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This Article Full Text Full Text (PDF) All Versions of this Article: 107/1/121    most recent 00210.2009v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Summers, S. M. Articles by Purdy, R. E. PubMed PubMed Citation Articles by Summers, S. M. Articles by Purdy, R. E.

Hindlimb unweighting induces changes in the p38^MAPK contractile pathway of the rat abdominal aorta

Department of Pharmacology, School of Medicine, University of California, Irvine, Irvine, California

Submitted 24 February 2009 ; accepted in final form 8 May 2009

Hindlimb unweighting (HLU) of rats is a model used to mimic the cephalic fluid shift potentially involved in the orthostatic intolerance experienced by astronauts. Certain arteries in these rats exhibit a decreased contractile response to adrenergic agonists. It was shown previously that this may be caused by changes in thick filament regulation (Summers et al., Vascul Pharmacol 48: 208–214, 2008). In the present study, it was hypothesized that HLU also modifies thin filament regulation by effects on p38^MAPK and ERK. Abdominal aorta rings from 20-day HLU rats and untreated controls were subjected to phenylephrine and phorbol 12,13-dibutyrate (PDBU) concentration response curves in the presence and absence of two inhibitors: the p38^MAPK inhibitor SB-203580 and the MEK inhibitor U-0126. SB-203580 decreased control sensitivity to both agonists, but HLU sensitivity was not significantly affected. U-0126, which blocks enzymes immediately upstream of ERK, affected sensitivity to both agonists equally between control and HLU. Western blot analysis revealed no change in total levels of p38^MAPK and its downstream target heat shock protein 27 but did reveal a decrease in phosphorylated levels of both after stimulation with PDBU and phenylephrine after HLU treatment. Neither total ERK nor phosphorylated levels after stimulation were affected by HLU. Total levels of caldesmon, a molecule downstream of both pathways, were decreased, but phosphorylated levels after stimulation were decreased by roughly twice as much. The results of this study demonstrate that HLU downregulates p38^MAPK, but not ERK, signaling. In turn, this may decrease actin availability for contraction.

extracellular signal-regulated kinase; phorbol ester; microgravity; orthostatic intolerance; heat shock protein 27