Abstract
We have previously demonstrated depressed vascular contractility in intralobar pulmonary artery (PA) rings isolated from rats with acutePseudomonas pneumonia. Here we describe the role of arachidonic acid (AA) metabolites in the regulation of pulmonary vascular tone in inflammation. Pneumonia was induced by intratracheal injection of P. aeruginosa organisms. Rats were sacrificed 44 h later. EETs and 20-HETE were formed at significantly lower rates in pneumonia compared with control lung microsomes. Vasoactive effects of 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 four EETs and 20-HETE were more potent PA vasoconstrictors than KCl or phenylephrine (PE). However, this potency was attenuated in PA rings from pneumonia lungs compared with control. In contrast, pneumonia had no effect on COX activity [total pulmonary prostaglandin (PG), PGE2, and 6-keto-PGF1α]. In vitro vascular contractility to KCl, PE, or PGF2α was assessed in small PA rings from control and pneumonia rats in the presence and absence of the COX-2 inhibitor NS-398 (10 μM). NS-398 did not reverse the attenuated contractile responses to KCl, PE, or PGF2α in pneumonia rats. Nitrite/nitrate levels, inducible nitric-oxide synthase and heme oxygenase activities were all significantly elevated in pneumonia lungs. In conclusion, vasodilator PGs produced by COX-2 do not contribute to the depressed PA contractility in this model of pneumonia. Depressed pulmonary production and vasoconstrictor effects of CYP metabolites of AA (possibly due to increased NO and/or carbon monoxide) indicate a potential role for these vasoactive metabolites in this model of acute pneumonia.
Footnotes
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Send reprint requests to: Dr. David G. McCormack, London Health Sciences Center, Victoria Campus, 375 South St., London, ON, Canada N6A 4G5. E-mail: david.mccormack{at}lhsc.on.ca
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This study was supported by a grant from the Canadian Institutes of Health Research (Grant MT13944 to Dr. D.G.M. and Grant MT9722 to J.R.B.). A postgraduate scholarship from the Natural Sciences and Engineering Research Council of Canada and an Ontario Graduate Scholarship in Science and Technology supported A.Y.
- Abbreviations:
- iNOS
- inducible nitric-oxide synthase
- COX
- cyclooxygenase
- PA
- pulmonary artery
- NO
- nitric oxide
- AA
- arachidonic acid
- CYP
- cytochrome P450
- EET
- epoxyeicosatrienoic acid
- 20-HETE
- 20-hydroxyeicosatetraenoic acid
- PG
- prostaglandin
- HO
- heme oxygenase
- CO
- carbon monoxide
- NOX
- nitrite/nitrate
- PE
- l-phenylephrine hydrochloride
- NS-398
- N-(2-cyclohexyl-4-nitrophenyl) methanesulfonamide
- PMSF
- phenylmethylsulfonyl fluoride
- EIA
- enzyme immunoassay
- HPLC
- high performance liquid chromatography
- l-NAME
- nitro-l-arginine methyl ester
- cNOS
- constitutive nitric-oxide synthase
- MANOVA
- repeated measures analysis of variance
- Received October 3, 2000.
- Accepted January 16, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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