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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