In rat ventricular myocytes, Ca(2+) influx via NCX is not important for normal excitation-contraction coupling. Furthermore, the inhibition of Ca(2+) efflux alone (as [Na(+)](i) rises) may be sufficient to cause glycoside inotropy. In contrast, Ca(2+) overload and spontaneous activity at high [Na(+)](i) was blocked by KBR, suggesting that net Ca(2+) influx (not merely reduced efflux) via NCX is involved in potentially arrhythmogenic Ca(2+) overload.

]m reduction. Cytosolic Na ϩ concentrations that yielded one-half maximal activity levels for mitoNCX were 3.6 mM at normal ⌬⌿ m and 7.6 mM at ⌬⌿m dissipation. We conclude that 1) the mitochondrial Ca 2ϩ uniporter accumulates Ca 2ϩ in a manner that is dependent on ⌬⌿m at the physiological range of [Ca 2ϩ ]c; 2) ⌬⌿m dissipation opens the mPTP and results in Ca 2ϩ influx to mitochondria; and 3) although mitoNCX activity is impaired, mitoNCX extrudes Ca 2ϩ from the matrix even after ⌬⌿m dissipation. permeability transition pore; Na ϩ /Ca 2ϩ exchange; depolarization; ischemia-reperfusion injury ACCUMULATING EVIDENCE REVEALS that mitochondria play primary roles in fatal cell damage during ischemia-reperfusion (33). Key events that occur during ischemia include cytosolic Ca 2ϩ elevation, ATP depletion, high P i concentration, depolarized membrane potential, and acidotic pH. On reperfusion and recovery of normal pH, a burst of reactive oxygen species occurs, mitochondrial Ca 2ϩ overload ensues, and these lead to opening of the mitochondrial permeability transition pore (mPTP; Refs. 8,12,34). Opening of the mPTP allows water and solutes Յ1,500 Da in size to enter the matrix and cause mitochondrial swelling, rupture of the outer mitochondrial membrane, and release of cytochrome c or apoptosis-inducing factor, which initiates apoptotic programmed cell death (12,24,34). Because previous studies (8,12,13) (10,11). Furthermore, recent studies (4,8,10,11,18) also suggest a possible contribution by the mPTP to Ca 2ϩ homeostasis in both the cytosol and mitochondria. Despite the considerable attention given to the pathophysiological significance of mitochondrial Ca 2ϩ , the regulation and/or modulation of mitochondrial Ca 2ϩ during pathophysiological conditions such as ischemia-reperfusion injury are unclear. In previous studies, information about mitochondrial Ca 2ϩ was obtained using isolated mitochondria, whereby the structural and functional properties of organelles were seriously affected, and other cellular architectures were separated from the mitochondria. In this study, we measured [Ca 2ϩ ] m in saponin-permeabilized rat ventricular myocytes and investigated how ⌬⌿ m depolarization affects [Ca 2ϩ ] m and mitochondrial Ca 2ϩ transport systems such as the Ca 2ϩ uniporter, the mPTP, and mitoNCX.

Recent studies have shown that arsenic trioxide (As 2 O 3 ) can induce complete remission in patients with acute promyelocytic leukemia (APL). We tested the efficacy and safety of As 2 O 3 for the treatment of patients with APL who had relapsed from or become refractory to all-trans retinoic acid (ATRA) and conventional chemotherapy in a prospective study.

Cardiac toxicity occurs during arsenic trioxide therapy in patients with acute promyelocytic leukemia. Such patients should be monitored for prolonged QT intervals and ventricular arrhythmia.

The data strongly suggest that sildenafil can be used as a valuable pulmonary vasodilator in patients with pulmonary hypertension, with good long-term hemodynamic effects and safety. The results necessitate larger trials to confirm these observations in a larger cohort of patients.