2-3-dinor-6-ketoprostaglandin-f1alpha and Inflammation

The use of cyclooxygenase-2 (COX-2) inhibitors has been reported to be associated with detrimental vascular events. The aim of our study was to evaluate the role of COX-2 activity in the control of human vascular tone under inflammatory conditions.. Using organ bath experiments, the contraction induced by norepinephrine (NE), U46619, acetylcholine, and KCl was performed on isolated human internal mammary arteries (IMA) cultured in the presence or absence of both interleukin-1beta (IL-1beta) and lipopolysaccharide (LPS) with or without endothelium. Under these conditions the COX (cyclooxygenase) isoforms were detected by immunohistochemistry and western blot, and the prostaglandins (PG) and thromboxane (Tx) released were measured using an enzyme immunoassay kit. A significant decrease in the maximal effect induced by NE but not by other stimuli was observed in the IL-1beta- and LPS-treated preparations after 6 and 24 h of culture (-19 +/- 6 and -25 +/- 4%, respectively), an effect that was endothelium independent. Under this inflammatory condition, the COX-2 inhibitors DFU (1 micromol/L), DuP-697 (0.5 micromol/L), and Etoricoxib (1 micromol/L) markedly restored and increased the vascular reactivity to NE. These alterations were not observed with SC-560 (1 micromol/L), a selective COX-1 inhibitor. In addition, the COX-1 isoform was always detected and the COX-2 isoform was only found in human IMA exposed for 6 or 24 h under inflammatory conditions. The COX-2 induction was accompanied by an increase in PGE(2) (prostaglandin E(2)) and PGI(2) (prostaglandin I(2)) release in the culture medium (approximately 2.5-fold) but not with an increase in TxA(2) (thromboxane A(2)) release.. These observations suggest that the inhibition of COX-2 directly potentiates the human vascular tone induced by NE under inflammatory conditions.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Aged; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Endothelium, Vascular; Female; Humans; Inflammation; Interleukin-1beta; Lipopolysaccharides; Male; Middle Aged; Norepinephrine; Organ Culture Techniques; Thromboxane B2; Vasoconstriction

Chronic proliferative responses of different vascular cell types have been involved in the pathogenesis of atherosclerosis. However, their functional role remains to be established. Sirolimus reduces neointimal proliferation after balloon angioplasty and chronic graft vessel disease. These studies were undertaken to investigate the effects of this anti-proliferative drug on atherogenesis.. Low-density lipoprotein receptor-deficient (LDL r-KO) mice on a cholesterol-rich diet were randomized to receive placebo or sirolimus (0.1; 0.3; or 1 mg.kg(-1)) in their diet for 8 or 16 weeks.. In both studies, plasma levels of the drug increased in a dose-dependent fashion, animals gained weight normally and, among groups, plasma lipids levels did not differ significantly. Compared with placebo, plasma levels of interleukin-6, monocyte chemoattractant protein-1, interferon gamma, tumour necrosis factor alpha and CD40, and their mRNA levels in aortic tissue were significantly reduced in sirolimus-treated mice. This effect resulted in a significant and dose-dependent reduction in atherosclerotic lesions, in both the root and aortic tree. Also these lesions contained less monocyte/macrophages and smooth muscle cells, but more collagen.. The present results demonstrated that at low doses, sirolimus was an effective and safe anti-atherogenic agent in the LDL r-KO mice. It attenuated the progression of atherosclerosis and modulated the plaque phenotype by reducing the pro-inflammatory vascular responses typical of the disease.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Atherosclerosis; Cholesterol; Collagen; Creatinine; Cytokines; Diet, Atherogenic; Dose-Response Relationship, Drug; Inflammation; Isoprostanes; Male; Mice; Mice, Knockout; Random Allocation; Receptors, LDL; Sirolimus; Thromboxane B2; Time Factors; Triglycerides