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

• Published in: Critical care medicine Vol. 31; no. 3; p. 910
• Main Authors: Loughrey, J P R, Laffey, J G, Moore, B J, Lynch, F, Boylan, J F, McLoughlin, P
• Format: Journal Article
• Language: English
• Published: United States 01.03.2003
• Subjects: Acetylcholine - immunology; Acetylcholine - pharmacology; Adrenergic alpha-Agonists - immunology; Adrenergic alpha-Agonists - pharmacology; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - immunology; Aorta, Thoracic - physiopathology; Dactinomycin - immunology; Dactinomycin - pharmacology; Disease Models, Animal; DNA; Endothelium, Vascular - drug effects; Endothelium, Vascular - immunology; Endothelium, Vascular - physiopathology; In Vitro Techniques; Interleukin-1 - immunology; Interleukin-1 - pharmacology; Male; Nitroprusside - pharmacology; Phenylephrine - immunology; Phenylephrine - pharmacology; Random Allocation; Rats; Rats, Sprague-Dawley; Sepsis - immunology; Sepsis - physiopathology; Transcription, Genetic - drug effects; Transcription, Genetic - physiology; Vasoconstrictor Agents - immunology; Vasoconstrictor Agents - pharmacology; Vasodilation - drug effects; Vasodilation - immunology; Vasodilator Agents - immunology; Vasodilator Agents - pharmacology
• ISSN: 0090-3493
• DOI: 10.1097/01.CCM.0000053516.15727.E5

This study examined the effects of interleukin-1 beta 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. Randomized, controlled, paired design. Animal laboratory within a university department of physiology. SUBJECTS Paired aortic thoracic aortic rings from specific pathogen-free Sprague-Dawley rats. Series I examined the potential for interleukin-1 beta to cause early arterial endothelial dysfunction. Paired aortic rings were incubated for 2 hrs with interleukin-1 beta or vehicle. Series II examined the potential for inhibition of DNA transcription to attenuate interleukin-1 beta-mediated endothelial dysfunction. Paired rings received either dactinomycin or vehicle before interleukin-1 beta incubation. Series III quantified the degree to which inhibition of DNA transcription inhibited early interleukin-1 beta-mediated endothelial dysfunction. Paired rings received either dactinomycin pretreatment followed by interleukin-1 beta incubation, or pretreatment and incubation with inert vehicles. Series IV assessed the effects of interleukin-1 beta on responsiveness to an exogenous nitric oxide donor, sodium nitroprusside, in the presence of the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester. Incubation with interleukin-1 beta for 2 hrs had no effect on contractile response but attenuated endothelium-dependent relaxation significantly relative to control. Dactinomycin pretreatment inhibited early interleukin-1 beta-mediated endothelial dysfunction. The combination of interleukin-1 beta and dactinomycin produced effects on endothelium-dependent relaxation that were not different from that seen in rings not exposed to interleukin-1 beta. Interleukin-1 beta attenuated responsiveness to sodium nitroprusside relative to control. Interleukin-1 beta 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-1 beta is at least partly mediated by a reduction in nitric oxide responsiveness.