AbstractA significant inflammatory reaction in the rat conjunctiva followed the subconjunctival injection of synthetic platelet activating factor (PAF) in doses which ranged from 10 ng to 1 μg, an inflammatory response being evaluated as the increase in both tissue weight and extravasation of Evans blue dye in the conjunctival tissue. Inflammation was still present 6 h after the injection of 0ṁ1 μg of PAF. Orally administered indomethacin or BW 755C failed to alter the response to 0ṁ1 μg of PAF. In contrast, the PAF-induced inflammation was blocked by the oral administration of the PAF receptor antagonist, L-652, 731, a dose as low as 5 mg kg−1 eliciting a significant inhibition. The topical administration of L-652, 731, (two doses of 100 μg as a 1% suspension), elicited a slight, but significant blockade of 23%. Its antagonistic action was more striking when it was co-injected subconjunctivally with 0ṁ1 μg of PAF, a dose as low as 3 μg evoking a significant blockade. The topical administration of 0ṁ1 μg of PAF did not elicit a significant inflammatory reaction and this contrasts with the results obtained after its subconjunctival injection.

01 Mar 2011·American Journal of Physiology-Heart and Circulatory PhysiologyQ2 · MEDICINE

Role of arachidonic acid lipoxygenase metabolites in acetylcholine-induced relaxations of mouse arteries

Q2 · MEDICINE

Article

Author: Gauthier, Kathryn M. ; Campbell, William B. ; Goldman, Daniel H. ; Aggarwal, Nitin T. ; Falck, J. R. ; Chawengsub, Yuttana

Arachidonic acid (AA) metabolites function as EDHFs in arteries of many species. They mediate cyclooxygenase (COX)- and nitric oxide (NO)-independent relaxations to acetylcholine (ACh). However, the role of AA metabolites as relaxing factors in mouse arteries remains incompletely defined. ACh caused concentration-dependent relaxations of the mouse thoracic and abdominal aorta and carotid, femoral, and mesentery arteries (maximal relaxation: 57 ± 4%, 72 ± 4%, 82 ± 3%, 80 ± 3%, and 85 ± 3%, respectively). The NO synthase inhibitor nitro-l-arginine (l-NA; 30 μM) blocked relaxations in the thoracic aorta, and l-NA plus the COX inhibitor indomethacin (10 μM) inhibited relaxations in the abdominal aorta and carotid, femoral, and mesenteric arteries (maximal relaxation: 31 ± 10%, 33 ± 5%, 41 ± 8%, and 73 ± 3%, respectively). In mesenteric arteries, NO- and COX-independent relaxations to ACh were inhibited by the lipoxygenase (LO) inhibitors nordihydroguaiaretic acid (NDGA; 10 μM) and BW-755C (200 μM), the K+channel inhibitor apamin (1 μM), and 60 mM KCl and eliminated by endothelium removal. They were not altered by the cytochrome P-450 inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (20 μM) or the epoxyeicosatrienoic acid antagonist 14,15-epoxyeicosa-5( Z)-enoic acid (10 μM). AA relaxations were attenuated by NDGA or apamin and eliminated by 60 mM KCl. Reverse-phase HPLC analysis revealed arterial [14C]AA metabolites that comigrated with prostaglandins, trihydroxyeicosatrienoic acids (THETAs), hydroxyepoxyeicosatrienoic acids (HEETAs), and hydroxyeicosatetraenoic acids (HETEs). Epoxyeicosatrienoic acids were not observed. Mass spectrometry confirmed the identity of 6-keto-PGF1α, PGE2, 12-HETE, 15-HETE, HEETAs, 11,12,15-THETA, and 11,14,15-THETA. AA metabolism was blocked by NDGA and endothelium removal. 11( R),12( S),15( S)-THETA relaxations (maximal relaxation: 73 ± 3%) were endothelium independent and blocked by 60 mM KCl. Western immunoblot analysis and RT-PCR of the aorta and mesenteric arteries demonstrated protein and mRNA expression of leukocyte-type 12/15-LO. Thus, in mouse resistance arteries, 12/15-LO AA metabolites mediate endothelium-dependent relaxations to ACh and AA.

01 Mar 2009·American Journal of Physiology-Heart and Circulatory PhysiologyQ2 · MEDICINE

Chronic hypoxia enhances 15-lipoxygenase-mediated vasorelaxation in rabbit arteries

Q2 · MEDICINE

Article

Author: Kathryn M. Gauthier ; John E. Baker ; Nitin T. Aggarwal ; Yuttana Chawengsub ; William B. Campbell ; Sandra L. Pfister

15-Lipoxygenase (15-LO-1) metabolizes arachidonic acid (AA) to 11,12,15-trihydroxyeicosatrienoic acids (THETAs) and 15-hydroxy-11,12-epoxyeicosatrienoic acids (HEETA) that dilate rabbit arteries. Increased endothelial 15-LO-1 expression enhances arterial relaxations to agonists. We tested the effect of hypoxia on 15-LO-1 expression, THETA and HEETA synthesis, and relaxations in rabbit arteries. The incubation of rabbit aortic endothelial cells and isolated aortas in 0.7% O2 increased 15-LO-1 expression. Rabbits were housed in a hypoxic atmosphere of 12% O2 for 5 days. 15-LO-1 expression increased in the endothelium of the arteries of rabbits in 12% O2 compared with room air. THETA and HEETA synthesis was also enhanced in aortas and mesenteric arteries. AA hyperpolarized the smooth muscle cells in indomethacin- and phenylephrine-treated mesenteric arteries of hypoxic rabbits from −29.4 ± 1 to −50.1 ± 3 mV. The hyperpolarization to AA was less in arteries of normoxic rabbits (from −26.0 ± 2 to −37 ± 2 mV). This AA-induced hyperpolarization was inhibited by the 15-LO inhibitor BW-755C. Nitric oxide and prostaglandin-independent maximum relaxations to acetylcholine (79.7 ± 2%) and AA (38.3 ± 4%) were enhanced in mesenteric arteries from hypoxic rabbits compared with the normoxic rabbits (49.7 ± 6% and 19.9 ± 2%, respectively). These relaxations were inhibited by BW-755C and nordihydroguaiaretic acid. Therefore, hypoxia increased the relaxations to agonists in the rabbit mesenteric arteries by enhancing endothelial 15-LO-1 expression and synthesis of the hyperpolarizing factors THETA and HEETA.

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Preclinical	-	GSK Plc	-
Thrombosis	Preclinical	CA	-	-
Thrombosis	Preclinical	CA	-	-
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