enhancement of intracellular signalling mechanisms.
Uddman
E
E
Department of Internal Medicine, Lund University Hospital, Sweden.
Möller
S
S
Adner
M
M
Edvinsson
L
L
D000818:Animals; D016207:Cytokines / Q000494:pharmacology*; D019332:Endothelin-1 / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014757:Viper Venoms / Q000494:pharmacology*
D016207:Cytokines; D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6