benazepril and Inflammation

Benazepril, an angiotensin-converting enzyme (ACE) inhibitor, has been used to treat hypertension, congestive heart failure, and chronic renal failure. However, its biological activity and mechanism of action in inflammation are not fully identified. The present study was designed to determine the in vivo anti-inflammatory effects of benazepril on LV hypertrophy in rats.. LV hypertrophy was produced in rats by abdominal aortic coarctation. They were then divided into the following groups: sham operation; LV hypertrophy; LV hypertrophy+benazepril (1mg/kg in a gavage, once a day for 4 weeks). Both morphological assays (hemodynamic and hemorheological measurement; LV hypertrophy assessment), and molecular assays (protein levels of Collagen type I/III, TNF-α and VCAM-1; TGF-β gene expression; NF-κB or Smad activation; intracellular ROS production) were performed.. The following effects were observed in rats treated with benazepril: (1) marked improvements in hemodynamic and hemorheological parameters; (2) significant reductions in LV hypertrophy, dilatation and fibrosis; (3) significantly attenuated protein levels of Collagen type I/III, TGF-β, TNF-α and VCAM-1, NF-κB or Smad activation, as well as intracellular ROS production.. These results suggest that the anti-inflammatory properties of benazepril may be ascribed to their down-regulation of both NF-κB and TGF-β signaling pathways by acting on the intracellular ROS production in rats with LV hypertrophy, thus supporting the use of benazepril as an anti-inflammatory agent.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Aorta; Aortic Coarctation; Benzazepines; Blood Pressure; Collagen Type I; Collagen Type III; Enzyme Activation; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Inflammation; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1

The incidence of cardiovascular diseases in premenopausal women is lower than in men or postmenopausal women. This study reports the discovery of a low grade of systemic inflammation, including monocyte adhesion to arterial endothelium, elicited by menopause or estrogen depletion. Chronic treatment with low dose of 17-beta-estradiol or inhibition of the renin-angiotensin system reduced this inflammation. Using an in vitro flow chamber system with human arterial and venous endothelial cells, we found that leukocytes from healthy postmenopausal women were more adhesive to the arterial endothelium than those from premenopausal women regardless of the stimulus used on endothelial cells. Increased circulating levels of IL-8, MCP-1, RANTES, and MIP-1alpha and monocyte CD11b expression were also encountered in postmenopausal vs premenopausal subjects. This translational data led us to investigate the mechanisms in Sprague-Dawley rats. Using intravital microscopy, we imaged mesenteric arterioles and found significant increases in arteriolar leukocyte adhesion, cell adhesion molecule expression, and plasma levels of cytokine-induced neutrophil chemoattractant (CINC/KC), MCP-1, and MIP-1alpha in 1-mo ovariectomized rats. Chronic treatment of ovariectomized rats with low dose of 17-beta-estradiol, losartan, both, or benazepril inhibited ovariectomy-induced arteriolar mononuclear leukocyte adhesion by 77%, 58%, 92%, and 65% respectively, partly by inhibition of cell adhesion molecule up-regulation and the increase in circulating chemokines. These results demonstrate that menopause and ovariectomy generate a low grade of systemic inflammation. Therefore, administration of low doses of estrogens or inhibition of the renin-angiotensin system, at early stages of estrogen deficiency, might prevent the systemic inflammation associated with menopause and decrease the risk of suffering further cardiovascular diseases.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Animals; Benzazepines; Case-Control Studies; Cell Adhesion; Cell Adhesion Molecules; Cells, Cultured; Chemokines; Endothelial Cells; Endothelium, Vascular; Estrogens; Female; Humans; Inflammation; Leukocytes; Losartan; Menopause; Middle Aged; Ovariectomy; Rats; Rats, Sprague-Dawley