Abstract
The efficacy and mechanism of protection of a new 2,2,5,5-tetramethylpyrroline derivative of mexiletine, MEX-NH, against ischemia/reperfusion-induced cardiac dysfunction are reported. The MEX-NH and its nitroxide metabolite are membrane-permeable antioxidants. Studies were performed in an isolated rat heart model to measure the efficacy of MEX-NH in preventing postischemic injury. Serial measurements of contractile function and coronary flow were performed on hearts subjected to 30 min of global 37°C ischemia followed by 45 min of reperfusion. Hearts were either untreated or treated with 25 μM MEX-NH or MEX for 1 min before ischemia. The hearts treated with MEX-NH showed marked recovery of left ventricular developed pressure (96.3 ± 2.7% of preischemic value) compared with untreated (13.7 ± 1.0%) or MEX-treated (19.9 ± 2.7%) hearts. The cardiac sarcolemmal Na+,K+-ATPase activity showed that the enzyme activity was fully restored in hearts treated with MEX-NH compared with 65 ± 5.3% inhibition in the untreated hearts. Competitive inhibition of [3H]ouabain binding revealed that the MEX-NH binds at the K+-binding site of the enzyme. The present study establishes that the compound MEX-NH provides marked protection against ischemia/reperfusion-induced contractile dysfunction in isolated hearts. A combination of reversible inhibition of Na+/K+-ATPase activity during ischemia and site-targeted antioxidative effect upon reperfusion seems to contribute to this cardioprotection.
Footnotes
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Send reprint requests to: Periannan Kuppusamy, Ph.D., Division of Cardiology, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail:kuppu{at}welch.jhu.edu
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↵1 This work was supported in part by National Institutes of Health Grants CA-78886, HL-38324, and HL52175, American Heart Association Grant 9951350U, and Hungarian Ministry of Education (FKFP 252/1999). P.K. was supported by an Established Investigator Award from the American Heart Association during the tenure of this study.
- Abbreviations:
- ROS
- reactive oxygen species
- MEX-NH
- 1-(2,6-dimethylphenoxy)-[2-N-(2,5-dihydro-3-methyl-2,2,5,5-tetramethyl-1H-pyrrol)]aminopropane
- MEX-NO
- 1-(2,6-dimethylphenoxy)-[2-N-(1-oxyl-2,5-dihydro-3-methyl-2,2,5,5-tetramethyl-1H-pyrrol)]aminopropane
- LDH
- lactate dehydrogenase
- DMPO
- 5,5-dimethyl-1-pyrroline-N-oxide
- LVEDP
- left ventricular end-diastolic pressure
- MEX
- 1-(2,6-dimethylphenoxy)-2-aminopropane
- CF
- coronary flow
- LVSP
- left ventricular systolic pressure
- HR
- heart rate
- SL
- sarcolemmal
- EPR
- electron paramagnetic resonance
- LVDP
- left ventricular developed pressure
- RPP
- rate-pressure product
- Received April 24, 2000.
- Accepted July 5, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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