1992
DOI: 10.1152/ajpheart.1992.262.6.h1699
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Cyclosporin inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes

Abstract: Exchangeable intracellular Ca2+ as measured by 45Ca2+ uptake more than doubled when isolated adult rat ventricular cardiomyocytes were incubated 30 min with 8 microM cyclosporin; nevertheless the cells retained a normal rod-shaped morphology. High concentrations of ouabain caused a similar increase in 45Ca2+ uptake, but in this case the Ca2+ overload caused nearly all cells to hypercontract into a round disorganized form. The response to cyclosporin was concentration dependent with an apparent half-maximal eff… Show more

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Cited by 86 publications
(81 citation statements)
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“…For example, past in vitro studies suggested that transient opening of the MPTP might allow the exchange of matrix Ca 2+ across the inner membrane without causing cellular demise. Evidence for this hypothesis emerged in 1992 in a study by Altschuld and colleagues, who showed that CsA increased mitochondrial Ca 2+ loading and inhibited efflux in isolated rabbit cardiomyocytes (23). This hypothesis was extended by Ichas et al, who presented a biophysical model of Ca 2+ -induced mitochondrial Ca 2+ release that involved low-conductance MPTP opening for mitochondrial Ca 2+ efflux (20).…”
Section: Discussionmentioning
confidence: 99%
“…For example, past in vitro studies suggested that transient opening of the MPTP might allow the exchange of matrix Ca 2+ across the inner membrane without causing cellular demise. Evidence for this hypothesis emerged in 1992 in a study by Altschuld and colleagues, who showed that CsA increased mitochondrial Ca 2+ loading and inhibited efflux in isolated rabbit cardiomyocytes (23). This hypothesis was extended by Ichas et al, who presented a biophysical model of Ca 2+ -induced mitochondrial Ca 2+ release that involved low-conductance MPTP opening for mitochondrial Ca 2+ efflux (20).…”
Section: Discussionmentioning
confidence: 99%
“…Recent experimental studies have suggested that dimers of mitochondrial ATP synthase may constitute the MPTP (Bonora et al, 2013;Giorgio et al, 2013). Interestingly, an insight into the potential physiological role of the MPTP was provided by Elrod et al (2010) who reported that mice deficient in mitochondrial cyclophilin D were more susceptible to calcium overload, suggesting that the MPTP may mediate mitochondrial calcium efflux, a mechanism that had been first proposed in 1992 (Altschuld et al, 1992). Another important discovery was the identity of the mitochondrial calcium uniporter (Baughman et al, 2011;De Stefani et al, 2011) and the surprising observation that mice deficient in the uniporter were not protected from myocardial infarction despite being resistant to MPTP opening (Pan et al, 2013).…”
Section: Confounders Of Cardioprotection 1145mentioning
confidence: 99%
“…This conformation is characterized by rapid and spontaneous fluctuations in Ψ m , suggesting that the low-conductance conformation is used as an 'emergency mechanism' during oxidative stress and/or Ca 2+ loading to release accumulated Ca 2+ and to prevent prolonged mPTP opening and mitochondrial membrane rupture (Hüser and Blatter, 1999). This form of the mPTP has also been implicated in being involved in Ca 2+ homeostasis during resting conditions, as myocyte mitochondria accumulate Ca 2+ in the presence of the mPTP inhibitor cyclosporin A (CsA) (Altschuld et al, 1992). While Ca 2+ loading appears to be the primary trigger of mPTP activation, its activity is also increased in the presence of reactive oxygen species, elevated phosphate, high pH and depolarized Ψ m , while mPTP opening is antagonized by the presence of ATP/ADP, matrix Mg 2+ and mitochondrial matrix pH <7.0 (Armstrong et al, 2003;Haworth and Hunter, 1979;Bernardi, 1992;Varanyuwatana and Halestrap, 2012).…”
Section: +mentioning
confidence: 99%