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.
Department of Medicine, University of California, San Diego, La Jolla, USA.
C M
CM
Stary
S
S
Kohin
M
M
Samaja
R A
RA
Howlett
M C
MC
Hogan
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