Trimetazidine reduces basal cytosolic Ca2+ concentration during hypoxia in single Xenopus skeletal myocytes.
We tested the hypotheses that: (1) Ca(2+) handling and force production would be irreversibly altered in skeletal muscle during steady-state contractions when subjected to severe, prolonged hypoxia and subsequent reoxygenation; and (2) application of the cardio-protective drug trimetazidine would attenuate these alterations. Single, living skeletal muscle fibres from Xenopus laevis were injected with the Ca(2+) indicator fura 2, and incubated for 1 h prior to stimulation in 100 micro M TMZ-Ringer solution (TMZ; n = 6) or standard Ringer solution (CON; n = 6). Force and relative free cytosolic Ca(2+) concentration ([Ca(2+)](c)) were measured during continuous tetanic contractions produced every 5 s as fibres were sequentially perfused in the following manner: 3 min high extracellular P(O(2)) (159 mmHg), 15 min hypoxic perfusion (3-5 mmHg) then 3 min high P(O(2)). Hypoxia caused a decrease in force and peak [Ca(2+)](c) in both the TMZ and CON fibres, with no significant (P < 0.05) difference between groups. However, basal [Ca(2+)](c) was significantly lower during hypoxia in the TMZ group vs. the CON group. While reoxygenation generated only modest recovery of relative force and peak [Ca(2+)](c) in both groups, basal [Ca(2+)](c) remained significantly less in the TMZ group. These results demonstrated that in contracting, single skeletal muscle fibres, TMZ prevented increases in basal [Ca(2+)](c) generated during a severe hypoxic insult and subsequent reoxygenation, yet failed to protect the cell from the deleterious effects of prolonged hypoxia followed by reoxygenation.
Stary
C M
CM
Department of Medicine, University of California, San Diego, La Jolla, USA.
Kohin
S
S
Samaja
M
M
Howlett
R A
RA
Hogan
M C
MC
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D005260:Female; D000860:Hypoxia / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D014292:Trimetazidine / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014982:Xenopus laevis
D014665:Vasodilator Agents; D014292:Trimetazidine; D002118:Calcium