Effect of MET-88, a gamma-butyrobetaine hydroxylase inhibitor, on myocardial derangements induced by hydrogen peroxide in the isolated perfused rat heart.
The effect of MET-88 (3-(2,2,2-trimethylhydrazinium) propionate dihydrate), a gamma-butyrobetaine (gamma-BB) hydroxylase inhibitor, on the hydrogen peroxide (H2O2)-induced mechanical and metabolic derangements was studied in the isolated rat heart, which was perfused aerobically by the Langendorff's technique at a constant flow rate and driven electrically. In the first series of experiments, MET-88 (100 mg/kg/d) was orally administered to rats for 10 days prior to isolation of the heart. In the second series of experiments, MET-88 or gamma-BB was directly infused to the isolated perfused heart. In both series of experiments, H2O2 (600 microM) decreased the left ventricular developed pressure (mechanical dysfunction) and the tissue levels of high-energy phosphates (metabolic derangement). In the first series of experiments, oral pretreatment with MET-88 attenuated the H2O2-induced metabolic derangement with a marked increase in the myocardial level of gamma-BB, while it did not attenuate the H2O2-induced mechanical dysfunction. In the second series of experiments, MET-88 (1 mM) did not attenuate the H2O2-induced metabolic derangement, whereas gamma-BB (500 microM or 1 mM) attenuated it. Nevertheless, gamma-BB did not modify the energy metabolism of H2O2-untreated heart (normal heart). These results suggest that oral pretreatment with MET-88 protects the energy metabolism against the H2O2-induced derangement and that the beneficial effect of the oral pretreatment with MET-88 may be mediated by gamma-BB that has accumulated in the myocardium because of inhibition of gamma-BB hydroxylase.
Akahira
M
M
Department of Pharmacology, Asahikawa Medical College, Japan.
Hara
A
A
Abiko
Y
Y
D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D006321:Heart / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008297:Male; D008763:Methylhydrazines / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016276:Ventricular Function / Q000187:drug effects; D050563:gamma-Butyrobetaine Dioxygenase
D008763:Methylhydrazines; D010725:Phosphocreatine; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; C050147:3-(2,2,2-trimethylhydrazine)propionate; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D006899:Mixed Function Oxygenases; D050563:gamma-Butyrobetaine Dioxygenase