Human pulmonary arteries dilate to 20-HETE, an endogenous eicosanoid of lung tissue.
We investigated the effect of 20-hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid metabolite of the cytochrome P-450 (cP450) 4A pathway, on human pulmonary arterial tone. 20-HETE elicited a dose-dependent and indomethacin-inhibitable vasodilation of isolated small pulmonary arteries. Whole lung microsomes metabolized [24C]arachidonic acid into 20-HETE and a variety of leukotrienes, epoxyeicosatrienoic acids, and prostanoids. Indomethacin blocked formation of prostanoids without effects on the conversion of arachidonate into 20-HETE, 20-HETE was converted by lung microsomes into prostanoids, raising the possibility that 20-HETE may be metabolized by cyclooxygenase enzymes in vascular tissue to a vasodilatory compound. Western blots probed with a polyclonal antibody to cP450 4A identified a protein of approximately 50 kDa immunologically similar to the cP450 4A in rat liver. We conclude that small arteries from human lungs dilate upon exposure to 20-HETE in a cyclooxygenase-dependent manner and that the proteins and enzymatic activity required to synthesize this product are present in lungs. Our observations suggest that cP450 enzyme products could be endogenous modulators of pulmonary vascular tone.
Birks
E K
EK
Department of Physiology, Medical College of Wisconsin, Milwaukee 53226, USA.
Bousamra
M
M
Presberg
K
K
Marsh
J A
JA
Effros
R M
RM
Jacobs
E R
ER
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002415:Cats; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000378:metabolism; D005260:Female; D005289:Ferrets; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011651:Pulmonary Artery / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D014664:Vasodilation
D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid