The effect of the beta2-adrenoceptor agonist prodrug BRL-47672 on cardiovascular function, skeletal muscle myosin heavy chain, and MyoD expression in the rat.
The intracellular mechanisms that regulate changes in postnatal myosin heavy chain (MHC) expression are not well established. The major objective of this study was to examine the acute and chronic effects of administration of BRL-47672, the prodrug of the beta2-adrenoceptor agonist clenbuterol on MHC and MyoD transcription factor expression to determine whether or not changes in MHC composition are preceded by changes in MyoD protein expression. To assess to what extent the use of BRL-47672 minimized cardiovascular effects, its hemodynamic actions were compared with those of clenbuterol. The effect of BRL-47672 on heart rate, mean arterial blood pressure, and hindquarters vascular conductance was significantly less than that of clenbuterol after a single i.p. injection (250 microg kg(-1) body mass). In the main study, 4-week old rats were given BRL-47672 (900 microg kg(-1) body mass) or an equivalent volume of saline (control) daily for 1, 28, or 56 days. Soleus muscle (SOL) was excised and MHC and MyoD expression analyzed. After 4 weeks, SOL from the BRL-47672-treated animals had significantly faster MHC composition (49 +/- 2% MHCIIA) compared with those from the control animal (39 +/- 3% MHCIIA, P <0.05). MyoD expression increased by 40% after 1 day of BRL-47672 administration (P <0.05) before a change in MHC composition. In conclusion, these data suggest that increased expression of fast-type MHCIIA expression in rat SOL induced by BRL-47672 administration is preceded by changes in the level of MyoD transcription factor expression.
Jones
S W
SW
Centre for Integrated Systems Biology and Medicine, Queens Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK.
Baker
D J
DJ
Gardiner
S M
SM
Bennett
T
T
Timmons
J A
JA
Greenhaff
P L
PL
D000251:Adenosine Triphosphatases / Q000378:metabolism; D058647:Adrenergic alpha-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002976:Clenbuterol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D017570:MyoD Protein / Q000096:biosynthesis* / Q000235:genetics; D009210:Myofibrils / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism*; D009930:Organic Chemicals; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013997:Time Factors
D058647:Adrenergic alpha-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; C089126:BRL 47672; D017570:MyoD Protein; D009930:Organic Chemicals; D000251:Adenosine Triphosphatases; D018995:Myosin Heavy Chains; D002976:Clenbuterol