Interleukin-1β rapidly inhibits aortic endothelium-dependent relaxation by a DNA transcription-dependent mechanism

Objectives: This study examined the effects of interleukin-1beta on isometric tension development and relaxation in isolated rat aortic rings in response to the alpha-1 adrenergic agonist phenylephrine, the endothelium-dependent vasodilator acetylcholine, and the endothelium-independent vasodilator sodium nitroprusside. Design: Randomized, controlled, paired design. Setting. Animal laboratory within a university department of physiology. Subjects. Paired ex vivo aortic thoracic aortic rings from specific pathogen-free Sprague-Dawley rats. Interventions: Series I examined the potential for interleukin-1beta to cause early arterial endothelial dysfunction. Paired aortic rings were incubated for 2 hrs with interleukin-1beta or vehicle. Series 11 examined the potential for inhibition of DNA transcription to attenuate interleukin-1beta-mediated endothelial dysfunction. Paired rings received either dactinomycin or vehicle before interleukin-1beta incubation. Series III quantified the degree to which inhibition of DNA transcription inhibited early interleukin-1beta-mediated endothelial dysfunction. Paired rings received either dactinomycin pretreatment followed by interleukin-1beta incubation, or pretreatment and incubation with inert vehicles. Series IV assessed the effects of interleukin-1 0 on responsiveness to an exogenous nitric oxide donor, sodium nitroprusside, in the presence of the nitric oxide synthesis inhibitor Nomega-nitro-L-arginine methyl ester. Measurements and Main Results., Incubation with interleukin-1beta for 2 hrs had no effect on contractile response but attenuated endothelium-dependent relaxation significantly relative to control. Dactinomycin pretreatment inhibited early interleukin-1beta-mediated endothelial dysfunction. The combination of interleukin-1beta and dactinomycin produced effects on endothelium-dependent relaxation that were not different from that seen in rings not exposed to interleukin-1beta. Interleukin-1beta attenuated responsiveness to sodium nitroprusside relative to control. Conclusions., Interleukin-1beta causes an early impairment of endothelium-dependent vasorelaxation with an onset that precedes its effects on systemic contractility. This impairment occurs via a mechanism that is wholly or predominantly dependent on DNA transcription. The altered vasorelaxation induced by interleukin-1beta is at least partly mediated by a reduction in nitric oxide responsiveness.