The effect of isoflurane during reoxygenation on the sarcoplasmic reticulum and cellular injury in isolated ventricular myocytes

Dworschak, Martin; Breukelmann, Dirk; Hannon, James D.

doi:10.1016/j.lfs.2005.05.088

Cited by 3 publications

(3 citation statements)

References 33 publications

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“…Using fluorescent biosensors to measure ER Ca 2+ in live neurons, we found that isoflurane reduced both resting baseline and electrical activity-evoked increases in presynaptic ER Ca 2+ concentration. The mechanisms of isoflurane effects on ER Ca 2+ regulation are better understood in other cell types, particularly in skeletal muscle and cardiomyocytes ( Davies et al, 2000 ; Pabelick et al, 2004 ; Dworschak et al, 2006 ; Klingler et al, 2014 ), but have not been characterized in neurons. Anesthetic depression of stimulation-evoked ER Ca 2+ could be attributed to reductions in presynaptic cytosolic Ca 2+ influx, but by reducing external Ca 2+ concentration to mimic the isoflurane-induced reduction in presynaptic cytosolic Ca 2+ we were able to distinguish between the known inhibition of presynaptic cytosolic Ca 2+ by isoflurane and a distinct effect to reduce ER Ca 2+ concentration.…”

Section: Discussionmentioning

confidence: 99%

Isoflurane Alters Presynaptic Endoplasmic Reticulum Calcium Dynamics in Wild-Type and Malignant Hyperthermia-Susceptible Rodent Hippocampal Neurons

Osman,

Speigel,

Patel

et al. 2023

eNeuro

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Volatile anesthetics reduce excitatory synaptic transmission by both presynaptic and postsynaptic mechanisms which include inhibition of depolarization-evoked increases in presynaptic Ca2+concentration and blockade of postsynaptic excitatory glutamate receptors. The presynaptic sites of action leading to reduced electrically evoked increases in presynaptic Ca2+concentration and Ca2+-dependent exocytosis are unknown. Endoplasmic reticulum (ER) of Ca2+release via ryanodine receptor 1 (RyR1) and uptake by SERCA are essential for regulation intracellular Ca2+and are potential targets for anesthetic action. Mutations in sarcoplasmic reticulum release channels mediate volatile anesthetic-induced malignant hyperthermia (MH), a potentially fatal pharmacogenetic condition characterized by unregulated Ca2+release and muscle hypermetabolism. However, the impact of MH mutations on neuronal function are unknown. We used primary cultures of postnatal hippocampal neurons to analyze volatile anesthetic-induced changes in ER Ca2+dynamics using a genetically encoded ER-targeted fluorescent Ca2+sensor in both rat and mouse wild-type neurons and in mouse mutant neurons harboring theRYR1T4826I MH-susceptibility mutation. The volatile anesthetic isoflurane reduced both baseline and electrical stimulation-evoked increases in ER Ca2+concentration in neurons independent of its depression of presynaptic cytoplasmic Ca2+concentrations. Isoflurane and sevoflurane, but not propofol, depressed depolarization-evoked increases in ER Ca2+concentration significantly more in mouseRYR1T4826I mutant neurons than in wild-type neurons. TheRYR1T4826I mutant neurons also showed markedly greater isoflurane-induced reductions in presynaptic cytosolic Ca2+concentration and synaptic vesicle exocytosis. These findings implicate RyR1 as a molecular target for the effects of isoflurane on presynaptic Ca2+handling.Significance StatementDespite their essential clinical roles, the molecular and cellular mechanisms of action of general anesthetics are not fully understood. Malignant hyperthermia is a potentially fatal pharmacogenetic disorder that leads to dysregulation of intracellular Ca2+handling in response to triggering by volatile anesthetics. While research on malignant hyperthermia has focused on skeletal muscle effects, much less is known about its neuronal effects. We identify neuronal endoplasmic reticulum Ca2+regulation as a novel target for volatile anesthetic action and as a potential target in malignant hyperthermia. While depression of CNS electrical activityin vivoby anesthesia has been observed in another model of malignant hyperthermia, our study reveals fundamental presynaptic mechanisms of volatile anesthetics with implications for the development of more selective anesthetics and for prevention and treatment of malignant hyperthermia.

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Section: Discussionmentioning

confidence: 99%

Isoflurane Alters Presynaptic Endoplasmic Reticulum Calcium Dynamics in Wild-Type and Malignant Hyperthermia-Susceptible Rodent Hippocampal Neurons

Osman,

Speigel,

Patel

et al. 2023

eNeuro

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“…In vivo studies have reported that myocardial stunning leads to a significant increase in the time delay of regional shortening in rabbits 11 and decreased regional work performed during systole, as well as an extended time of shortening, in dogs 10,23 . Contraction is often unchanged, but delayed 30,31 . These changes occur against a background of unchanged regional O 2 consumption 10,11 .…”

Section: Discussionmentioning

confidence: 99%

“…In the present in vitro study, we did not observe changes in basal contraction, but found that stunned myocytes had a blunted response to positive inotropic agents in terms of both contractility and Ca 2+ transients. Most studies report reduced function on reperfusion; 11,23 however, some report full restoration 30,31 …”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible Factor‐1 Improves the Actions of Positive Inotropic Agents in Stunned Cardiac Myocytes

Tan¹,

Luciano

Scholz

et al. 2009

Clin Exp Pharma Physio

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1. In the present study, we tested hypothesis that upregulation of hypoxia-inducible factor-1 (HIF-1) would improve the actions of positive inotropic agents in cardiac myocytes after simulated ischaemia-reperfusion (I/R). 2. Hypoxia-inducible factor-1α was upregulated with deferoxamine (150 mg/kg per day for 2 days). Rabbit cardiac myocytes were subjected to simulated ischaemia (15 min, 95% N(2)-5% CO2) and reperfusion (re-oxygenation) and compared with control myocytes. Cell contraction and calcium transients were measured at baseline and after forskolin (10(-7) and 10(-6) mol/L) or ouabain (10(-5) and 10(-4) mol/L). 3. Under control conditions, high-dose forskolin and ouabain increased percentage shortening by 20 and 18%, respectively. Deferoxamine-treated control myocytes responded similarly. In stunned myocytes, forskolin and ouabain did not significantly increase shortening (increases of 8% and 9%, respectively). Deferoxamine restored the effects of forskolin (+26%) and ouabain (+28%) in stunning. The results for maximum shortening and relaxation rates were similar. The increased calcium transients caused by forskolin and ouabain were also depressed in stunned myocytes, but were maintained by HIF-1 upregulation. 4. These results suggest that simulated I/R impaired the functional and calcium transient effects of positive inotropic agents. Upregulation of HIF-1 protects cardiac myocyte function after I/R by maintaining calcium release.

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Role of Anesthetic Agents on Cardiac and Immune Systems

2011

Shock

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A growing body of evidence indicates that anesthetic agents may play some roles in the cardiovascular and immune systems after injury. Myocardial anesthetic preconditioning is found to be involved in the anesthetic-induced cardioprotective effect. Such protective phenomenon is reported to be implicated in a variety of intracellular signaling pathways including the regulation of the opening of adenosine triphosphate-sensitive potassium channels, the maintenance of intracellular and mitochondrial calcium homeostasis, and the mediation of nitric oxide formation and reactive oxygen species release. Moreover, through anti-inflammatory effects and antioxidant properties, the anesthetic agents are believed to modulate immune response of individuals after injury. Thus, alteration or modulation of cardiovascular and immune function by the administration of anesthetic agents to the patients at the time of injury appears to be appropriate and important.

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The effect of isoflurane during reoxygenation on the sarcoplasmic reticulum and cellular injury in isolated ventricular myocytes

Cited by 3 publications

References 33 publications

Isoflurane Alters Presynaptic Endoplasmic Reticulum Calcium Dynamics in Wild-Type and Malignant Hyperthermia-Susceptible Rodent Hippocampal Neurons

Isoflurane Alters Presynaptic Endoplasmic Reticulum Calcium Dynamics in Wild-Type and Malignant Hyperthermia-Susceptible Rodent Hippocampal Neurons

Hypoxia‐inducible Factor‐1 Improves the Actions of Positive Inotropic Agents in Stunned Cardiac Myocytes

Role of Anesthetic Agents on Cardiac and Immune Systems

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