Cytokines induce increased endothelin ET(B) receptor-mediated contraction

Area of Science:

• Vascular biology
• Molecular pharmacology
• Immunology

Background:

• Endothelin ET(B) receptors play a role in vascular tone.
• The influence of cytokines on endothelin receptor function is not fully understood.

Purpose of the Study:

• To investigate the effect of cytokines on the induction of contractile endothelin ET(B) receptors in rat superior mesenteric artery segments.
• To elucidate the mechanisms underlying cytokine-mediated changes in endothelin ET(B) receptor activity.

Main Methods:

• Organ culture of rat superior mesenteric artery segments with or without cytokines (interleukin-1beta, TNF-alpha, interleukin-2).
• Assessment of endothelin ET(B) receptor-mediated contractions using specific agonists (sarafotoxin 6c, IRL 1620) and antagonists (FR 139317, IRL 2500).
• Analysis of endothelin ET(A) and ET(B) receptor mRNA levels using reverse transcriptase-polymerase chain reaction.

Main Results:

• Organ culture induced contractile endothelin ET(B) receptors.
• Interleukin-1beta and TNF-alpha significantly enhanced ET(B) receptor-mediated contractions.
• Interleukin-2 had no significant effect.
• Cytokines did not alter endothelin-1-induced contractions or the ratio of ET(A)/ET(B) receptor mRNA.
• Increased ET(B) mRNA levels suggested de novo transcription, while enhanced contraction indicated improved intracellular signaling.

Conclusions:

• Contractile endothelin ET(B) receptors are induced during organ culture, likely through de novo transcription.
• Pro-inflammatory cytokines, specifically IL-1beta and TNF-alpha, potentiate ET(B) receptor-mediated contractions.
• The potentiation mechanism involves enhanced intracellular signaling pathways rather than changes in receptor mRNA expression levels.