Hypothermia-Induced Loss of Endothelial Barrier Function Is Restored after Dopamine Pretreatment: Role of p42/p44 Activation

Brinkkoetter, Paul-Thomas; Beck, Grietje; Göttmann, Uwe; Loesel, Ralf; Schnetzke, Ulf; Rudic, Boris; Hanusch, C; Rafat, Neysan; Liu, Zhenzi; Weiß, Christel; Leuvinik, Henri G. D.; Ploeg, Rutger J.; Braun, Claude; Schnuelle, Peter; Woude, Fokko J. van der; Yard, Benito A.

doi:10.1097/01.tp.0000229396.34362.e2

Cited by 34 publications

(46 citation statements)

References 33 publications

(36 reference statements)

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“…Another study on ischemia/ reperfusion injury in neonate rat cardiomyocytes supports that cardiac D 1 receptors are not involved in cytoprotection, because selective activation of D 1 receptors with the agonist SKF-38393 (1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol) induces apoptotic cell death (Li et al, 2008). As NOD has been shown not to act on dopamine receptors (Lösel et al, 2010), our data clearly support that DA's cytoprotective action does not require dopamine receptor engagement (Brinkkoetter et al, 2006(Brinkkoetter et al, , 2008Benck et al, 2011). Direct evidence to underpin this assumption is provided by the data demonstrating that the protective effects of DA and NOD are not abrogated by the D 1 /D 2 receptor antagonist fluphenazine.…”

Section: Dopamine and Its Lipophilic Derivates Providesupporting

confidence: 62%

“…Iron-mediated production of reactive oxygen species, impairment of Ca 21 homeostasis, and ATP depletion seem to be of instrumental importance in the sequel of hypothermic preservation injury (Rauen et al, 2000;Brinkkoetter et al, 2006;Bartels-Stringer et al, 2007;Radovits et al, 2008). Earlier reports have concluded that prolonged cold ischemic time is not a risk factor for decreased long-term survival in cardiac allograft recipients (Morgan et al, 2003), yet more recent studies have indicated that it is a predictor of a 5-year conditional mortality (Taylor et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…The beneficial effect of DA was more pronounced when cold ischemic time exceeded 17 hours, and this in turn translated into a better graft survival in patients in this particular subgroup (Schnuelle et al, 2009). Based on a substantial number of in vitro studies, current evidence indicates that DA mitigates cell damage related to cold preservation Brinkkoetter et al, 2006;Rudic et al, 2010). The cytoprotective properties of DA directly originate from structural entities, which enable the molecule to act as an iron chelator and to scavenge reactive oxygen species .…”

Section: Introductionmentioning

confidence: 99%

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Dopamine and Lipophilic Derivates Protect Cardiomyocytes against Cold Preservation Injury

Vettel

Hottenrott

et al. 2013

J Pharmacol Exp Ther

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Donor heart allografts are extremely susceptible to prolonged static cold storage. Because donor treatment with low-dose dopamine improves clinical outcome after heart transplantation, we tested the hypothesis that dopamine and its lipophilic derivate, N-octanoyl dopamine (NOD), protect cardiomyocytes from cold storage injury. Neonatal rat cardiomyocytes were treated with dopamine or NOD or left untreated and subsequently subjected to static cold storage (8-12 hours). Dopamine-and NOD-treated cardiomyocytes displayed a better viability compared with untreated cells after hypothermia. In untreated cardiomyocytes, cell damage was reflected by lactate dehydrogenase (LDH) release and a decrease in intracellular ATP. NOD was approximately 20-fold more potent than dopamine. Similarly to cardiomyocytes in vitro, rat hearts perfused with NOD before explantation showed significantly lower LDH release after static cold storage. ATP regeneration and spontaneous contractions after cold storage and rewarming only occurred in treated cardiomyocytes. Hypothermia severely attenuated isoprenaline-induced cAMP formation in control but not in dopamine-or NOD-treated cells. Esterified derivates of NOD with redox potential and lipophilic side chains reduced cell damage during cold storage similarly to NOD. In contrast to dopamine, neither NOD nor its derivates induced a significant b-adrenoceptor-mediated elevation of cellular cAMP levels. The b 1 -adrenoceptor antagonist atenolol and D 1 /D 2 receptor antagonist fluphenazine had no impact on the protective effect of NOD or dopamine. We conclude that dopamine as well as NOD treatment mitigates cold preservation injury to cardiomyocytes. The beneficial effects are independent of b-adrenoceptor or dopaminergic receptor stimulation but correlate with redox potential and lipophilic properties.

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Section: Dopamine and Its Lipophilic Derivates Providesupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dopamine and Lipophilic Derivates Protect Cardiomyocytes against Cold Preservation Injury

Vettel

Hottenrott

et al. 2013

J Pharmacol Exp Ther

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“…We are aware of the studies of Roberts et al [35] showing that cold preservation of HUVEC results in activation of NF-κB, ERK 1/2 and p38 MAPK pathways. We have previously shown that ERK 1/2 is completely dephosphorylated upon cold storage, suggesting that no activation of this pathway occurs in our model [36]. Similarly, unpublished findings also argue against a role of NFκB in the protective effect of dopamine.…”

Section: Discussionmentioning

confidence: 53%

Hypothermic Injury: the Mitochondrial Calcium, ATP and ROS Love-Hate Triangle out of Balance

Brinkkoetter

Song²,

Lösel³

et al. 2008

Cell Physiol Biochem

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Background/Aims: Catecholamines prevent hypothermic cell death which accounts for severe tissue damage and impaired allograft function after prolonged organ preservation. Here, we identified cellular processes which govern hypothermia-mediated cell death in endothelial cells and how they are influenced by dopamine. Methods: Lactate dehydrogenase assay, intracellular ATP, reactive oxygen species and reduced thio-group measurement, intracellular calcium measurement and mitochondrial calcium staining were performed in the study. Results: Intracellular ATP was almost completely depleted within 12 hrs of hypothermic preservation in untreated human umbilical vein endothelial cells (HUVEC), while dopamine pre-treatment significantly delayed ATP depletion. 4 hrs after hypothermia a redox imbalance was observed in untreated cells, which increased with the duration of hypothermia. The redox imbalance was primarily caused by depletion of SH reduction equivalents and was significantly inhibited by dopamine. In addition, hypothermia-induced Ca²⁺ influx and mitochondrial Ca²⁺ accumulation were both prevented by dopamine. The protective effect of dopamine was abrogated by ionomycin and sodium azide and partly by oligomycin and CCCP. Conclusions: Our data demonstrated that loss of intracellular ATP, generation of a redox imbalance and accumulation of intracellular Ca²⁺ underlie cold preservation injury. Dopamine improves the redox balance, prevents intracellular Ca²⁺ accumulation and delays ATP depletion.

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“…Many of the clinical complications that are associated with prolonged cold ischaemia time of allografts are caused by the loss of endothelial barrier function. Redistribution of endothelial adherence and tight junction proteins are responsible for endothelial barrier dysfunction as well as the breakdown of the cytoskeletal architecture [13,20]. An important and clinical relevant consequence of barrier dysfunction is the occurrence of tissue oedema.…”

Section: Vcam/s16 Ratiomentioning

confidence: 99%

Hypothermic preservation of lung allograft inhibits cytokine-induced chemoattractant-1, endothelial leucocyte adhesion molecule, vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 expression

Hanusch

Nowak²,

Gill

et al. 2007

Clinical and Experimental Immunology

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SummaryOrgan dysfunction is a major clinical problem after lung transplantation. Prolonged cold ischaemia and reperfusion injury are believed to play a central role in this complication. The influence of cold preservation on subsequent warm reperfusion was studied in an isolated, ventilated and perfused rat lung. Rat lungs were flushed with cold Perfadex-solution and stored at 4°C for different time periods. Thereafter lungs were perfused and ventilated for up to 3 h. Physiological parameters, production of inflammatory mediators and leucocyte infiltration were measured before and after perfusion. Lungs subjected to a cold ischaemia time of up to 6 h showed stable physiological conditions when perfused for 3 h. However, cold-ischaemia time beyond 6 h resulted in profound tissue oedema, thereby impairing ventilation and perfusion. Warm reperfusion and ventilation per se induced a strong inflammatory response, as demonstrated by a significant up-regulation of chemokines and adhesion molecules (cytokine-induced chemoattractant-1, intracellular adhesion molecule and endothelial leucocyte adhesion molecule), accompanied by enhanced leucocyte infiltration. Although the up-regulation of inflammatory mediators was blunted in lungs that were subjected to cold ischaemia, this did not influence leucocyte infiltration. In fact, cold ischaemia time correlated with leucocyte sequestration. Although cold preservation inhibits the expression of inflammatory mediators it does not affect leucocyte sequestration during warm reperfusion. Cold preservation might cause impairment of the endothelial barrier function, as evidenced by tissue oedema and profound leucocyte infiltration.

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Hypothermia-Induced Loss of Endothelial Barrier Function Is Restored after Dopamine Pretreatment: Role of p42/p44 Activation

Abstract: Our study demonstrates beneficial effects of dopamine treatment on cold storage induced endothelial barrier disturbances. This may contribute to the positive effects of catecholamines on immediate graft function of renal allografts in men.

Cited by 34 publications

References 33 publications

Dopamine and Lipophilic Derivates Protect Cardiomyocytes against Cold Preservation Injury

Dopamine and Lipophilic Derivates Protect Cardiomyocytes against Cold Preservation Injury

Hypothermic Injury: the Mitochondrial Calcium, ATP and ROS Love-Hate Triangle out of Balance

Hypothermic preservation of lung allograft inhibits cytokine-induced chemoattractant-1, endothelial leucocyte adhesion molecule, vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 expression

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