A drug cocktail for protecting against ischemia-reperfusion injury

Ischemia followed by reperfusion (I/R) of cardiomyocytes causes release of a large amount of inducible nitric oxide (NO) synthase (iNOS) followed by an increase of asymmetric dimethylarginine (ADMA). ADMA disrupts NO signaling by switching of the NOS activity from NO to the production of reactive ox...

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Published inFrontiers in bioscience Vol. 25; no. 4; pp. 722 - 735
Main Authors Krzywonos-Zawadzka, Anna, Wozniak, Mieczyslaw, Sawicki, Grzegorz, Bil-Lula, Iwona
Format Journal Article
LanguageEnglish
Published Singapore IMR Press 01.01.2020
Subjects
adma
Amidines - pharmacology
Animals
Arginine - analogs & derivatives
Arginine - metabolism
Benzylamines - pharmacology
Enzyme Inhibitors - pharmacology
Heart - drug effects
Heart - physiopathology
inos
ischemia-reperfusion injury
isolated rat hearts
Male
Matrix Metalloproteinase 2 - metabolism
mmp-2
Myocardial Contraction - drug effects
Myocardial Reperfusion Injury - physiopathology
Myocardial Reperfusion Injury - prevention & control
Myocardium - metabolism
Myosin Light Chains - metabolism
Nitric Oxide - metabolism
Nitric Oxide Synthase Type II - antagonists & inhibitors
Nitric Oxide Synthase Type II - metabolism
Protective Agents - pharmacology
Rats, Wistar
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Summary:Ischemia followed by reperfusion (I/R) of cardiomyocytes causes release of a large amount of inducible nitric oxide (NO) synthase (iNOS) followed by an increase of asymmetric dimethylarginine (ADMA). ADMA disrupts NO signaling by switching of the NOS activity from NO to the production of reactive oxygen species (ROS). Previously, we have shown that pretreatment of the hearts by co-administration of sub-threshold concentrations of doxycycline, a matrix metalloproteinase (MMPs) inhibitor, ML-7 an inhibitor of myosin light-chain kinase (MLCK) and L-NAME a non-selective NOS inhibitor protects the heart against I/R injury. In this study, we replaced the L-NAME with 1400W (selective inhibitor of iNOS) in the drug cocktail that was Langendorff-perfused into the hearts of Wistar rats before (prevention) or after (treatment) the induction of I/R. This pre-treatment resulted in full protection of contractility, decreased production of iNOS and ADMA and normalized the bioavailability of NO in the I/R hearts. Thus, the formulated drug cocktail protects the heart from I/R injury.
ISSN:1093-9946
2768-6701
2768-6698
1093-4715
DOI:10.2741/4831