Calcium channel blocker nilvadipine, but not diltiazem, inhibits ocular inflammation in endotoxin-induced uveitis.
ABSTRACT Calcium channel blockers (CCBs), widely used for hypertensive patients, have recently been shown to inhibit atherosclerosis by their antioxidative action. The aim of the present study was to examine whether the CCBs nilvadipine and diltiazem reduce ocular inflammation in endotoxin-induced uveitis (EIU).
EIU was induced in male C57/B6 mice with a single intraperitoneal injection of lipopolysaccharide (LPS). The animals received intraperitoneal injections of either nilvadipine, diltiazem, or vehicle for 5 days before the LPS application. Twenty-four hours after EIU induction, adherent leukocytes to the retinal vasculature were counted with a concanavalin A lectin perfusion-labeling technique. The protein concentration in the aqueous humor was measured to assess blood-ocular barrier breakdown. Retinal levels of intercellular adhesion molecule (ICAM)-1 and monocyte chemotactic protein (MCP)-1 were analyzed by enzyme-linked immunosorbent assay. LPS-stimulated generation of superoxide in murine microvascular endothelial cells was examined with a nitroblue tetrazolium assay.
Compared to vehicle treatment, application of nilvadipine, but not diltiazem, led to significant suppression of EIU-associated retinal leukocyte adhesion, together with anterior-chamber protein leakage, retinal expression of ICAM-1 and MCP-1, and LPS-induced superoxide generation in vitro.
The CCB nilvadipine exercises an inhibitory effect on the pathogenesis of ocular inflammation through the suppression of inflammation-related molecules.
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ABSTRACT: To investigate whether nisoldipine and olmesartan improve endothelial function, decrease asymmetric dimethylarginine (ADMA) and alleviate the inflammatory and oxidative process. Fifty-five essential hypertensive patients were randomized to receive nisoldipine or olmesartan for 8 weeks according to a parallel-group, active-controlled, single blind study, and 28 matched normotensive subjects served as healthy controls. Flow-mediated dilation (FMD), and plasma levels of nitric oxide (NO), endothelin-1 (ET-1), high-sensitive C-reactive protein (hs-CRP), 8-isoprostane (also named 8-isoPGF2α), and ADMA were determined. At baseline, the plasma levels of ADMA, ET-1, hs-CRP, and 8-isoPGF2α were markedly higher in patients with essential hypertension than in normotensive subjects (P < 0.05). A significant positive correlation was observed between plasma levels of ET-1 and ADMA in patients with essential hypertension, but not in normotensive subjects. The NO plasma concentrations were significantly lower in patients with essential hypertension than in normotensive subjects. Furthermore, hypertensive subjects demonstrated significantly lower FMD than healthy control (P < 0.05). Nisoldipine and olmesartan significantly and similarly reduced blood pressure in patients with essential hypertension (P < 0.001). At the end of the 8-week treatment, plasma ADMA and ET-1 levels were decreased significantly (P < 0.01). FMD increased significantly in nisoldipine or olmesartan-treated patients (P < 0.05). A significant decrease in plasma hs-CRP contents was observed in patients receiving nisoldipine (P < 0.05). The findings demonstrate that nisoldipine and olmesartan both improve FMD in patients with essential hypertension. This may be associated with decreased circulating levels of CRP, ET-1, and ADMA.CNS Neuroscience & Therapeutics 05/2012; 18(5):400-5. · 4.46 Impact Factor
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ABSTRACT: We recently proposed a role for the 2-pore-domain K(+) (K2P) channel TREK-1 in the regulation of cytokine release from alveolar epithelial cells (AECs) by demonstrating decreased IL-6 secretion from TREK-1 deficient cells, but the effects of altered TREK-1 expression on other inflammatory mediators remain poorly understood. We now examined the role of TREK-1 in TNF-α-induced MCP-1 release from human A549 cells. We hypothesized that TREK-1 regulates TNF-α-induced MCP-1 secretion via c-Jun N-terminal kinases (JNK)- and protein kinase-C (PKC)-dependent pathways. In contrast to IL-6 secretion, we found that TREK-1 deficiency resulted in increased MCP-1 production and secretion, although baseline MCP-1 gene expression was unchanged in TREK-1 deficient cells. In contrast to TREK-1 deficient AECs, overexpression of MCP-1 had no effect on MCP-1 secretion. Phosphorylation of JNK1/2/3 was increased in TREK-1 deficient cells upon TNF-α stimulation, but pharmacological inhibition of JNK1/2/3 decreased MCP-1 release from both control and TREK-1 deficient cells. Similarly, pharmacological inhibition of PKC decreased MCP-1 secretion from control and TREK-1 deficient cells, suggesting that alterations in JNK and PKC signaling pathways were unlikely the cause for the increased MCP-1 secretion from TREK-1 deficient cells. Furthermore, MCP-1 secretion from control and TREK-1 deficient cells was independent of extracellular Ca(2+) but sensitive to inhibition of intracellular Ca(2+) reuptake mechanisms. In summary, we report for the first time that TREK-1 deficiency in human AECs resulted in increased MCP-1 production and secretion, and this effect appeared unrelated to alterations in JNK-, PKC- or Ca(2+)-mediated signaling pathways in TREK-1 deficient cells.American Journal of Translational Research 01/2013; 5(5):530-42.