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Inhibition of Cyclooxygenase-2 by Natriuretic Peptides

Department of Pharmacy (A.K.K., A.M.V.), Center of Drug Research, University of Munich, 81377 Munich, Germany; and University of Konstanz (M.D.L., T.H.), Biochemical Pharmacology, 78457 Konstanz, Germany

Address all correspondence and requests for reprints to: Alexandra K. Kiemer, Ph.D., Department of Pharmacy-Center of Drug Research, Butenandtstrasse 5-13, 81377 Munich, Germany. E-mail: . alexandra.kiemer{at}cup.uni-muenchen.de

The atrial natriuretic peptide (ANP) has been suggested to possess immunomodulatory potential because of its property to alter macrophage functions via its guanylate-cylcase- coupled A-receptor (NPR-A), such as inhibiting the expression of inducible nitric oxide synthase or TNF-. The aim of this study was to investigate whether ANP influences COX-2. COX-2 expression in murine macrophages and in mice was induced by lipopolysaccharide. Release of PGE₂ and thromboxane B₂ was significantly reduced in the presence of ANP. C-type natriuretic peptide (CNP) also significantly reduced PGE₂-accumulation in macrophages. Northern and Western blots showed that ANP attenuates COX-2 mRNA and protein. Reduction of neither COX-2 nor of PGE₂ production was significantly abrogated by an NPR-A antagonist, suggesting a pathway independent of cGMP. Furthermore, dibutyryl-cGMP did not affect PGE₂-accumulation. cANF, the specific ligand for the natriuretic peptide (NP) clearance-receptor (NPR-C), significantly inhibited PGE₂-production. Because some biological activities of ANP have been reported to be mediated via an NPR-C-mediated inhibition of adenylate-cyclase, we determined cAMP levels. ANP, CNP, and cANF significantly attenuated intracellular cAMP. In summary, ANP was shown to attenuate PGE₂-production of lipopolysaccharide-activated macrophages predominantly via the NP clearance-receptor. ANP reduces COX-2-protein and -mRNA levels. The inhibition seems to be mediated via NPR-C and related to an attenuation of cAMP production.

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