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.

Cell volume and monovalent ion transporters: their role in cell death machinery triggering and progression

“…We noted that the death of ouabain-treated MDCK cells was completely abolished by acidification of medium from pH 7.4 to 7.0, i.e., under conditions when pH i was decreased from ϳ7.2 to 6.9 (3). This observation contrasted with the lack of any impact of acidification on the appearance of necrotic and apoptotic markers in atrial cardiomyocytes subjected to ischemia-reperfusion (8). Surprisingly, almost complete Na/K pump inhibition and fullscale increase of the [Na ϩ ] i /[K ϩ ] i ratio evoked by K ϩ -free medium did not affect the survival of MDCK cells (36,105).…”

Acid enhancement of ROS generation by complex-I reverse electron transport is balanced by acid inhibition of complex-II: Relevance for tissue reperfusion injury

“…We and others have demonstrated that Cx-II inhibition at the start of reperfusion is protective in animal and perfused organ models of IR injury [ 15 , [27] , [28] , [29] , [30] ]. In addition, it is known that prolongation of ischemic tissue acidosis into the reperfusion period can improve recovery from IR injury [ 31 , 32 ]. While the exact protective mechanism of “acid post-conditioning” is poorly characterized, it may involve a recently described pH sensor on the PT pore [ 33 ].…”

Upregulation of Na+,Cl--Coupled Betaine/ γ-Amino-Butyric Acid Transporter BGT1 by Tau Tubulin Kinase 2

“…Osmolyte transporters counteract cell shrinkage, which is known to parallel and facilitate suicidal cell death [51,52,53,54,55,56,57,58,59,60]. BGT1 participates in the cellular accumulation of organic osmolytes [9,10], which are well known to foster cell survival [8,26].…”