Reduced ischemia/reperfusion injury via glutathione-initiated nitric oxide-releasing dendrimers.

Abstract

We report the therapeutic potential of S-nitroso-N-acetylpenicillamine-derivatized generation-4 polyamidoamine dendrimers (G4-SNAP) for reducing ischemia/reperfusion (I/R) injury in an isolated, perfused rat heart. The use of this dendrimer scaffold to deliver the nitrosothiol therapeutic did not inhibit NO donor activity as the required dose of G4-SNAP to minimize I/R injury (31nM corresponding to 2microM SNAP) was consistent with the optimum concentration of small molecule SNAP alone. An exploration of G4-SNAP NO release kinetics in the presence of physiologically relevant concentrations of glutathione (GSH) indicated enhanced NO release (t[NO]=1.28microM NO/mg) at 500microM GSH. Reperfusion experiments conducted with 500microM GSH further lowered the optimal therapeutic G4-SNAP dose to 230pM (i.e., 15nM SNAP). The unique combination of G4-SNAP dendrimer and glutathione trigger represents a novel strategy with possible clinical relevance toward salvaging ischemic tissue.

• Authors: Timothy A Johnson, Nathan A Stasko, Jessica L Matthews, Wayne E Cascio, Ekhson L Holmuhamedov, C Bryce Johnson, Mark H Schoenfisch
• Journal: Nitric oxide : biology and chemistry (Nitric Oxide) Vol. 22 Issue 1 Pg. 30-6 (Jan 01 2010) ISSN: 1089-8611 [Electronic] United States
• PMID: 19914388 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dendrimers
• Polyamines
• Nitric Oxide
• Glutathione

Topics

• Animals
• Cells, Cultured
• Dendrimers (pharmacology)
• Disease Models, Animal
• Glutathione (pharmacology)
• Male
• Nitric Oxide (metabolism)
• Polyamines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (metabolism, prevention & control)