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02 October 2003

GW274150 inhibits nitric oxide production by primary cultures of rat proximal tubular cells

Prabal K. Chatterjee, Espen O. Kvale, Nimesh S.A. Patel, Christoph Thiemermann

Med Sci Monit 2003; 9(10): BR357-362 :: ID: 13216

Abstract

Background:Production of nitric oxide (NO) subsequent to expression of inducible NO synthase (iNOS) contributes to the development of ischemic renal injury and inflammation. Here we investigate the effects of GW274150, a potent, long-acting and highly selective inhibitor of iNOS activity, on NO production by primary cultures of rat proximal tubular cells (PTC).Material/Methods:Pure populations of PTC were isolated from the cortex of kidneys obtained from male Wistar rats using a combination of collagenase digestion, sieving and Percoll centrifugation. Confluent PTC cultures were incubated for 1–24 h with MEM, interferon-gamma (IFN-gamma, 100 mcg/ml), bacterial lipopolysaccharide (LPS, 10 mcg/ml) in combination after which NO production was determined. PTC were also incubated with IFN-gamma (100 mcg/ml) and LPS (10 mcg/ml) and increasing concentrations of GW274150 or L-N[sup]6[/sup]-(1-iminoethyl)lysine (L-NIL) (10 nM – 1 mM) for 24 h after which nitrite levels in the incubation medium were measured.Results:IFN-gamma and LPS in combination produced a significant, time-dependent increase in NO production. Both GW274150 and L-NIL produced a significant and concentration-dependent inhibition of NO production. However, GW274150 was markedly more potent (EC[sub]50[/sub] ~ 100 nM) than L-NIL (EC[sub]50[/sub] ~ 10 mcM).Conclusions:GW274150 inhibits NO production by primary cultures of PTCs and may therefore be useful in conditions associated with nitrosative stress of the kidney.

Keywords: Dose-Response Relationship, Drug, Enzyme Inhibitors - pharmacology, Interferon Type II - metabolism, Kidney - metabolism, Kidney Tubules - cytology, Kidney Tubules - drug effects, Kidney Tubules - metabolism, Lipopolysaccharides - metabolism, Lysine - analogs & derivatives, Lysine - metabolism, NG-Nitroarginine Methyl Ester - metabolism, Nitrates - metabolism, Nitric Oxide - metabolism, Nitric Oxide Synthase - antagonists & inhibitors, Nitric Oxide Synthase - metabolism, Nitric Oxide Synthase Type II, Nitrites - metabolism, Nitrogen - metabolism, Rats, Wistar, Sulfides - pharmacology, Time Factors

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750