u 46619

U-46619 is an effective thromboxane A2 (TXA2) agonist and a thromboxane A2 analog (endoperoxide), capable of inducing contraction in the aortic smooth muscle (SM) of mice with a myosin light chain 9 (Myl9) gene deletion.

CI-930 is a PDE-III inhibitor with broad-spectrum activity. It exerts its anti-aggregation effects through a dual mechanism: enhancing cAMP levels and selectively inhibiting the synthesis of TXA2 in platelets. CI-930 effectively inhibits platelet aggregation induced by AA, U-46619, ADP, collagen, and PAF, with IC50 values of 0.91, 0.73, 2.12, 2.35, and 7.15 mumols L, respectively.

(±)11-HDHA is an autoxidation product of docosahexaenoic acid (DHA) in vitro. It is also produced from incubations of DHA in rat liver, brain, and intestinal microsomes. DHA is metabolized to 11(S)-HDHA by human platelets and canine retina. In addition to 11(S)-HDHA, 14(S)-HDHA is also produced by platelets. 11(S)-HDHA was shown to be an inhibitor of U-46619-induced human platelet aggregation and rabbit and rat aortic smooth muscle contraction with IC50 values of about 50, 4.7, and 7.5 μM, respectively. (±)11-HDHA is a potential marker of oxidative stress in brain and retina where DHA is an abundant polyunsaturated fatty acid.

8-iso PGE2 is one of several isoprostanes produced from arachidonic acid during lipid peroxidation. It is a potent renal vasoconstrictor in the rat. 8-iso PGE2 inhibits U-46619 or I-BOP-induced platelet aggregation with IC50 values of 0.5 and 5 μM, respectively. When infused into the renal artery of the rat at a concentration of 4 μg/kg/min, 8-iso PGE2 decreases the GFR and renal plasma flow by 80% without affecting blood pressure.

8-iso-13,14-dihydro-15-keto Prostaglandin F2α (8-iso-13,14-dihydro-15-keto PGF2α) is a metabolite of the isoprostane, 8-isoprostane (8-iso PGF2α), in rabbits, monkeys and humans. 8-iso PGF2α is a PG-like product of non-specific lipid peroxidation. In both humans and monkeys, exogenously infused 8-isoprostane is converted primarily to metabolites having 2 or 4 carbon atoms removed from the top side chain by β-oxidation. A similar pattern is observed when tritiated 8-isoprostane is infused into rabbits. Early in the infusion (within 10 minutes) 8-iso-13,14-dihydro-15-keto PGF2α was a significant component of the metabolite profile, which was comprised mostly of dinor 8-isoprostane metabolites. 8-iso-13,14-dihydro-15-keto PGF2α weakly inhibits the U-46619 or collagen-induced aggregation of human platelets, although a number of the E-series isoprostanes are much more potent in this assay.

TPα and TPβ are two isoforms of the human TP receptor, the G protein-coupled receptor (GPCR) that mediates the actions of thromboxane A2 (TXA2). Although their distinct physiological functions have not been fully elucidated, TPβ is believed to be responsible for vascular endothelial growth factor-induced endothelial cell differentiation and migration whereas TPα appears to be the predominant isoform expressed in platelets. CAY10535 is a TP receptor antagonist that shows ~20-fold selectivity for TPβ (IC50 = 99 nM) relative to TPα (IC50 = 1,970 nM) in the inhibition of U46619-mediated Ca2+ mobilization. This compound exhibits relatively poor activity on platelets (IC50 = 985 nM) when inhibiting U-46619-induced platelet aggregation.

Adrenomedullin (13-52) is a truncated form of adrenomedullin (1-52) . It induces nitric oxide-dependent relaxation of and inhibits release of angiotensin II and endothelin-1 from isolated rat aorta. In vivo, adrenomedullin (13-52) decreases mean arterial pressure (MAP) in spontaneously and renal hypertensive rats in a dose-dependent manner. Adrenomedullin (13-52) (10-3,000 ng per animal) reverses increases in lobar arterial pressure induced by U-46619 in a dose-dependent manner in cats but has no effect on basal lobar arterial pressure or systemic arterial pressure. It also potentiates inflammatory edema and neutrophil accumulation in rats.

(±)17-HDHA is an autoxidation product of docosahexaenoic acid in vitro. It is also produced from incubations of DHA in rat liver, brain, and intestinal microsomes. 17(S)-HDHA could be produced by enzymatic oxidation of DHA using soybean lipoxygenase (LO) and is the putative product of mammalian 15-LOs. 17(S)-HDHA was shown to be an inhibitor of U-46619 -induced rabbit and rat aortic smooth muscle contraction with IC50 values of 4.9 and 7.2 μM, respectively. (±)17-HDHA is a potential marker of oxidative stress in brain and retina where DHA is an abundant polyunsaturated fatty acid.

13(R)-HODE is the opposite enantiomer of 13(S)-HODE produced when linoleic acid is incubated with soybean lipoxygenase. Its presence in supernatants and membranes of cultured bovine endothelial cells has been attributed to COX metabolism. 13(R)-HODE is a weak (IC50 = 2.7 μM) inhibitor of U-46619-induced platelet aggregation.

(±)13,14-EDT, an oxylipin metabolite derived from adrenic acid through the cytochrome P450 (CYP) pathway, acts as a potent activator of large-conductance calcium-activated potassium channels (KCa1.1/BK) in isolated rat coronary small arterial smooth muscle cells at 50 nM, promoting dilation. Additionally, it induces arteriole dilation in isolated porcine samples with an EC50 of 12 pM and relaxes isolated bovine coronary arteries previously contracted by TP receptor agonist U-46619.

(±)16,17-EDT, an oxylipin metabolite of adrenic acid produced through the cytochrome P450 (CYP) pathway, effectively induces dilation in isolated porcine arterioles (EC50 = 11 pM) and promotes relaxation of isolated bovine coronary arteries previously contracted by the TP receptor agonist U-46619.