pig-15

14,15-Leukotriene D4 (14,15-LTD4) is a member of an alternate class of LTs synthesized by a pathway involving the dual actions of 15- and 12-lipoxygenases (15- and 12-LOs) on arachidonic acid via 15-HpETE and 14,15-LTA4 intermediates. 14,15-LTD4 is classified as an eoxin (EXD4), because it is formed mostly by eosinophils. However, mast cells and nasal polyps can synthesize 14,15-LTD4 as well. Little is known about the physiological actions of 14,15-LTD4. It has weak contractile activity on both guinea pig ileum and pulmonary parenchyma in contrast to the effects of 5-LO-derived LTs. However, in an in vitro permeability assay, 14,15-LTD4 can increase vascular permeability of human endothelial cell monolayers, with similar potency to that of 5-LO-derived LTs, resulting in plasma leakage, a hallmark of inflammation.

14-Anhydrodigitoxigenin is a cardenolide and a derivative of digitoxin.1 It reduces the activity of guinea pig heart Na+/K+-ATPase by 15% when used at a concentration of 10 μM.2

14S(15R)-EET is an oxylipin and a cytochrome P450 metabolite of arachidonic acid .114S(15R)-EET binds to isolated guinea pig monocytes with a Kivalue of 612.5 nM in a competitive binding assay using [3H]14(15)-EET.2It induces dilation of precontracted isolated canine epicardial arterioles (EC50= 4 pM) and denuded porcine subepicardial arterioles (EC50= 3 pM).3Unlike 14R(15S)-EET, 14S(15R)-EET does not inhibit COX in enzyme assays or isolated platelets.4 1.Daikh, B.E., Lasker, J.M., Raucy, J.L., et al.Regio- and stereoselective epoxidation of arachidonic acid by human cytochromes P450 2C8 and 2C91J. Pharmacol. Exp. Ther.271(3)1427-1433(1994) 2.Wong, P.Y.-K., Lai, P.-S., and Falck, J.R.Mechanism and signal transduction of 14 (R), 15 (S)-epoxyeicosatrienoic acid (14,15-EET) binding in guinea pig monocytesProstaglandins Other Lipid Mediat.62(4)321-333(2000) 3.Zhang, Y., Oltman, C.L., Lu, T., et al.EET homologs potently dilate coronary microvessels and activate BKCa channelsAm. J. Physiol. Heart Circ. Physiol.280(6)H2430-H2440(2001) 4.Fitzpatrick, F.A., Ennis, M.D., Baze, M.E., et al.Inhibition of cyclooxygenase activity and platelet aggregation by epoxyeicosatrienoic acidsJ. Biol. Chem.261(2)15334-15338(1986)

The lipoxins are trihydroxy fatty acids containing a 7,9,11,13-conjugated tetraene. Lipoxin A4 (LXA4) was first described as a metabolite of 15-HpETE and/or 15-HETE when added in vitro to isolated human leukocytes. The material obtained in this manner consists of at least four distinct isomers: 5(S), 6(S); 5(S), 6(R); and the 11-trans and 11-cis isomers of each of these. 6(S)-LXA4 is one of the original four metabolites first identified by Serhan, Nicolaou, and Samuelsson. It was considered to be an artifact by these authors because it lacked the potency of the 5(S),6(R) isomer with respect to contraction of isolated guinea pig lung parenchymal strips. It has not been possible to isolate natural LXA4 from humans or other mammals in amounts sufficient for determination of absolute stereochemistry. Most authors refer to LXA4 as the 5(S)

15(S)-HEPE is a monohydroxy fatty acid synthesized from EPA by the action of 15-LO. The biosynthesis of 15-HEPE from EPA in guinea pig epidermal enzyme preparations has been documented. 15(S)-HEPE generated by soybean lipoxygenation of EPA inhibits RBL-1 cell 5-LO with an IC50 value of 28 μM.

14S(15R)-EET methyl ester, an oxylipin derived from arachidonic acid through cytochrome P450 metabolism, demonstrates specific biological activities. It exhibits affinity for isolated guinea pig monocytes, evidenced by a competitive binding assay with a Ki value of 612.5 nM using [3H]14(15)-EET. This compound notably enhances the dilation of precontracted isolated canine epicardial arterioles (EC50= 4 pM) and denuded porcine subepicardial arterioles (EC50= 3 pM), indicating potent vasodilatory effects. Unlike its isomer 14R(15S)-EET, 14S(15R)-EET methyl ester does not inhibit COX activity in enzyme assays or affect isolated platelets, highlighting its distinct functional profile.

AM-211 sodium is a novel and potent antagonist of the prostaglandin D2 receptor type 2. AM-211 is active in animal models of allergic inflammation. AM211 has high affinity for human, mouse, rat, and guinea pig DP2 and it shows selectivity over other prostanoid receptors and enzymes. AM211 exhibits good oral bioavailability in rats and dogs and dose-dependently inhibits 13,14-dihydro-15-keto-PGD(2)-induced leukocytosis in a guinea pig pharmacodynamic assay.

BI-749327 is a high selectivity and orally bioavailable antagonist of TRPC6 (IC50s: 13 nM, 19 nM and 15 nM for mouse, human and guinea pig TRPC6).

5,6-dehydro Arachidonic acid is an analog of arachidonic acid with an acetylene in the 5,6 position. It inhibits 5-LO in rat basophilic leukemia cells, with a Ki value of 15 μM. In guinea pig leukocytes, 5-LO is inhibited by 5,6-dehydro arachidonic acid with an IC50 value of 10 μM.

Leukotriene C4 (14,15-LTC4) is an inflammatory mediator synthesized from arachidonic acid through the actions of 15- and 12-lipoxygenases (LOs), involving intermediates such as 15-HpETE and 14,15-LTA4. Unlike the majority of leukotrienes formed via the 5-LO pathway, 14,15-LTC4 is an eoxin predominantly produced by eosinophils, although mast cells and nasal polyps can also synthesize it. While its physiological roles are not well understood, 14,15-LTC4 exhibits limited contractile activity on guinea pig ileum and pulmonary parenchyma. However, it can increase vascular permeability in human endothelial cell monolayers in vitro with potency comparable to 5-LO-derived leukotrienes, contributing to plasma leakage characteristic of inflammation.

11β-13,14-Dihydro-15-keto PGF2α, a PGD2 metabolite in the 15-hydroxy PGDH pathway, is formed in human males upon infusion or inhalation of tritiated PGD2, with peak plasma levels of both 11β-PGF2α and 11β-13,14-dihydro-15-keto PGF2α observed within 10 minutes. In human lung homogenates, PGD2 is metabolized firstly to 11β-PGF2α and subsequently to 11β-15-keto-PGF2α in the presence of NAD+, but not to 11β-13,14-dihydro-15-keto PGF2α. Conversely, guinea pig liver and kidney homogenates can metabolize PGD2 to 11β-13,14-dihydro-15-keto PGF2α via 11β-PGF2α, with both NAD+ and NADP+ being requisite for this conversion.

Prostaglandin A1 (PGA1) was first isolated as a dehydration product of the PGE1 compounds found in human semen. 15-keto PGA1 is a metabolite of PGA1, produced by 15-hydroxy PG dehydrogenase. It can be produced from PGA1 in pig lung, trachea, aorta, and pulmonary artery tissue preparations. 15-keto PGA1, given at a concentration of 6 μM, causes vasoconstriction of rabbit lung that is comparable to that induced by angiotensin II.