Early alterations of polyamine metabolism induced after acute administration of clenbuterol in mouse heart.
An acute treatment of mice with clenbuterol, a beta-adrenergic agonist, produced a marked increase of polyamines levels in heart, particularly during the early phase of administration of the drug. A single dose of 1.5 mg/kg caused as much as a 10 fold induction in activity of ornithine decarboxylase (ODC) and 3 to 4 fold increase in levels of putrescine, spermidine and spermine in mouse heart. Maximum changes were observed 3 to 4 hours post-administration of clenbuterol. This treatment did not produce any change in S-adenosylmethionine decarboxylase activity. The induction of cardiac ODC by clenbuterol was also dose dependent with a peak at about 5 micromol/kg. Co-administration of difluoromethylornithine, an irreversible inhibitor of ODC, or propranolol, a nonspecific beta-antagonist, with clenbuterol completely prevented the induction of ODC activity as well as the increase in polyamine levels in heart. However, pretreatment with alprenolol or metoprolol, the specific beta1 and beta2-antagonists, respectively, produced only partial prevention. The cardiac ODC from controls as well as clenbuterol treated mice exhibited similar affinity (Km) for its substrate, ornithine, while maximum enzyme activity (Vmax) was about 14 fold higher in clenbuterol treated mouse heart than in the control. Clenbuterol produced no change in the level of specific ODC mRNA or the protein, but the enzyme from the drug-treated mouse heart was considerably more stable than the control. Pretreatment of mice with either cycloheximide or actinomycin D followed by administration of clenbuterol could not prevent the induction in ODC activity suggesting that de novo biosynthesis of the enzyme protein or ODC mRNA was not responsible for induction of ODC activity. Post-translational changes in ODC may be responsible for an early increase of ODC activity due to clenbuterol treatment.
Cubría
J C
JC
Departamento de Fisiología, Farmacología y Toxicología (INTOXCAL), Universidad de León, Spain.
Ordóñez
C
C
Reguera
R M
RM
Tekwani
B L
BL
Balaña-Fouce
R
R
Ordóñez
D
D
D012437:Adenosylmethionine Decarboxylase / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism*; D015153:Blotting, Western; D002976:Clenbuterol / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000518:Eflornithine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000378:metabolism*; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D015317:Biogenic Polyamines; D012333:RNA, Messenger; D003513:Cycloheximide; D009955:Ornithine Decarboxylase; D012437:Adenosylmethionine Decarboxylase; D002976:Clenbuterol; D000518:Eflornithine