Abstract-We tested the hypothesis that endothelin-converting enzyme (ECE) inhibition ameliorates end-organ damage in rats harboring both human renin and human angiotensinogen genes (dTGR). Hypertension develops in the animals, and they die by age 7 weeks of heart and kidney failure. Three groups were studied: dTGR (nϭ12) receiving vehicle, dTGR receiving ECE inhibitor (RO0687629; 30 mg/kg by gavage; nϭ10), and Sprague-Dawley control rats (SD; nϭ10) receiving vehicle, all after week 4, with euthanasia at week 7. Systolic blood pressure was not reduced by ECE inhibitor compared with dTGR (205Ϯ6 versus 206Ϯ6 mm Hg at week 7, respectively). In contrast, ECE inhibitor treatment significantly reduced mortality rate to 20% (2 of 10), whereas untreated dTGR had a 52% mortality rate (7 of 12). ECE inhibitor treatment ameliorated cardiac damage and reduced left ventricular ECE activity below SD levels. Echocardiography at week 7 showed reduced cardiac hypertrophy (4.8Ϯ0.2 versus 5.7Ϯ0.2 mg/g, PϽ0.01) and increased left ventricular cavity diameter (5.5Ϯ0.3 versus 3.1Ϯ0.1 mm, PϽ0.001) and filling volume (0.42Ϯ0.04 versus 0.16Ϯ0.06 mL, PϽ0.05) after ECE inhibitor compared with untreated dTGR. ECE inhibitor treatment also reduced cardiac fibrosis, tissue factor expression, left ventricular basic fibroblast growth factor mRNA levels, and immunostaining in the vessel wall, independent of high blood pressure. In contrast, the ECE inhibitor treatment showed no renoprotective effect. These data are the first to show that ECE inhibition reduces angiotensin II-induced cardiac damage. Key Words: angiotensin II Ⅲ enzymes Ⅲ fibrosis Ⅲ hypertrophy A ngiotensin (Ang) II-related vascular effects are partially mediated by endothelin-1 (ET-1). Long-term Ang II infusion induces preproendothelin mRNA expression. 1 In rats transgenic for both the human renin and human angiotensinogen genes (dTGR), hypertension as well as severe heart and kidney damage develop, largely independent of blood pressure elevation. The rats die by age 7 weeks. 2 The ET-1 A and B (ETA/B) receptor blocker bosentan inhibits the activation of both nuclear factor-kappa B (NF-B) and transcription factor activator protein (AP)-1 in the kidney and the heart, independent of blood pressure reduction in these rats. 3 Bohlender et al 4 studied the same rat strain and showed that a specific ETA receptor blocker is effective, particularly when combined with an Ang II receptor blocker. ET-1 is a 21-amino acid peptide that was first isolated from porcine endothelial cells. 5 Two structurally related peptides differing by 2 (ET-2) and 6 (ET-3) amino acids were subsequently identified. The endothelin precursors are processed by 2 proteases that create mature active forms, termed preproendothelins. The preproendothelins are cleaved at dibasic sites by furin-like endopeptidases to produce inactive intermediates termed big endothelins. Big endothelins are cleaved to form the final products. A family of membrane-bound zinc metalloproteases from the neprilysin superfamily conducts the last...

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Intestinal microcirculatory disturbances play an important role in the pathophysiology of sepsis. A neural antiinflammatory pathway has been suggested as a potential target for therapy that may dampen systemic inflammation. The aim of this study is to investigate the effects of physostigmine, a cholinesterase inhibitor, on the intestinal microcirculation and vascular contractility in experimental endotoxemia. Endotoxemia was induced in Lewis rats by intravenous lipopolysaccharide (LPS) administration. Animals were treated with either physostigmine or saline (control) following LPS challenge. The intestinal microcirculation, including leukocyte-endothelial interaction, functional capillary density (FCD) and non-perfused capillary density (NCD), was examined by intravital microscopy (IVM) 2 hours after LPS administration. The impact of physostigmine on vascular contractility of rat aortic rings was examined by in vitro myography. Physostigmine significantly reduced the number of adhering leukocytes in intestinal submucosal venules (V1 venules: −61%, V3 venules: −36%) of LPS animals. FCD was significantly increased by physostigmine treatment (circular muscle layer: +180%, longitudinal muscle layer: +162%, mucosa: +149%). Low concentrations of physostigmine produced significant contraction of aortic ring preparations, whereas high concentrations produced relaxation. In conclusion, physostigmine treatment significantly improved the intestinal microcirculation in experimental endotoxemia by reducing leukocyte adhesion and increasing FCD.

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