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Dodecafluoropentane emulsion elicits cardiac protection against myocardial infarction through an ATP-Sensitive K+ channel dependent mechanism.

Strom J, Swyers T, Wilson D, Unger E, Chen QM, Larson DF - Cardiovasc Drugs Ther (2014)

Bottom Line: DDFPe treatment reduced infarct size by approximately 72% (36.9 ± 4.2% for vehicle vs 10.4 ± 2.3% for DDFPe; p < 0.01; n = 6-8) at 24 h.Serum cTnI levels were similarly reduced by DDFPe (35.0 ± 4.6 ng/ml for vehicle vs 15.8 ± 1.6 ng/ml for DDFPe; p < 0.01; n = 6-8).Our data indicate a cardiac protective role of DDFPe that persists beyond its retention time in the body and is dependent on mitoK(ATP), an important mediator of ischemic preconditioning induced cardiac protection.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology; College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ, 85724, USA.

ABSTRACT

Purpose: Dodecafluoropentane emulsion (DDFPe) is a perfluorocarbon with high oxygen dissolving, transport, and delivery capacity that may offer the potential to limit ischemic injury prior to clinical reperfusion. Here we investigated the cardiac protective potential of DDFPe in a mouse model of myocardial infarction.

Methods: Myocardial infarction was initiated by permanent ligation of the left anterior descending (LAD) coronary artery. Mice were administered vehicle or 5-hydroxydecanoate (5-HD) intravenously 10 min before LAD occlusion followed by a single intravenous administration of vehicle or DDFPe immediately after occlusion. Heart tissue and serum samples were collected 24 after LAD occlusion for measurement of infarct size and cardiac troponin I (cTnI) levels, respectively.

Results: DDFPe treatment reduced infarct size by approximately 72% (36.9 ± 4.2% for vehicle vs 10.4 ± 2.3% for DDFPe; p < 0.01; n = 6-8) at 24 h. Serum cTnI levels were similarly reduced by DDFPe (35.0 ± 4.6 ng/ml for vehicle vs 15.8 ± 1.6 ng/ml for DDFPe; p < 0.01; n = 6-8). Pretreatment with 5-HD, a mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) inhibitor, blocked the reduction in infarct size (29.2 ± 4.4% for 5-HD vs 35.4 ± 7.4% for 5-HD+DDFPe; p = 0.48; n = 6-8) and serum cTnI levels (27.4 ± 5.1 ng/ml for 5-HD vs 34.6 ± 5.3 ng/ml for 5-HD+DDFPe; p = 0.86; n = 6-8) by DDFPe.

Conclusion: Our data indicate a cardiac protective role of DDFPe that persists beyond its retention time in the body and is dependent on mitoK(ATP), an important mediator of ischemic preconditioning induced cardiac protection.

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Related in: MedlinePlus

5-HD prevents the decrease in plasma cTnI levels by DDFPe. Mice were pretreated with saline vehicle or 5-HD prior to LAD ligation and saline vehicle or DDFPe administration. Blood plasma was collected 24 h after LAD ligation. Plasma samples from 6 mice in each group, indicated by animal number, were analyzed by Western blot for cTnI levels or ponceau stain for protein loading (a). Normalized cTnI band intensities were graphed (b). n = 6. Data is plotted as means ± SEM. * indicates significant difference (p < 0.05) between means as determined by Whitney-Man rank sum tests
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Fig3: 5-HD prevents the decrease in plasma cTnI levels by DDFPe. Mice were pretreated with saline vehicle or 5-HD prior to LAD ligation and saline vehicle or DDFPe administration. Blood plasma was collected 24 h after LAD ligation. Plasma samples from 6 mice in each group, indicated by animal number, were analyzed by Western blot for cTnI levels or ponceau stain for protein loading (a). Normalized cTnI band intensities were graphed (b). n = 6. Data is plotted as means ± SEM. * indicates significant difference (p < 0.05) between means as determined by Whitney-Man rank sum tests

Mentions: Ischemic preconditioning is a well-established, classical method of eliciting cardiac protection from ischemic insults. Investigations into the mechanisms of cardiac protection have identified mitochondrial ATP-sensitive potassium channels (KATP) as important mediators of both ischemic and pharmacological preconditioning in the myocardium. In order to investigate a potential role of DDFPe in eliciting cardiac protection through a preconditioning mechanism involving KATP, mice were administered the selective mitochondrial KATP antagonist 5-hydroxydecanoate (5-HD) prior to LAD ligation. Mice administered 5-HD with or without DDFPe experienced similar areas at risk (51 % ± 2.6 for 5-HD + Vehicle vs 46 % ± 5.4 for 5-HD + DDFPe; p = 0.64) consistent with those for groups receiving vehicle or DDFPe alone (Fig. 2b). In mice treated with 5-HD, DDFPe failed to reduce infarct size measured by TTC staining (29.2 % ± 4.1 for 5-HD + Vehicle vs 35.4 % ± 7.4 for 5-HD + DDFPe; p = 0.48) (Fig. 2c). Likewise, 5-HD attenuated DDFPe associated decreases in cTnI release into the blood as measured by ELISA assay (27.4 ± 5.1 ng/ml for 5-HD vs 34.6 ± 5.3 ng/ml for 5-HD + DDFPe; p = 0.86) (Fig. 2d). Western blot analysis of cTnI levels in the plasma confirmed that while DDFPe alone reduced the release of cTnI into the blood following MI, this effect was blocked by pretreatment with 5-HD (Fig. 3a–b).Fig. 2


Dodecafluoropentane emulsion elicits cardiac protection against myocardial infarction through an ATP-Sensitive K+ channel dependent mechanism.

Strom J, Swyers T, Wilson D, Unger E, Chen QM, Larson DF - Cardiovasc Drugs Ther (2014)

5-HD prevents the decrease in plasma cTnI levels by DDFPe. Mice were pretreated with saline vehicle or 5-HD prior to LAD ligation and saline vehicle or DDFPe administration. Blood plasma was collected 24 h after LAD ligation. Plasma samples from 6 mice in each group, indicated by animal number, were analyzed by Western blot for cTnI levels or ponceau stain for protein loading (a). Normalized cTnI band intensities were graphed (b). n = 6. Data is plotted as means ± SEM. * indicates significant difference (p < 0.05) between means as determined by Whitney-Man rank sum tests
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4260113&req=5

Fig3: 5-HD prevents the decrease in plasma cTnI levels by DDFPe. Mice were pretreated with saline vehicle or 5-HD prior to LAD ligation and saline vehicle or DDFPe administration. Blood plasma was collected 24 h after LAD ligation. Plasma samples from 6 mice in each group, indicated by animal number, were analyzed by Western blot for cTnI levels or ponceau stain for protein loading (a). Normalized cTnI band intensities were graphed (b). n = 6. Data is plotted as means ± SEM. * indicates significant difference (p < 0.05) between means as determined by Whitney-Man rank sum tests
Mentions: Ischemic preconditioning is a well-established, classical method of eliciting cardiac protection from ischemic insults. Investigations into the mechanisms of cardiac protection have identified mitochondrial ATP-sensitive potassium channels (KATP) as important mediators of both ischemic and pharmacological preconditioning in the myocardium. In order to investigate a potential role of DDFPe in eliciting cardiac protection through a preconditioning mechanism involving KATP, mice were administered the selective mitochondrial KATP antagonist 5-hydroxydecanoate (5-HD) prior to LAD ligation. Mice administered 5-HD with or without DDFPe experienced similar areas at risk (51 % ± 2.6 for 5-HD + Vehicle vs 46 % ± 5.4 for 5-HD + DDFPe; p = 0.64) consistent with those for groups receiving vehicle or DDFPe alone (Fig. 2b). In mice treated with 5-HD, DDFPe failed to reduce infarct size measured by TTC staining (29.2 % ± 4.1 for 5-HD + Vehicle vs 35.4 % ± 7.4 for 5-HD + DDFPe; p = 0.48) (Fig. 2c). Likewise, 5-HD attenuated DDFPe associated decreases in cTnI release into the blood as measured by ELISA assay (27.4 ± 5.1 ng/ml for 5-HD vs 34.6 ± 5.3 ng/ml for 5-HD + DDFPe; p = 0.86) (Fig. 2d). Western blot analysis of cTnI levels in the plasma confirmed that while DDFPe alone reduced the release of cTnI into the blood following MI, this effect was blocked by pretreatment with 5-HD (Fig. 3a–b).Fig. 2

Bottom Line: DDFPe treatment reduced infarct size by approximately 72% (36.9 ± 4.2% for vehicle vs 10.4 ± 2.3% for DDFPe; p < 0.01; n = 6-8) at 24 h.Serum cTnI levels were similarly reduced by DDFPe (35.0 ± 4.6 ng/ml for vehicle vs 15.8 ± 1.6 ng/ml for DDFPe; p < 0.01; n = 6-8).Our data indicate a cardiac protective role of DDFPe that persists beyond its retention time in the body and is dependent on mitoK(ATP), an important mediator of ischemic preconditioning induced cardiac protection.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology; College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ, 85724, USA.

ABSTRACT

Purpose: Dodecafluoropentane emulsion (DDFPe) is a perfluorocarbon with high oxygen dissolving, transport, and delivery capacity that may offer the potential to limit ischemic injury prior to clinical reperfusion. Here we investigated the cardiac protective potential of DDFPe in a mouse model of myocardial infarction.

Methods: Myocardial infarction was initiated by permanent ligation of the left anterior descending (LAD) coronary artery. Mice were administered vehicle or 5-hydroxydecanoate (5-HD) intravenously 10 min before LAD occlusion followed by a single intravenous administration of vehicle or DDFPe immediately after occlusion. Heart tissue and serum samples were collected 24 after LAD occlusion for measurement of infarct size and cardiac troponin I (cTnI) levels, respectively.

Results: DDFPe treatment reduced infarct size by approximately 72% (36.9 ± 4.2% for vehicle vs 10.4 ± 2.3% for DDFPe; p < 0.01; n = 6-8) at 24 h. Serum cTnI levels were similarly reduced by DDFPe (35.0 ± 4.6 ng/ml for vehicle vs 15.8 ± 1.6 ng/ml for DDFPe; p < 0.01; n = 6-8). Pretreatment with 5-HD, a mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) inhibitor, blocked the reduction in infarct size (29.2 ± 4.4% for 5-HD vs 35.4 ± 7.4% for 5-HD+DDFPe; p = 0.48; n = 6-8) and serum cTnI levels (27.4 ± 5.1 ng/ml for 5-HD vs 34.6 ± 5.3 ng/ml for 5-HD+DDFPe; p = 0.86; n = 6-8) by DDFPe.

Conclusion: Our data indicate a cardiac protective role of DDFPe that persists beyond its retention time in the body and is dependent on mitoK(ATP), an important mediator of ischemic preconditioning induced cardiac protection.

Show MeSH
Related in: MedlinePlus