Molecular Actions of a Mn(III)Porphyrin Superoxide Dismutase Mimetic and Peroxynitrite Scavenger: Reaction with Nitric Oxide and Direct Inhibition of NO Synthase and Soluble Guanylyl Cyclase

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Vol. 53, Issue 4, 795-800, April 1998

Molecular Actions of a Mn(III)Porphyrin Superoxide Dismutase Mimetic and Peroxynitrite Scavenger: Reaction with Nitric Oxide and Direct Inhibition of NO Synthase and Soluble Guanylyl Cyclase

Silvia Pfeiffer, Astrid Schrammel, Doris Koesling, Kurt Schmidt, and Bernd Mayer

Institut für Pharmakologie und Toxikologie, Karl-Franzens Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria (S.P., A.S., K.S., B.M.) and Institut für Pharmakologie, Freie Universität Berlin, Thielallee 67-73, D-14195 Berlin 33, Germany (D.K.)

Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), described as a superoxide dismutase mimetic and peroxynitrite scavenger,has been used previously to investigate the cytotoxic potentialof superoxide and peroxynitrite in several pathological models.Here we report on the interference of MnTMPyP with NO/cGMP signalingusing cultured endothelial cells as well as purified soluble guanylylcyclase (sGC) either activated by the NO donor 2,2-diethyl-1-nitroso-oxyhydrazinesodium salt (DEA/NO) or reconstituted with nitric oxide synthase(NOS). MnTMPyP inhibited endothelial cGMP accumulation inducedby A23187 (0.3 µM) with an IC₅₀ of 75.0 ± 10.4 µM but had no significanteffect on the potency of the Ca²⁺ ionophore. Purified NOS was inhibited by MnTMPyP (IC₅₀ = 5.5± 0.8 µM) because of an interference of the Mn-porphyrin withthe reductase domain of the enzyme. The most pronounced actionsof MnTMPyP were direct inhibition of sGC and scavenging of NO.Purified sGC stimulated with either Ca²⁺/calmodulin-activated NOS (in the presence of GSH) or DEA/NO (inthe absence of GSH) was inhibited with IC₅₀ values of 0.8 ± 0.09µM and 0.6 ± 0.2 µM, respectively. In the presence of GSH, MnTMPyPwas reduced to the Mn(II) complex, resulting in efficient scavengingof NO under these conditions. Our data demonstrate that MnTMPyP(i) interferes with the reductase domain of NOS, (ii) scavengesNO in the presence of GSH, and (iii) is a potent direct inhibitorof sGC. These results cast doubt on the usefulness of MnTMPyPand related Mn-porphyrin complexes as probes to study the involvementof peroxynitrite/superoxide in biological systems.

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