Ischemic preconditioning and Na+/H+ exchange inhibition improve reperfusion ion homeostasis

doi:10.1016/S0003-4975(01)03309-4

The Annals of Thoracic Surgery

Volume 73, Issue 2, February 2002, Pages 569-574

https://doi.org/10.1016/S0003-4975(01)03309-4 Get rights and content

Abstract

Background. Intramyocyte sodium (Na⁺) increases during ischemia and reperfusion, which causes myocardial calcium (Ca²⁺) uptake and leads to myocyte injury or death. This study determines if ischemic preconditioning and myocyte sodium-hydrogen ion (Na⁺-H⁺) exchange (NHE) inhibition decreases Na⁺ gain that otherwise occurs with cardioplegic arrest and reperfusion.

Methods. Pigs had 1 hour of cardioplegic arrest followed by reperfusion. Group 1 had no intervention (controls). Group 2 received dimethyl amiloride (DMA, an NHE inhibitor), and group 3 had ischemic preconditioning before cardioplegic arrest. Precardioplegia to postreperfusion change in intramyocyte ion content was measured with atomic absorption spectrometry. The time to initial electrical activity and number of defibrillations needed to establish an organized rhythm postreperfusion were used as electrophysiologic variables to measure ischemia-reperfusion injury.

Results. Intramyocyte Na⁺ content for group 1 increased from 45.9 ± 6.7 to 61.9 ± 22.5 μmol/g (p = 0.02). Group 2 had an insignificant decrease in intramyocyte Na⁺ of 27.7 ± 19.58 μmol/g (p = 0.06), and group 3 had an insignificant decrease of 10.8 ± 46.33 μmol/g (p = 0.48). Interstitial water increased significantly in all groups, but there were no significant increases in intramyocyte water content. Electrophysiologic recovery was similar for all three groups.

Conclusions. The NHE inhibition and ischemic preconditioning each eliminated the increase in intramyocyte Na⁺ content that otherwise occurred with cardioplegic arrest and reperfusion in this porcine model. Because their mechanisms are distinct, it is possible that an additive beneficial effect against ischemia-reperfusion injury can be achieved by using NHE inhibition together with a preconditioning stimulus as prereperfusion therapy.

Section snippets

Surgical preparation and experimental interventions

Thirty pigs of both sexes, weighing 25 to 30 kg, were anesthetized, intubated, and mechanically ventilated. A constant infusion of sodium pentobarbital was used to maintain anesthesia. All animals in this study received humane care in compliance with the “Principles of Laboratory Animal Care,” formulated by the National Society for Medical Research, and the “Guide for the Care and Use of Laboratory Animals,” prepared by the Institute of Laboratory Animal Resources and published by the National

Biochemical analysis

Precardioplegia and postreperfusion values for intramyocyte sodium and potassium content are shown in Table 1. Initially there were 10 animals per group, however 2 animals in the control group and 2 animals in the DMA group were excluded because of values for intramyocyte Na⁺ content that were negative, despite repeated atomic absorption spectrometry measurements of the biopsy material. Negative values are impossible and reflect the derived nature of atomic absorption spectrometry measurements

Comment

Our goal in the present study was to examine the change in intracellular Na⁺ content during postcardioplegia reperfusion in three groups of animals: (1) a control group, (2) a group subjected to cardioplegic arrest and reperfusion in the presence of 5-(N,N-dimethyl amiloride) (DMA), a potent and selective inhibitor of NHE, and (3) a group subjected to cardioplegic arrest and reperfusion after a preconditioning stimulus. Atomic absorption spectrometry was used to determine intracellular ion

Acknowledgements

This work was partially funded by American Heart Association Grant-In-Aid No. 96006390 (William L. Holman), National Institutes of Health RO1 HL66015 (William L. Holman), and National Institutes of Health National Research Service Award HL-09493 (Jonathan L. Skinner).

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Experimental and clinical investigations suggest that blockade of Na⁺/H⁺ exchange (NHE) with cariporide provides functional protection during ischemia and reperfusion in mature hearts. The benefit on aged human myocardium is unknown. Therefore, the impact of cardiac aging on cardio-protection by cariporide after prolonged ischemia was studied in isolated myocardium of adult (⩽55 years), old (56–69 years), and very old (⩾70 years) patients with coronary artery disease. Isolated atrial trabeculae were subjected to 30 min of simulated ischemia with and without cariporide, and early post-ischemic contractile recovery was determined. During the reoxygenation period, trabeculae of adults, but not those of old or very old patients, improved after treatment with cariporide. After 90 min of reoxygenation, cariporide-treated adult trabeculae developed 41 ± 5% of their pre-ischemic force (non-treated control group, 27 ± 5%; P < 0.05), and old trabeculae recovered to 41 ± 7% (control, 25 ± 6%), whereas very old trabeculae recovered to only 26 ± 2% (control, 28 ± 6%). Trabeculae of all patients <70 years with CCS stage I–II angina pectoris recovered well (45 ± 6%; control, 22 ± 5%; P < 0.01), which was in contrast to patients with CCS stage III (34 ± 4%; control, 31 ± 5%). Subsequent immunoblot analyses indicated no concomitant alterations in the myocardial NHE1 protein level depending on age. In very old myocardium, higher levels of active p38MAPK in atrial trabeculae after ischemia pointed at an increased cellular stress, which was even more pronounced after post-ischemic reperfusion. In summary, cariporide is protective against ischemia–reperfusion injury in mature human hearts but has no benefit on the post-ischemic functional recovery of the aging myocardium.
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Citation Excerpt :
Second, protection of mitochondria from ischemia-reperfusion injury by opening mitochondrial K+ATP channels results in improved intra-myocyte ion homeostasis after ischemia-reperfusion injury [9]. Third, pharmacologic blockade of sarcolemmal Na+-H+ exchange limits the gain in intra-myocyte Na+ that otherwise occurs after ischemia and reperfusion [12] and is protective against ischemia-reperfusion injury. The treatments used in this study were based on this information and include: controlled post-ischemic reperfusion with normothermic hypocalcemic and hyperkalemic blood cardioplegia, pre-ischemic treatment with diazoxide (ie, a drug that is specific to mitochondrial K+ATP channels), and pre-ischemic treatment with cariporide (ie, a drug that is specific to the Na+-H+ exchanger).
This study evaluates a multiple treatment approach (ie, pharmacologic preconditioning [diazoxide], sodium-proton exchange inhibition [cariporide], and controlled reperfusion) to improve the outcome from severe cardiac ischemia-reperfusion injury that occurs during a cardiac operation.
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Original article: cardiovascularIschemic preconditioning and Na+/H+ exchange inhibition improve reperfusion ion homeostasis

Abstract

Section snippets

Surgical preparation and experimental interventions

Biochemical analysis

Comment

Acknowledgements

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

J Am Coll Cardiol

J Thorac Cardiovasc Surg

J Mol Cell Cardiol

The myocardial Na+-H+ exchangestructure, regulation, and its role in heart disease

Circ Res

Activation of mitochondrial ATP-sensitive K+ channel for cardiac protection against ischemic injury is dependent on protein kinase C activity

Circ Res

Role of protein kinase C in mitochondrial KATP channel-mediated protection against Ca2+ overload injury in rat myocardium

Circ Res

Role of Na+-H+ exchange on reperfusion related myocardial injury and arrhythmias in an open-chest swine model

PACE

Protection against infarction afforded by preconditioning is mediated by A1 adensoine receptors in rabbit hearts

Circulation

The resolution and recemization of potassium ethylenediaminetetraacetatocobaltate

J Physiol Chem

Original article: cardiovascular
Ischemic preconditioning and Na⁺/H⁺ exchange inhibition improve reperfusion ion homeostasis

The myocardial Na⁺-H⁺ exchangestructure, regulation, and its role in heart disease

Activation of mitochondrial ATP-sensitive K⁺ channel for cardiac protection against ischemic injury is dependent on protein kinase C activity

Role of protein kinase C in mitochondrial K_ATP channel-mediated protection against Ca²⁺ overload injury in rat myocardium

Role of Na⁺-H⁺ exchange on reperfusion related myocardial injury and arrhythmias in an open-chest swine model

Protection against infarction afforded by preconditioning is mediated by A₁ adensoine receptors in rabbit hearts