Abstract
This study investigates whether protective effects of an angiotensin
II type 1 receptor antagonist (losartan) in ischemia and reperfusion
are mediated by actions on Ca(2+) cycling. Effects of exposure to
losartan (10 microM) in ischemia were evaluated in isolated guinea
pig ventricular myocytes exposed to simulated ischemia and reperfusion
at 37 degrees C. Field-stimulated myocytes were exposed to 30 min
of simulated ischemia (hypoxia, acidosis, lactate, hyperkalemia,
and glucose-free) and reperfusion with Tyrode's solution for 40 min.
Cell shortening was measured with a video edge detector, and Ca(2+)
concentration was measured with fura-2. Field-stimulated myocytes
exhibited stunning in reperfusion, which was abolished in cells exposed
to losartan. In microelectrode studies, losartan did not alter the
responses of resting potentials or action potentials to ischemia
and reperfusion. In the absence of losartan, diastolic Ca(2+) increased
in ischemia, and Ca(2+) transients exhibited a rebound overshoot
in early reperfusion. Losartan did not affect amplitudes of Ca(2+)
transients in ischemia but prevented elevations in diastolic Ca(2+)
in ischemia. Furthermore, losartan prevented the overshoot of Ca(2+)
transients in early reperfusion and increased the magnitude of Ca(2+)
transients in late reperfusion. Sarcoplasmic reticulum (SR) Ca(2+)
stores, determined as Ca(2+) released by rapid application of 10
mM caffeine, were not altered in ischemia and reperfusion. However,
losartan increased SR Ca(2+) stores in late reperfusion, even in
cells that were not exposed to simulated ischemia. We conclude that
losartan abolishes stunning in reperfusion by preserving normal diastolic
Ca(2+) in ischemia and by increasing Ca(2+) transients through elevation
of releasable SR Ca(2+).
- /&/
- action
- animals;
- biological;
- calcium,
- contraction,
- control;
- cytosol,
- drug
- effects/physiology;
- effects;
- guinea
- heart,
- injury,
- ischemia,
- losartan,
- membrane
- metabolism
- metabolism;
- models,
- myocardial
- myocardium,
- pathology;
- pharmacology/therapeutic
- pigs;
- potentials,
- prevention
- reperfusion
- reperfusion;
- reticulum,
- sarcoplasmic
- stunning,
- use;
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