QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.107.135350v1 326/3/864    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chiao, C.-W. Articles by Webb, R. C. Search for Related Content PubMed PubMed Citation Articles by Chiao, C.-W. Articles by Webb, R. C.

CARDIOVASCULAR

P2X₇ Receptor Activation Amplifies Lipopolysaccharide-Induced Vascular Hyporeactivity via Interleukin-1β Release

Department of Physiology, Medical College of Georgia, Augusta, Georgia (C.-W.C., R.C.T., R.C.W.); and Department of Pharmacology, University of Sao Paulo, Sao Paulo, Brazil (R.C.T.)

Lipopolysaccharide (LPS) stimulates cytoplasmic accumulation of pro-interleukin (IL)-1β. Activation of P2X₇ receptors stimulates conversion of pro-IL-1β into mature IL-1β, which is then secreted. Because both LPS (in vivo) and IL-1β (in vitro) decrease vascular reactivity to contractile agents, we hypothesized the following: 1) P2X₇ receptor activation contributes to LPS-induced vascular hyporeactivity, and 2) IL-1β mediates this change. Thoracic aortas were obtained from 12-week-old male C57BL/6 mice. The aortic rings were incubated for 24 h in Dulbecco's modified Eagle's medium, LPS, benzoylbenzoyl-ATP (BzATP; P2X₇ receptor agonist), LPS plus BzATP, oxidized ATP (oATP; P2X₇ receptor antagonist), or oATP plus LPS plus BzATP. After the treatment, the rings were either mounted in a myograph for evaluation of contractile activity or homogenized for IL-1β and inducible nitric-oxide synthase (iNOS) protein measurement. In endothelium-intact aortic rings, phenylephrine (PE)-induced contractions were not altered by incubation with LPS or BzATP, but they significantly decreased in aortic rings incubated with LPS plus BzATP. Treatment with oATP or IL-1ra (IL-1β receptor antagonist) reversed LPS plus BzATP-induced hyporeactivity to PE. In the presence of N^G-nitro-L-arginine methyl ester or N-([3-(aminomethyl)phenyl]methyl)ethanimidamide (selective iNOS inhibitor), the vascular hyporeactivity induced by LPS plus BzATP on PE responses was not observed. BzATP augmented LPS-induced IL-1β release and iNOS protein expression, and these effects were also inhibited by oATP. Moreover, incubation of endothelium-intact aortic rings with IL-1β induced iNOS protein expression. Thus, activation of P2X₇ receptor amplifies LPS-induced hyporeactivity in mouse endothelium-intact aorta, which is associated with IL-1β-mediated release of nitric oxide by iNOS.

Address correspondence to: Dr. Chin-Wei Chiao, Department of Physiology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912. E-mail: cwchiao{at}mcg.edu

This article has been cited by other articles:

				D. Fernandes, R. Sordi, L. K. Pacheco, G. M. Nardi, B. T. Heckert, C. G. Villela, A. R. Lobo, C. Barja-Fidalgo, and J. Assreuy Late, but Not Early, Inhibition of Soluble Guanylate Cyclase Decreases Mortality in a Rat Sepsis Model J. Pharmacol. Exp. Ther., March 1, 2009; 328(3): 991 - 999. [Abstract] [Full Text] [PDF]