NHE inhibition does not improve Na(+) or Ca(2+) overload during reperfusion: using modeling to illuminate the mechanisms underlying a therapeutic failure.

Reperfusion injury results from pathologies of cardiac myocyte physiology that develop when previously ischemic myocardium experiences a restoration of normal perfusion. Events in the development of reperfusion injury begin with the restoration of a proton gradient upon reperfusion, which then allow...

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Autores principales:	Byron N Roberts, David J Christini
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/e2210c65c06548518518355f66deefc4
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spelling	oai:doaj.org-article:e2210c65c06548518518355f66deefc42021-11-18T05:51:51ZNHE inhibition does not improve Na(+) or Ca(2+) overload during reperfusion: using modeling to illuminate the mechanisms underlying a therapeutic failure.1553-734X1553-735810.1371/journal.pcbi.1002241https://doaj.org/article/e2210c65c06548518518355f66deefc42011-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22028644/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Reperfusion injury results from pathologies of cardiac myocyte physiology that develop when previously ischemic myocardium experiences a restoration of normal perfusion. Events in the development of reperfusion injury begin with the restoration of a proton gradient upon reperfusion, which then allows the sodium-proton exchanger (NHE) to increase flux, removing protons from the intracellular space while importing sodium. The resulting sodium overload drives increased reverse-mode sodium-calcium exchanger (NCX) activity, creating a secondary calcium overload that has pathologic consequences. One of the attempts to reduce reperfusion-related damage, NHE inhibition, has shown little clinical benefit, and only when NHE inhibitors are given prior to reperfusion. In an effort to further understand why NHE inhibitors have been largely unsuccessful, we employed a new mathematical cardiomyocyte model that we developed for the study of ischemia and reperfusion. Using this model, we simulated 20 minutes of ischemia and 10 minutes of reperfusion, while also simulating NHE inhibition by reducing NHE flux in our model by varying amounts and at different time points. In our simulations, when NHE inhibition is applied at the onset of reperfusion, increasing the degree of inhibition increases the peak sodium and calcium concentrations, as well as reducing intracellular pH recovery. When inhibition was instituted at earlier time points, some modest improvements were seen, largely due to reduced sodium concentrations prior to reperfusion. Analysis of all sodium flux pathways suggests that the sodium-potassium pump (NaK) plays the largest role in exacerbated sodium overload during reperfusion, and that reduced NaK flux is largely the result of impaired pH recovery. While NHE inhibition does indeed reduce sodium influx through that exchanger, the resulting prolongation of intracellular acidosis paradoxically increases sodium overload, largely mediated by impaired NaK function.Byron N RobertsDavid J ChristiniPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 7, Iss 10, p e1002241 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Byron N Roberts David J Christini NHE inhibition does not improve Na(+) or Ca(2+) overload during reperfusion: using modeling to illuminate the mechanisms underlying a therapeutic failure.
description	Reperfusion injury results from pathologies of cardiac myocyte physiology that develop when previously ischemic myocardium experiences a restoration of normal perfusion. Events in the development of reperfusion injury begin with the restoration of a proton gradient upon reperfusion, which then allows the sodium-proton exchanger (NHE) to increase flux, removing protons from the intracellular space while importing sodium. The resulting sodium overload drives increased reverse-mode sodium-calcium exchanger (NCX) activity, creating a secondary calcium overload that has pathologic consequences. One of the attempts to reduce reperfusion-related damage, NHE inhibition, has shown little clinical benefit, and only when NHE inhibitors are given prior to reperfusion. In an effort to further understand why NHE inhibitors have been largely unsuccessful, we employed a new mathematical cardiomyocyte model that we developed for the study of ischemia and reperfusion. Using this model, we simulated 20 minutes of ischemia and 10 minutes of reperfusion, while also simulating NHE inhibition by reducing NHE flux in our model by varying amounts and at different time points. In our simulations, when NHE inhibition is applied at the onset of reperfusion, increasing the degree of inhibition increases the peak sodium and calcium concentrations, as well as reducing intracellular pH recovery. When inhibition was instituted at earlier time points, some modest improvements were seen, largely due to reduced sodium concentrations prior to reperfusion. Analysis of all sodium flux pathways suggests that the sodium-potassium pump (NaK) plays the largest role in exacerbated sodium overload during reperfusion, and that reduced NaK flux is largely the result of impaired pH recovery. While NHE inhibition does indeed reduce sodium influx through that exchanger, the resulting prolongation of intracellular acidosis paradoxically increases sodium overload, largely mediated by impaired NaK function.
format	article
author	Byron N Roberts David J Christini
author_facet	Byron N Roberts David J Christini
author_sort	Byron N Roberts
title	NHE inhibition does not improve Na(+) or Ca(2+) overload during reperfusion: using modeling to illuminate the mechanisms underlying a therapeutic failure.
title_short	NHE inhibition does not improve Na(+) or Ca(2+) overload during reperfusion: using modeling to illuminate the mechanisms underlying a therapeutic failure.
title_full	NHE inhibition does not improve Na(+) or Ca(2+) overload during reperfusion: using modeling to illuminate the mechanisms underlying a therapeutic failure.
title_fullStr	NHE inhibition does not improve Na(+) or Ca(2+) overload during reperfusion: using modeling to illuminate the mechanisms underlying a therapeutic failure.
title_full_unstemmed	NHE inhibition does not improve Na(+) or Ca(2+) overload during reperfusion: using modeling to illuminate the mechanisms underlying a therapeutic failure.
title_sort	nhe inhibition does not improve na(+) or ca(2+) overload during reperfusion: using modeling to illuminate the mechanisms underlying a therapeutic failure.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/e2210c65c06548518518355f66deefc4
work_keys_str_mv	AT byronnroberts nheinhibitiondoesnotimprovenaorca2overloadduringreperfusionusingmodelingtoilluminatethemechanismsunderlyingatherapeuticfailure AT davidjchristini nheinhibitiondoesnotimprovenaorca2overloadduringreperfusionusingmodelingtoilluminatethemechanismsunderlyingatherapeuticfailure
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NHE inhibition does not improve Na(+) or Ca(2+) overload during reperfusion: using modeling to illuminate the mechanisms underlying a therapeutic failure.

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