Cytokines induce increased endothelin ETB receptor-mediated contraction

The effect of cytokines on the induction of contractile endothelin ETB 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-1 beta, tumor necrosis factor-alpha (TNF-alpha) or interleukin-2. In fresh arterial segments there was no endothelin ETB receptor-induced contraction. After incubation, the selective endothelin ETB receptor agonist sarafotoxin 6c evoked a contraction of 22 +/- 6% relative to that induced by 60 mM K+. The endothelin ETB receptor-induced contraction was further increased to 125 +/- 25% and 157 +/- 29% by interleukin-1 beta and TNF-alpha; respectively, while interleukin-2 did not alter the endothelin ETB receptor-induced contraction. The identity of the contractile receptor was confirmed as the endothelin ETB receptor by the use of an additional specific endothelin ETB 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 ETB mRNA, relative to endothelin ETA mRNA following organ culture, suggesting that contractile endothelin ETB receptors appear via de novo transcription. None of the cytokines changed the ratio of endothelin ETA and endothelin ETB receptor mRNA, indicating that the further increased sarafotoxin 6c-induced contraction is mediated through an enhancement of intracellular signalling mechanisms. (C) 1999 Elsevier Science B.V. All rights reserved.