In vitro, the stable six-membered ring
nitroxide 2,2,6,6-tetramethyl-1-piperidine-N-oxyl (
TEMPO) is known to protect the ischemic and reperfused myocardium through a mechanism likely to involve the limitation of
free radical damage. In vivo,
TEMPO's high rate of reduction into diamagnetic nonactive compounds could limit its pharmacological use and its potential as an ESR probe in oxymetry studies. Recently, beta-phosphorylated
nitrones and
pyrrolidines have been reported to protect against
myocardial reperfusion injury better than their nonphosphorylated analogs. Using hemodynamic, metabolic, and enzymatic indices of
reperfusion injury, the efficacy of
2-diethoxyphosphoryl-2,5,5-trimethylpyrrolidinoxyl (TMPPO), a five-membered ring beta-phosphorylated
nitroxide, has been compared to that of
TEMPO when added at a nontoxic concentration (1 mM) in
buffer-perfused isolated rat hearts during low-flow
ischemia, total
ischemia, and reflow. TMPPO, which is five times as hydrophilic and eight times as resistant to reduction in a
biological medium as
TEMPO, was more effective in reducing postischemic
contracture and myocardial enzymatic leakage. Since a diamagnetic analog of TMPPO was far less protective and both nitroxides showed an antilipoperoxidant effect and acted mainly when administered only at reflow, it was proposed that beta-phosphorylated nitroxides such as TMPPO could be interesting alternatives in pharmacological and ESR applications.