Differential vasoconstrictor potencies of free fatty acids in the lung vasculature: 2-versus 3-series prostanoid generation.
Pulmonary vasoconstrictor potencies of the 2- and 3-series prostanoid precursors arachidonic acid (AA) and eicosapentaenoic acid (EPA) were compared with each other and three reference fatty acids [palmitic acid (PAL), oleic acid (OA) and eicosatrienoic acid (ETA)]. Dose-effect curves were established from transient pulmonary artery pressor responses (approximately 5-50 mm Hg) evoked by intravascular application of nonesterified fatty acids in buffer-perfused rabbit lungs. Release of di- and trienoic prostanoids into the recirculating perfusate was quantified by a post high-performance liquid chromatography enzyme-linked immunosorbent assay technique. EPA and the three reference fatty acids were used in concentrations up to 10 microM; the rank order of vasoconstrictor potencies was ETA < PAL < OA < EPA. In contrast, AA evoked even larger pressor responses at concentrations two orders of magnitude lower (up to 80 nM). All fatty acids induced both thromboxane A2 and prostaglandin I2 release, ranking with ETA approximately PAL approximately OA < EPA as established for 10 microM concentrations; the dienoic prostanoid release in response to 80 nM AA approximated that elicited by 10 microM EPA. The n-3 fatty acid, however, provoked the liberation of excessive quantities of thromboxane A3 and prostaglandin I3, which surpassed the respective 2-series prostanoids 15- to 20-fold; no 3-series cyclooxygenase products were detected in response to AA, ETA, PAL or OA stimulation. Cyclooxygenase (acetylsalicylic acid) and thromboxane synthetase (OKY 046, Ozagrel, (E)-p-(imidazol-1-ylmethyl)cinnamic acid, C13H12N2O2, MW 228.2) inhibition largely suppressed the EPA-evoked pressor responses.(ABSTRACT TRUNCATED AT 250 WORDS)
Grimminger
F
F
Department of Internal Medicine, Justus-Liebig University, Giessen, Germany.
Mayer
K
K
Krämer
H J
HJ
Stevens
J
J
Walmrath
D
D
Seeger
W
W
D015126:8,11,14-Eicosatrienoic Acid / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000737:chemistry / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D011652:Pulmonary Circulation / Q000187:drug effects*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013930:Thromboxane-A Synthase / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents
D005230:Fatty Acids, Nonesterified; D005231:Fatty Acids, Unsaturated; D011453:Prostaglandins; D014662:Vasoconstrictor Agents; D016718:Arachidonic Acid; D015118:Eicosapentaenoic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D013930:Thromboxane-A Synthase; D015126:8,11,14-Eicosatrienoic Acid