Cytokines induce increased endothelin ET B receptor-mediated contraction

Abstract

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-1β, tumor necrosis factor-α (TNF-α) 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-1β and TNF-α, 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.