Layered Plaque in Organic Lesions in Patients With Coronary Artery Spasm.

Background Coronary artery spasm plays a vital role in the pathogenesis of coronary plaques. We sought to investigate the plaque characteristics of co-existing organic lesions in patients with coronary artery spasm in comparison to those without coronary artery spasm by intracoronary optical coherence tomography (OCT). Methods and Results We included 39 patients who presented with a symptom suspected of coronary spastic angina and had an organic lesion, defined as ≥plaque burden of 50% assessed by OCT. Coronary artery spasm was diagnosed by positive acetylcholine provocation test, or by spontaneous spasm detected during coronary angiography. A total of 51 vessels with an organic lesion were identified. Of these, coronary artery spasm was observed in 30 vessels (spasm), while not in 21 vessels (non-spasm). Organic lesions in the spasm vessels, compared with those in the non-spasm vessels, had a higher prevalence of layered plaque (93% versus 38%, P<0.001), macrophages (80% versus 43%, P=0.016), and intraplaque microchannels (73% versus 24%, P<0.001), and lower prevalence of macrocalcification (23% versus 62%, P=0.009) as assessed by OCT. Conclusions Layered plaque, macrophages, and intraplaque microchannels, were frequently observed in organic lesions in patients with coronary artery spasm. These findings suggest that coronary artery spasm induces local thrombus formation as well as active inflammatory response, therefore increasing the risk of rapid plaque progression and ischemic events in patients with coronary artery spasm.

Tetraalkoxyphenanthrene-Fused Hexadecadehydro[20]- and Tetracosadehydro[30]annulenes: Syntheses, Aromaticity/Antiaromaticity, Electronic Properties, and Self-Assembly.

Tetraalkoxyphenanthrene-fused hexadecadehydro[20]- and tetracosadehydro[30]annulenes possessing octatetrayne linkages were synthesized and their properties together with those of phenanthrene-fused octadehydro[12]- and dodecadehydro[18]annulenes have been investigated. Various spectroscopic and electrochemical measurements as well as quantum chemical calculations support that planar [20]- and [30]annulenes are weakly antiaromatic and nonaromatic, respectively. The detailed concentration- and temperature-dependent 1H NMR and UV-vis data of present dehydroannulenes provided evidence for the enhancement of π-π stacking interactions by extension of the acetylenic linkages. Dehydroannulenes formed self-assembled clusters and their morphology and crystallinity proved to depend on the length of acetylenic linkages, the shape of dehydroannulene core, and the bulkiness of alkoxy groups appended to the phenanthrene moieties.

Tetraalkoxyphenanthrene-Fused Thiadiazoloquinoxalines: Synthesis, Electronic, Optical, and Electrochemical Properties, and Self-Assembly.

π-Extended thiadiazoloquinoxaline (TQ) derivatives 1a,b-3a,b, in which a tetraalkoxyphenanthrene moiety is annulated with the TQ core and benzene rings are incorporated via the ethynylene spacer, were synthesized. They display absorption bands reaching into 750 nm and possess the electron-affinity comparable to [60]fullerene. The CF3- and OMe-substituents on the benzene rings have moderate effects on modulation of the HOMO and LUMO levels. Tetraalkoxyphenanthrene-fused TQs 1a,b-3a,b aggregate in the solid state and assemble in solution through π-π stacking interactions. The self-assembly of 1a,b-3a,b into 1D superstructures was confirmed, and the difference in the alkoxy groups and the solvents for self-assembly proved to change their morphology. Comparison of the properties of 1a and those of reference compounds 4 and 5 clarified the effects of both the fusion of the phenanthrene moiety and the introduction of ethynylene spacers on the properties.

Effect of a selective inhibitor of secretory phospholipase A2, S-5920/LY315920Na, on experimental acute pancreatitis in rats.

We investigated the efficacy of a potent inhibitor of secretory phospholipase A2 (sPLA2), S-5920/LY315920Na, in an experimental model of acute pancreatitis in rats. Combined intraductal injection of sodium taurocholate (5 mg/rat) and porcine pancreatic sPLA2-IB (300 microg/rat) caused severe hemorrhagic necrotizing pancreatitis resulting in high mortality, along with rapid increases of catalytic PLA2 and lipase activities in plasma and ascites and with gradual increases of plasma amylase and aspartate aminotransferase levels over 9 h after the pancreatitis. Prophylactic intravenous treatment with S-5920/LY315920Na significantly reduced mortality at 7 days, and strongly abrogated PLA2 activities in both plasma and ascites along with significant reduction of lipase activity, amylase, aspartate aminotransferase, and hemorrhage at 6 h. It also significantly reduced histological damage such as edema and parenchymal and fat necroses of the pancreatic tissue. This sPLA2 inhibitor could become an effective agent for the treatment of severe acute pancreatitis.

Role of group IIA phospholipase A2 in rat colitis induced by dextran sulfate sodium.

Although group IIA phospholipase A(2) has been suggested to be implicated in inflammatory bowel disease, its pathophysiological role in colitis remains unclear. We investigated whether group IIA phospholipase A(2) had pro-inflammatory roles in dextran sulfate sodium-induced colitis in the rat. Secretory phospholipase A(2) activity was markedly increased in the distal colon with two peaks. Strong immunostaining for group IIA phospholipase A(2) was found in subepithelial tissue and lamina propria at early stage and in deeper tissues of the erosion area at later stage. Treatment with a specific group IIA phospholipase A(2) inhibitor, S-3013/LY333013 (methyl[[3-(aminooxoacetyl)-2-ethyl-1-(phenylmethyl)]-1H-indol-4yl]oxy) acetate), reduced erosion area, shortening of colon and colonic inflammation, and strongly inhibited the increase in secretory phospholipase A(2) activity and moderately reduced myeloperoxidase activity in the colon in vivo, while eicosanoid levels were not affected. Marked group IIA phospholipase A(2) expression in the erosion area and the improvement of colitis by the group IIA phospholipase A(2) inhibitor strongly suggest that this enzyme plays pro-inflammatory roles in this colitis model.

Characterization of a novel inhibitor of cytosolic phospholipase A2alpha, pyrrophenone.

Cytosolic phospholipase A(2)alpha (cPLA(2)alpha), one of the three subtypes of cPLA(2) (alpha, beta and gamma), is thought to be a rate-limiting enzyme in eicosanoid biosynthesis. We developed a novel and potent cPLA(2)alpha inhibitor with an optically active pyrrolidine, termed pyrrophenone, and characterized this compound in detail using enzyme and cellular assay systems. Pyrrophenone, which shows strong inhibition of cPLA(2)alpha activity, is one of the most potent cPLA(2)alpha inhibitors reported to date. Similar inhibitory potencies for cPLA(2)alpha were obtained from three different assays. The inhibitory activity of pyrrophenone is two or three orders of magnitude more potent than arachidonyl trifluoromethyl ketone (AACOCF(3)) under the same assay conditions. Pyrrophenone shows reversible inhibition of cPLA(2)alpha and displays no characteristics of the slow-binding inhibition observed for AACOCF(3). Pyrrophenone also inhibited the esterase and lysophospholipase activities of cPLA(2)alpha. However, the inhibition by pyrrophenone of 14 kDa secretory PLA(2)s, types IB and IIA, was over two orders of magnitude less potent than that for cPLA(2)alpha. Pyrrophenone strongly inhibited arachidonic acid release in calcium ionophore (A23187)-stimulated human monocytic cells (THP-1 cells) in a dose-dependent manner with an IC(50) value of 0.024 microM, followed by suppression of eicosanoid synthesis, and also showed dose-dependent inhibition for interleukin-1-induced prostaglandin E(2) synthesis in human renal mesangial cells with an IC(50) value of 0.0081 microM. The mechanism of inhibition of eicosanoid synthesis in these cell-based assays was due to inhibition of only one step of arachidonic acid release without any effect on cyclo-oxygenase or lipoxygenase pathways. These results suggest that pyrrophenone could be a potential therapeutic agent for inflammatory diseases.