Hemodynamic Effects of Glutathione-Liganded Binuclear Dinitrosyl Iron Complex: Evidence for Nitroxyl Generation and Modulation by Plasma Albumin

• Published in: Molecular pharmacology 2018-05, Vol.93 (5), p.427-437
• Main Authors: Liu, Taiming, Zhang, Meijuan, Terry, Michael H., Schroeder, Hobe, Wilson, Sean M., Power, Gordon G., Li, Qian, Tipple, Trent E., Borchardt, Dan, Blood, Arlin B.
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - pharmacology; Electron Spin Resonance Spectroscopy; Female; Glutathione - metabolism; Hemodynamics - drug effects; Iron - metabolism; Iron - pharmacokinetics; Iron - pharmacology; Ligands; Male; Mesenteric Arteries - drug effects; Mesenteric Arteries - physiology; Myography; Nitric Oxide Donors - pharmacology; Nitrogen Oxides - metabolism; Nitrogen Oxides - pharmacokinetics; Nitrogen Oxides - pharmacology; Rats; Serum Albumin - metabolism; Sheep; Vasodilation - drug effects; Vasodilator Agents - pharmacology
• ISSN: 0026-895X; 1521-0111; 1521-0111
• DOI: 10.1124/mol.117.110957

Glutathione-liganded binuclear dinitrosyl iron complex (glut-BDNIC) has been proposed to be a donor of nitric oxide (NO). This study was undertaken to investigate the mechanisms of vasoactivity, systemic hemodynamic effects, and pharmacokinetics of glut-BDNIC. To test the hypothesis that glut-BDNICs vasodilate by releasing NO in its reduced [nitroxyl (HNO)] state, a bioassay method of isolated, preconstricted ovine mesenteric arterial rings was used in the presence of selective scavengers of HNO or NO free radical (NO•); the vasodilatory effects of glut-BDNIC were found to have characteristics similar to those of an HNO donor and markedly different than an NO• donor. In addition, products of the reaction of glut-BDNIC with CPTIO [2-(4-carboxyphenyl)-4,4,5-tetramethyl imidazoline-1-oxyl-3-oxide] were found to have electron paramagnetic characteristics similar to those of an HNO donor compared with an NO• donor. In contrast to S-nitroso-glutathione, which was vasodilative both in vitro and in vivo, the potency of glut-BDNIC–mediated vasodilation was markedly diminished in both rats and sheep. Wire myography showed that plasma albumin contributed to this loss of hypotensive effects, an effect abolished by modification of the cysteine-thiol residue of albumin. High doses of glut-BDNIC caused long-lasting hypotension in rats that can be at least partially attributed to its long circulating half-life of ∼44 minutes. This study suggests that glut-BDNIC is an HNO donor, and that its vasoactive effects are modulated by binding to the cysteine residue of plasma proteins, such as albumin.