A Prostaglandin E2 Receptor Subtype Ep4 Agonist Attenuates Cardiovascular Depression in Endotoxin Shock by Inhibiting Inflammatory Cytokines and Nitric Oxide Production

Abstract

The prostaglandin (PG) E2 receptor subtype EP4 has been found to mediate regulation of inflammatory cytokines in macrophages and neutrophils in vitro by PGE2. Yet the role of EP4 receptors in endotoxin shock in vivo and whether EP4 activation is a beneficial treatment are not clear. We tested the effect of an EP4 agonist on hemodynamic changes and production of inflammatory cytokines in a rat endotoxin-induced shock model. In rats under pentobarbital anesthesia, lipopolysaccharide (LPS) was injected, and an EP4 agonist (ONO-AE1-329) was administered at one of three concentrations (1, 3, or 10 microg/kg bolus i.v. hourly). Mean arterial pressure (MAP) was monitored throughout the experiment, and pressor responses to norepinephrine were determined 6 h after LPS injection. Serum tumor necrosis factor (TNF)-alpha and serum interleukin (IL)-6 were measured 1 h and 6 h after LPS injection. Venous nitrosyl hemoglobin (NO-Hb) concentration was measured by electron spin resonance. Expression of mRNAs encoding TNF-alpha and inducible nitric oxide synthase (iNOS) in the left ventricle and descending aorta was determined with a real-time reverse transcription polymerase chain reaction. As time progressed, LPS significantly depressed MAP and decreased reactivity to norepinephrine. Infusion of higher doses of the EP4 agonist at 3 and 10 microg/kg/h attenuated LPS-induced hypotension and hyporeactivity to norepinephrine. LPS significantly increased serum concentrations of TNF-alpha and IL-6, and higher doses of EP4 agonist significantly attenuated these increases. Left ventricular and aortic expression of mRNAs encoding TNF-alpha and iNOS was increased by LPS; again, EP4 agonist at higher doses attenuated the increases. LPS-induced production of inflammatory mediators and cardiovascular depression were attenuated by EP4 agonist administration in an in vivo endotoxin shock model. Anti-inflammatory effects thus would be involved in protection by EP4 agonist against cardiovascular depression in endotoxin shock.

Lipopolysaccharide-Induced Up-Regulation of Triggering Receptor Expressed on Myeloid Cells-1 Expression on Macrophages Is Regulated by Endogenous Prostaglandin E2

“…This is consistent with the previous finding that PGE 2 and EP4 agonists attenuated LPS-induced cytokine production in mice (40). However, a number of studies have provided evidence that COX inhibitors can improve survival after the onset of endotoxic shock and COXdeficient mice are resistant to endotoxin-induced inflammation and death (17,19,41).…”

Prevention of Trinitrobenzene Sulfonic Acid-Induced Experimental Colitis by Oral Administration of a Poly(lactic-coglycolic Acid) Microsphere Containing Prostaglandin E2 Receptor Subtype 4 Agonist

“…EP4-selective agonists therefore represent a novel class of immune-modulator drugs that could be useful for the management of inflammatory diseases such as arthritis (Shibata-Nozaki et al, 2011), sepsis (Sakamoto et al, 2004), inflammatory pain (Omote et al, 2002), and colitis (Kabashima et al, 2002;Nitta et al, 2002;Jiang et al, 2007Jiang et al, , 2010. In a human study, patients with UC refractory to 5-ASA responded favorably to treatment with [[3-[[(1R) (Nakase et al, 2010).…”

Peroxynitrites and impaired modulation of nitric oxide concentrations in embryos from diabetic rats during early organogenesis

“…We have previously found that 15dPGJ 2 is a negative regulator of NO levels in the embryo from control and mild diabetic rats during embryo organogenesis . NO concentrations have also been found to be regulated by PGE 2 in different tissues (Paliege et al 2004, Sakamoto et al 2004. On the other hand, NO is a positive regulator of PGE 2 concentrations during embryo organogenesis in both control and mild diabetic rats (Jawerbaum et al 1998).…”