title: Influence of beta-blockers on the myocardial mRNA expressions of circadian clock- and metabolism-related genes.
abstract: Daily rhythms are regulated by a master clock-system in the suprachiasmatic nucleus and by a peripheral clock-system in each organ. Because norepinephrine is one of the timekeepers for the myocardial circadian clock that influences cardiac metabolism, it is speculated that a beta-blocker may affect the circadian clock and metabolism in heart tissue. In this study, thirty mg/kg/day of propranolol (a lipophilic beta-blocker) or atenolol (a hydrophilic beta-blocker) was given orally to Wistar rats for 4 weeks. The mRNA expressions of Bmal1 and E4BP4 in heart tissue were suppressed by the beta-blockers. However, the mRNA expressions of these clock genes in the suprachiasmatic nucleus were unchanged. Myocardial mRNA expressions of lactate dehydrogenase a and pyruvate dehydrogenase kinase 4 were also suppressed by the beta-blockers. In addition, ATP content in heart tissue was significantly elevated by the beta-blockers throughout 24 hours. The effects of propranolol and atenolol did not differ significantly. This study showed for the first time that a beta-blocker affects myocardial clock gene expression. Propranolol and atenolol increased ATP content in heart tissue throughout 24 hours. The influences of beta-blockers may be negligible on the SCN, and may be independent of lipid solubility on heart tissue. It is well known that these drugs exert a protective effect against myocardial ischemia, which may be mediated by an increase in the preservation of myocardial ATP.
authors: Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Tochigi, Japan.
authors: Kentarou
authors: K
authors: Ushijima
authors: Tomohiro
authors: T
authors: Maekawa
authors: Eiko
authors: E
authors: Ishikawa-Kobayashi
authors: Hitoshi
authors: H
authors: Ando
authors: Tsuyoshi
authors: T
authors: Shiga
authors: Akio
authors: A
authors: Fujimura
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001262:Atenolol / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D057906:Circadian Clocks / Q000187:drug effects*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; D000319:Adrenergic beta-Antagonists; D007527:Isoenzymes; C558007:NFIL3 protein, rat; C498263:Nr1d1 protein, rat; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; C539024:Per1 protein, rat; C513311:Per2 protein, rat; D056950:Period Circadian Proteins; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; D012097:Repressor Proteins; D001262:Atenolol; D011433:Propranolol; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D056926:CLOCK Proteins; C538945:Clock protein, rat; D017346:Protein Serine-Threonine Kinases