Ϫ ) react with nitric oxide (NO) to form peroxynitrite (ONOO Ϫ ), a process that limits NO availability, results in NO synthase (NOS) uncoupling, and, through the action of ONOO Ϫ , leads to protein and thiol oxidation as well as tyrosine nitration. 1 Hydrogen peroxide (H 2 O 2 ), the dismutation product of O 2 Ϫ , also elicits multiple effects, among them smooth muscle cell hypertrophy, activation of metalloproteinases, and, in higher concentrations, NOS inhibition by phosphorylation of tyrosine 657 through the redox-activated tyrosine kinase Pyk2. 2 Interestingly, H 2 O 2 also induces positive endothelial effects because it can activate protein kinase-G I␣ by thiol oxidation and subsequent dimerization. 3 Moreover, H 2 O 2 induces as well as activates endothelial NOS (eNOS). 4

Epoxyeicotrienoic acids (EETs) are cytochrome P450-dependent anti-hypertensive and anti-inflammatory derivatives of arachidonic acid, which are highly abundant in the kidney and considered reno-protective. EETs are degraded by the enzyme soluble epoxide hydrolase (sEH) and sEH inhibitors are considered treatment for chronic renal failure (CRF). We determined whether sEH inhibition attenuates the progression of CRF in the 5/6-nephrectomy model (5/6-Nx) in mice. 5/6-Nx mice were treated with a placebo, an ACE-inhibitor (Ramipril, 40 mg/kg), the sEH-inhibitor cAUCB or the CYP-inhibitor fenbendazole for 8 weeks. 5/6-Nx induced hypertension, albuminuria, glomerulosclerosis and tubulo-interstitial damage and these effects were attenuated by Ramipril. In contrast, cAUCB failed to lower the blood pressure and albuminuria was more severe as compared to placebo. Plasma EET-levels were doubled in 5/6 Nx-mice as compared to sham mice receiving placebo. Renal sEH expression was attenuated in 5/6-Nx mice but cAUCB in these animals still further increased the EET-level. cAUCB also increased 5-HETE and 15-HETE, which derive from peroxidation or lipoxygenases. Similar to cAUCB, CYP450 inhibition increased HETEs and promoted albuminuria. Thus, sEH-inhibition failed to elicit protective effects in the 5/6-Nx model and showed a tendency to aggravate the disease. These effects might be consequence of a shift of arachidonic acid metabolism into the lipoxygenase pathway.

Levosimendan attenuates pulmonary vascular remodeling, presumably by an antiproliferative and anti-inflammatory effect which is mediated by cellular hyperpolarization. The compound also has a direct inhibitory effect on cardiac hypertrophy, which is however K(+)-channel independent.

Objective-Epoxyeicosatrienoic acids (EETs) have antiinflammatory effects and are required for normal endothelial function. The soluble epoxide hydrolase (sEH) metabolizes EETs to their less active diols. We hypothesized that knockout and inhibition of sEH prevents neointima formation in hyperlipidemic ApoE Ϫ/Ϫ mice. Methods and Results-Inhibition of sEH by 12-(3-adamantan-1-yl-ureido) dodecanoic acid or knockout of the enzyme significantly increased plasma EET levels. sEH activity was detectable in femoral and carotid arteries. sEH knockout or inhibition resulted in a significant reduction of neointima formation in the femoral artery cuff model but not following carotid artery ligation. Although macrophage infiltration occurred abundantly at the site of cuff placement in both sEH ϩ/ϩ and sEH Ϫ/Ϫ , the expression of proinflammatory genes was significantly reduced in femoral arteries from sEH Ϫ/Ϫ mice. Moreover, an in vivo 5-bromo-2Ј-deoxyuridine assay revealed that smooth muscle cell proliferation at the site of cuff placement was attenuated in sEH knockout and sEH inhibitor-treated animals. Key Words: epoxyeicosatrienoic acids Ⅲ lipid mediators Ⅲ neointima Ⅲ migration Ⅲ smooth muscle cells N eointima formation is an important clinical problem contributing to vaso-occlusive diseases, such as restenosis after coronary angioplasty or atherosclerosis. The process is complex and, at least in rodents, involves proliferation of smooth muscle cells (SMCs) in response to growth factors (such as platelet-derived growth factor), migration of SMCs into the subendothelial layer, 1 and recruitment of monocytes and transdifferentiation of circulating progenitor cells at the site of the lesion. 2 Many systemic and local factors modulate these events. Mechanical injury, inflammation, oxidative stress, 3 and hyperlipidemia promote neointima formation, whereas nitric oxide (NO), generated by either endothelial or inducible NO synthases, attenuates neointima formation. 4 Several different models of neointima development can be studied in rodents. In almost every model, hyperlipidemia, induced by fat feeding or genetic deletion of the low-density lipoprotein receptor or apolipoproteins, is a prerequisite for neointima formation, which is then combined with a second stimulus. 5 Such a second stimulus is usually an alteration in blood flow and subsequent changes in local endothelial NO production, as it occurs in the carotid artery ligation model 6 ; mechanical injury and endothelial denudation, as in the oversized balloon model; or vascular irritation induced by a foreign body, as in the femoral artery cuff model. 4 Although all of these interventions promote neointima formation, the degree of inflammation and the contribution of NO to the process vary considerably. In general, the femoral artery cuff model is considered more inflammatory than the carotid ligation model, the latter being dominated by NO withdrawal. Conclusion-TheseNitric oxide, however, is not the only vasoprotective endothelial autacoid. Prostacyclin and epoxyeic...

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