Abstract
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 β2-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 μg kg-1 body mass). In the main study, 4-week old rats were given BRL-47672 (900 μg 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.
Footnotes
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Financial support was provided by Pfizer Global Research and Development, Sandwich, UK.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.104.071589.
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ABBREVIATIONS: MHC, myosin heavy chain; MRF, myogenic regulatory factor; SOL, soleus muscle; PAGE, polyacrylamide gel electrophoresis; DTT, dithiothreitol; AEBSF, 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride; ECL, enhanced chemiluminescence; ANOVA, analysis of variance; ICI-118551, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol; CGP-20712A, ([2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-4-trifluormethyl-2-imidazolyl)-phenoxy]-2-propanolmethanesulfonate.
- Received May 17, 2004.
- Accepted July 7, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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