Background-Impaired endothelium-mediated vasodilatation (EMVD) in congestive cardiac failure (CCF) has been linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O 2 ·Ϫ ), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, endothelial nitric oxide synthase (eNOS) produces O 2 ·Ϫ . We studied the functional consequences of eNOS uncoupling in relation to EMVD in patients with CCF. Methods and Results-We employed the platelet as a compartmentalized ex-vivo model to examine O 2 ·Ϫ and NO production. When eNOS is functioning normally, incorporation of N -Nitro-L-Arginine methyl ester (L-NAME, 1 mmol/L), results in increased O 2 ·Ϫ detection, as inhibition of NO production prevents NO scavenging of O 2 ·Ϫ . This was observed in controls and 9 of the CCF patients, in whom O 2 ·Ϫ detection increased by 63% and 101%, respectively. In the remaining 9 CCF patients, incorporation of L-NAME reduced O 2 ·Ϫ production by 39%, indicating O 2 ·Ϫ production by eNOS uncoupling. Detection of platelet-derived NO was significantly greater in eNOS-coupled platelets compared with the uncoupled group (2.8Ϯ1.4 versus 0.9Ϯ0.4 pmol/10 8 platelets, Pϭ0.04). Endothelium-dependent and -independent vasodilator responses to acetylcholine and sodium nitroprusside recorded using venous occlusion plethysmography were significantly impaired in patients exhibiting eNOS uncoupling. Conclusions-This study provides first evidence that platelet eNOS can become uncoupled in human CCF. Impaired endothelium-dependent and -independent vasodilator responses and diminished platelet-derived NO production occurred in association with enzyme uncoupling.

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The study examined the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor, vildagliptin in cyclosporine (CsA)-induced hepatotoxicity. Rats were divided into 4 groups treated for 28 days: control (vehicle), vildagliptin (10 mg/kg, orally), CsA( 20 mg/kg, SC) and CsA-vildagliptin group. Liver function was assessed by measuring serum levels of Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (γGT), lactate dehydrogenase (LDH), albumin, and histopathological changes of liver were examined.Oxidative stress markers were evaluated. Assessment of nuclear factor-kappa B (NF-κB) activity in hepatic nuclear extract, serum DPP-4 and expression of Bax and Bcl2 using were also done.CsA-induced hepatotoxicity was evidenced by increase in serum levels of AST, ALT and γGT; a decrease in serum albumin and a significant alteration in hepatic architecture. Also, significant increase in thiobarbituricacid reactive substance (TBARS) and decrease in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH) levels, increased expression Bax proteins with deceased expression of Bcl2, increased hepatic activity of NF-κB, and serum DPP-4 level were observed upon CsA treatment. Vildagliptin significantly improved all altered parameters induced by CsA administration. Vildagliptin has the potential to protect the liver against CsA-induced hepatotoxicity by reducing oxidative stress, DPP-4 activity, apoptosis and inflammation.

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