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First published on August 1, 2006; DOI: 10.1124/mol.106.027870

0026-895X/06/7005-1672-1680$20.00
Mol Pharmacol 70:1672-1680, 2006

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Electron Spin Resonance and Chemiluminescence Analyses to Elucidate the Vasodilating Mechanism of Sodium Nitroprusside

Giancarlo Aldini, Federica Pirrone, Mariangela Albertini, Marica Orioli, Angela Piccoli, Silvia Mazzola, Maria Giovanna Clement, and Marina Carini

Istituto di Chimica Farmaceutica e Tossicologica "Pietro Pratesi", Faculty of Pharmacy, University of Milan, Milan, Italy (G.A., M.O., A.P., M.C.); and Dipartimento di Patologia Animale Igiene e Sanità Pubblica Veterinaria, University of Milan, Milan, Italy (F.P., M.A., S.M., M.G.C.)

The aim of this study was to elucidate the vasodilating mechanism of sodium nitroprusside (SNP). To do this, SNP was intravenously infused in pigs (1.67 µmol/kg), and the following paramagnetic metabolites were identified by electron spin resonance: 1) nitrosylhemoglobin [HbFe(II)NO] as an index of the bioconservative pathway; 2) transferrin; 3) [Fe(II)(CN)5 NO]3- and [Fe(II)(CN)4 NO]2-, the reduced penta- and tetracoordinated intermediates of SNP, respectively; and 4) methemoglobin (met-Hb). The results indicate the following: 1) {approx}17% of the dose is converted to HbFe(II)NO at the end of infusion; 2) NO administered as SNP does not undergo bioinactivation (oxidative metabolism), because no significant increase of met-Hb was observed; 3) the equilibrium involving the paramagnetic species of SNP is shifted toward HbFe(II)NO, because a significant increase of transferrin but no detection of the reduced paramagnetic intermediates of SNP was observed. The results obtained indicate that the hemodynamic effect induced by SNP is not mediated by HbFe(II)NO, at least under physiological conditions; hence, a direct release of NO from SNP in the vascular target should be considered. To demonstrate this mechanism, endothelial cells were incubated with SNP, and the release of NO was determined by a novel chemiluminescence method. The results indicate that the endothelium is able to metabolize SNP, with the formation of stoichiometric amounts of NO. In conclusion, SNP is rapidly metabolized to HbFe(II)NO, but the pharmacological response is mediated by a direct mechanism of NO release of the parent compound at the cellular target.

Received June 13, 2006; accepted August 1, 2006

Address correspondence to: Dr. Giancarlo Aldini, Address: Istituto di Chimica Farmaceutica e Tossicologica "Pietro Pratesi", Viale Abruzzi 42, 20131 Milan, Italy. E-mail: giancarlo.aldini{at}unimi.it






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