Effect of an Imidazolineoxyl Nitric Oxide on Prostaglandin Synthesis in Experimental Shock: Possible Role of Nitrogen Dioxide in Prostacyclin Synthase Inactivation

Abstract

The effect of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO), a nitric oxide (NO) scavenger that yields nitrogen dioxide (NO(2)) in a rat endotoxemia model was investigated. Endotoxin (lipopolysaccharide [LPS]) increased NO synthase (NOS) activity and inducible NOS expression measured in lung and plasma levels of nitrite/nitrate, 6-oxo-prostaglandin (PG) F(1alpha), thromboxane B(2), and PGF(2alpha). Infusion of cPTIO significantly reduced LPS-induced mean arterial blood pressure decline and mortality and selectively reduced LPS-induced 6-oxo-PGF(1alpha) plasma levels and prostacyclin synthase (PGIS) activity measured in the lung and aorta. In vitro, PGIS activity in aorta rings was not modified by SNAP (NO donor), cPTIO slightly inhibited the enzyme but not in the presence of L-N(G)-monomethyl arginine, and SNAP in combination with cPTIO significantly inhibited PGIS. Thus, cPTIO may be beneficial in endotoxic shock because of NO scavenging and PGIS inactivation, which could be mediated by NO(2).

Activation of the PGI 2 /IP System Contributes to the Development of Circulatory Failure in a Rat Model of Endotoxic Shock

“…12 In line with this, the positive effect of cPTIO on LPS-induced cardiovascular failure and mortality has been linked in part to an inhibition of PGI 2 synthesis via inactivation of PGIS. 32 Furthermore, it has been suggested that the induction of COX-2 in the heart is involved in myocardial dysfunction 33,34 and that increased PGI 2 synthesis via COX-2 could in part mediate LPS-induced cardiac failure. 35,36 Therefore, our data provide further evidence for the involvement of COX-2-derived PGI 2 in endotoxin-induced cardiovascular dysfunction.…”

Hypoxia upregulates PGI-synthase and increases PGI2 release in human vascular cells exposed to inflammatory stimuli

“…Other mechanisms of PGIS inactivation involve tyrosine nitration at the catalytic center by nitrating agents derived from nitric oxide, which are produced in abundance under infl ammatory conditions ( 25,31,33,53 ). This nitric oxide-dependent inactivation of PGIS has been observed in systemic infl ammatory syndromes, atherosclerosis, hypoxia-reoxygenation injury, and diabetes ( 36,(54)(55)(56)(57)(58) ). An oxygen tension-dependent downregulation of nitrotyrosine-containing protein levels has been reported under hypoxic conditions ( 59,60 ), and we consistently observed that hypoxia reduces IL-1 ␤ -induced nitration of PGIS.…”

p21(WAF1)-mediated transcriptional targeting of inducible nitric oxide synthase gene therapy sensitizes tumours to fractionated radiotherapy

“…The effectiveness of iNOS gene therapy as an anticancer treatment has been well documented, with reports that it suppresses tumourigenicity and metastatic potential in vitro and results in effective growth inhibition in vivo. 40,41 We were the first group to report on the use of iNOS gene Radiosensitization using targeted iNOS gene therapy HO McCarthy et al therapy to radiosensitize rodent and human tumour xenografts in vivo. 18,19 In these studies, we also demonstrated that NO K was generated in vivo following injection of both CMV-driven iNOS and WAF-driven iNOS and that this effect could be inhibited in vitro using the NOS inhibitor L-NAME.…”