The cardioprotective effect of brief acidic reperfusion after ischemia in perfused rat hearts is not mimicked by inhibition of the Na+/H+ exchanger NHE1

Ann-Dorit Andersen; Bo Hjorth Bentzen; H. Salling; Henrik Klingberg; Morten Kanneworff; Morten Grunnet; Stine Helene Falsig Pedersen

doi:10.1159/000331709

The cardioprotective effect of brief acidic reperfusion after ischemia in perfused rat hearts is not mimicked by inhibition of the Na⁺/H⁺ exchanger NHE1

Ann-Dorit Andersen, Bo Hjorth Bentzen, H. Salling, Henrik Klingberg, Morten Kanneworff, Morten Grunnet, Stine Helene Falsig Pedersen

6 Citations (Scopus)

Abstract

Background: Ischemic postconditioning (PostC), i.e. brief ischemia-reperfusion cycles before full reperfusion, is protective against cardiac ischemia/reperfusion (I/R) injury. Inhibition of the Na ⁺ /H ⁺ exchanger NHE1 and delayed intracellular pH-normalization have been proposed to underlie protection by PostC. Methods and Results: We used Langendorff perfused rat hearts exposed to 35 min global ischemia to show that 15 min acidic (pH 6.5) treatment at onset of reperfusion decreased infarct size and functional deterioration at least to the same extent as PostC. In contrast, NHE1 inhibition by EIPA was detrimental. To evaluate HL-1 atrial cardiomyocytes as a cellular model for PostC, we exposed the cells to simulated ischemia/reperfusion (I/R) mimicking that in perfused hearts. Necrosis and apoptosis induced by I/R were unaffected by 15 min of pH 6.0 at onset of reperfusion. I/R increased the activity of c-Jun N-terminal Kinase 1/2 (JNK1/2) and Akt, but not of p38 MAPK, with no further effect of acidic reperfusion or EIPA. Conclusion: In rat hearts, 15 min acidic reperfusion improves myocardial performance at least as much as does PostC, whereas NHE1 inhibition is detrimental. In contrast, in HL-1 cardiomyocytes, acidic reperfusion or NHE1 inhibition affect neither survival nor JNK1/2-, Akt-, and p38 MAPK activity after I/R, pointing to different mechanisms of damage and protection in these systems.

Original language	English
Journal	Cellular Physiology and Biochemistry
Volume	28
Issue number	1
Pages (from-to)	13-24
Number of pages	12
ISSN	1015-8987
DOIs	https://doi.org/10.1159/000331709
Publication status	Published - 2011

Keywords

Acids
Amiloride
Animals
Apoptosis
Cells, Cultured
Hydrogen-Ion Concentration
Ischemic Postconditioning
Male
Mitogen-Activated Protein Kinase 8
Mitogen-Activated Protein Kinase 9
Models, Biological
Myocardial Ischemia
Myocardial Reperfusion Injury
Myocytes, Cardiac
Necrosis
Neuroprotective Agents
Proto-Oncogene Proteins c-akt
Rats
Rats, Sprague-Dawley
Sodium-Hydrogen Antiporter
p38 Mitogen-Activated Protein Kinases

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10.1159/000331709

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The cardioprotective effect of brief acidic reperfusion after ischemia in perfused rat hearts is not mimicked by inhibition of the Na⁺/H⁺ exchanger NHE1. / Andersen, Ann-Dorit; Bentzen, Bo Hjorth; Salling, H. et al.

In: Cellular Physiology and Biochemistry, Vol. 28, No. 1, 2011, p. 13-24.

Research output: Contribution to journal › Journal article › Research › peer-review

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title = "The cardioprotective effect of brief acidic reperfusion after ischemia in perfused rat hearts is not mimicked by inhibition of the Na+/H+ exchanger NHE1",

abstract = " Background: Ischemic postconditioning (PostC), i.e. brief ischemia-reperfusion cycles before full reperfusion, is protective against cardiac ischemia/reperfusion (I/R) injury. Inhibition of the Na + /H + exchanger NHE1 and delayed intracellular pH-normalization have been proposed to underlie protection by PostC. Methods and Results: We used Langendorff perfused rat hearts exposed to 35 min global ischemia to show that 15 min acidic (pH 6.5) treatment at onset of reperfusion decreased infarct size and functional deterioration at least to the same extent as PostC. In contrast, NHE1 inhibition by EIPA was detrimental. To evaluate HL-1 atrial cardiomyocytes as a cellular model for PostC, we exposed the cells to simulated ischemia/reperfusion (I/R) mimicking that in perfused hearts. Necrosis and apoptosis induced by I/R were unaffected by 15 min of pH 6.0 at onset of reperfusion. I/R increased the activity of c-Jun N-terminal Kinase 1/2 (JNK1/2) and Akt, but not of p38 MAPK, with no further effect of acidic reperfusion or EIPA. Conclusion: In rat hearts, 15 min acidic reperfusion improves myocardial performance at least as much as does PostC, whereas NHE1 inhibition is detrimental. In contrast, in HL-1 cardiomyocytes, acidic reperfusion or NHE1 inhibition affect neither survival nor JNK1/2-, Akt-, and p38 MAPK activity after I/R, pointing to different mechanisms of damage and protection in these systems.",

keywords = "Acids, Amiloride, Animals, Apoptosis, Cells, Cultured, Hydrogen-Ion Concentration, Ischemic Postconditioning, Male, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinase 9, Models, Biological, Myocardial Ischemia, Myocardial Reperfusion Injury, Myocytes, Cardiac, Necrosis, Neuroprotective Agents, Proto-Oncogene Proteins c-akt, Rats, Rats, Sprague-Dawley, Sodium-Hydrogen Antiporter, p38 Mitogen-Activated Protein Kinases",

author = "Ann-Dorit Andersen and Bentzen, {Bo Hjorth} and H. Salling and Henrik Klingberg and Morten Kanneworff and Morten Grunnet and Pedersen, {Stine Helene Falsig}",

note = "Copyright {\textcopyright} 2011 S. Karger AG, Basel.",

year = "2011",

doi = "10.1159/000331709",

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pages = "13--24",

journal = "Cellular Physiology and Biochemistry",

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TY - JOUR

T1 - The cardioprotective effect of brief acidic reperfusion after ischemia in perfused rat hearts is not mimicked by inhibition of the Na+/H+ exchanger NHE1

AU - Andersen, Ann-Dorit

AU - Bentzen, Bo Hjorth

AU - Salling, H.

AU - Klingberg, Henrik

AU - Kanneworff, Morten

AU - Grunnet, Morten

AU - Pedersen, Stine Helene Falsig

PY - 2011

Y1 - 2011

N2 - Background: Ischemic postconditioning (PostC), i.e. brief ischemia-reperfusion cycles before full reperfusion, is protective against cardiac ischemia/reperfusion (I/R) injury. Inhibition of the Na + /H + exchanger NHE1 and delayed intracellular pH-normalization have been proposed to underlie protection by PostC. Methods and Results: We used Langendorff perfused rat hearts exposed to 35 min global ischemia to show that 15 min acidic (pH 6.5) treatment at onset of reperfusion decreased infarct size and functional deterioration at least to the same extent as PostC. In contrast, NHE1 inhibition by EIPA was detrimental. To evaluate HL-1 atrial cardiomyocytes as a cellular model for PostC, we exposed the cells to simulated ischemia/reperfusion (I/R) mimicking that in perfused hearts. Necrosis and apoptosis induced by I/R were unaffected by 15 min of pH 6.0 at onset of reperfusion. I/R increased the activity of c-Jun N-terminal Kinase 1/2 (JNK1/2) and Akt, but not of p38 MAPK, with no further effect of acidic reperfusion or EIPA. Conclusion: In rat hearts, 15 min acidic reperfusion improves myocardial performance at least as much as does PostC, whereas NHE1 inhibition is detrimental. In contrast, in HL-1 cardiomyocytes, acidic reperfusion or NHE1 inhibition affect neither survival nor JNK1/2-, Akt-, and p38 MAPK activity after I/R, pointing to different mechanisms of damage and protection in these systems.

AB - Background: Ischemic postconditioning (PostC), i.e. brief ischemia-reperfusion cycles before full reperfusion, is protective against cardiac ischemia/reperfusion (I/R) injury. Inhibition of the Na + /H + exchanger NHE1 and delayed intracellular pH-normalization have been proposed to underlie protection by PostC. Methods and Results: We used Langendorff perfused rat hearts exposed to 35 min global ischemia to show that 15 min acidic (pH 6.5) treatment at onset of reperfusion decreased infarct size and functional deterioration at least to the same extent as PostC. In contrast, NHE1 inhibition by EIPA was detrimental. To evaluate HL-1 atrial cardiomyocytes as a cellular model for PostC, we exposed the cells to simulated ischemia/reperfusion (I/R) mimicking that in perfused hearts. Necrosis and apoptosis induced by I/R were unaffected by 15 min of pH 6.0 at onset of reperfusion. I/R increased the activity of c-Jun N-terminal Kinase 1/2 (JNK1/2) and Akt, but not of p38 MAPK, with no further effect of acidic reperfusion or EIPA. Conclusion: In rat hearts, 15 min acidic reperfusion improves myocardial performance at least as much as does PostC, whereas NHE1 inhibition is detrimental. In contrast, in HL-1 cardiomyocytes, acidic reperfusion or NHE1 inhibition affect neither survival nor JNK1/2-, Akt-, and p38 MAPK activity after I/R, pointing to different mechanisms of damage and protection in these systems.

KW - Acids

KW - Amiloride

KW - Animals

KW - Apoptosis

KW - Cells, Cultured

KW - Hydrogen-Ion Concentration

KW - Ischemic Postconditioning

KW - Male

KW - Mitogen-Activated Protein Kinase 8

KW - Mitogen-Activated Protein Kinase 9

KW - Models, Biological

KW - Myocardial Ischemia

KW - Myocardial Reperfusion Injury

KW - Myocytes, Cardiac

KW - Necrosis

KW - Neuroprotective Agents

KW - Proto-Oncogene Proteins c-akt

KW - Rats

KW - Rats, Sprague-Dawley

KW - Sodium-Hydrogen Antiporter

KW - p38 Mitogen-Activated Protein Kinases

U2 - 10.1159/000331709

DO - 10.1159/000331709

M3 - Journal article

C2 - 21865844

SN - 1015-8987

VL - 28

SP - 13

EP - 24

JO - Cellular Physiology and Biochemistry

JF - Cellular Physiology and Biochemistry

IS - 1

ER -