Selective inhibition of angiotensin II-mediated vasoconstriction by lipoxygenase blockade.
We have previously demonstrated that the lipoxygenase (LO) pathway has a specific role in the effect of angiotensin II (ANG II) on aldosterone secretion. To elucidate whether the LO pathway also participates in the vascular effects of ANG II, the nonselective LO inhibitor phenidone (PHE; 30 mg/kg) was administered to rats 1 h before graded dose ANG II infusion. PHE reduced the LO product 12-hydroxyeicosatetraenoic acid (12-HETE) in deendothelialized aortas by an average of 36% as determined by radiometric detection with high-performance liquid chromatography and radioimmunoassay methods. In parallel, the peak systolic pressor response to ANG II was lowered from 36.2 +/- 3.7 to 16.8 +/- 2.0 mmHg. The peak pressor responses to ANG II were also reduced by two other LO inhibitors, baicalein (30 mg/kg) and esculetin (60 mg/kg) (13.9 +/- 2.4 and 22.1 +/- 4.7 mmHg, respectively; P less than 0.01 compared with control rats for both), but not by the cyclooxygenase inhibitor indomethacin. The LO inhibitors baicalein (7.5 X 10(-5) M) and PHE (10(-4) M) markedly attenuated the in vitro contractile response to ANG II of femoral artery rings. In contrast, neither the in vivo nor in vitro constrictor responses to norepinephrine were affected by baicalein. Thus lipoxygenase blockade induces a direct and selective inhibition of ANG II-induced vasoconstriction. The LO pathway may have an important role in mediating the pressor effect of ANG II.
Stern
N
N
Department of Medicine, University of California, Los Angeles.
Golub
M
M
Nozawa
K
K
Berger
M
M
Knoll
E
E
Yanagawa
N
N
Natarajan
R
R
Nadler
J L
JL
Tuck
M L
ML
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D003971:Diastole / Q000187:drug effects; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology*; D044950:Flavanones; D005419:Flavonoids / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013599:Systole / Q000187:drug effects; D014468:Umbelliferones / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D044950:Flavanones; D005419:Flavonoids; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D014468:Umbelliferones; D000804:Angiotensin II; C006680:baicalein; D011189:Potassium Chloride; C015429:phenidone; C007628:esculetin; D009638:Norepinephrine; D007213:Indomethacin