Cytochrome P450 metabolites of arachidonic acid but not cyclooxygenase-2 metabolites contribute to the pulmonary vascular hyporeactivity in rats withacute Pseudomonas pneumonia

We have previously demonstrated depressed vascular contractility in intralo bar pulmonary artery (PA) rings isolated from rats with acute Pseudomonas p neumonia. Here we describe the role of arachidonic acid (AA) metabolites in the regulation of pulmonary vascular tone in inflammation. Pneumonia was i nduced by intratracheal injection of P. aeruginosa organisms. Rats were sac rificed 44 h later. EETs and 20-HETE were formed at significantly lower rat es in pneumonia compared with control lung microsomes. Vasoactive effects o f CYP metabolites (5,6-EET, 8,9-EET, 11,12-EET, 14,15-EET, and 20-HETE) on small PA rings from control or pneumonia rats were assessed in vitro. All f our EETs and 20-HETE were more potent PA vasoconstrictors than KCl or pheny lephrine (PE). However, this potency was attenuated in PA rings from pneumo nia lungs compared with control. In contrast, pneumonia had no effect on CO X activity [total pulmonary prostaglandin (PG), PGE(2), and 6-keto-PGF(1 al pha)]. In vitro vascular contractility to KCl, PE, or PGF(2 alpha) was asse ssed in small PA rings from control and pneumonia rats in the presence and absence of the COX-2 inhibitor NS-398 (10 muM). NS-398 did not reverse the attenuated contractile responses to KCl, PE, or PGF(2 alpha) in pneumonia r ats. Nitrite/nitrate levels, inducible nitric-oxide synthase and heme oxyge nase activities were all significantly elevated in pneumonia lungs. In conc lusion, vasodilator PGs produced by COX-2 do not contribute to the depresse d PA contractility in this model of pneumonia. Depressed pulmonary producti on and vasoconstrictor effects of CYP metabolites of AA (possibly due to in creased NO and/or carbon monoxide) indicate a potential role for these vaso active metabolites in this model of acute pneumonia.