Role of the Na⁺–H⁺exchanger (NHE1) in heart muscle function during transient acidosis. A study in papillary muscles from rat and guinea pig hearts

Abstract

The sodium-hydrogen exchanger (NHE) helps the cell to recover from intracellular acidosis. In this study, we have investigated the effect of HOE 642 (a specific NHE1 blocker) on papillary muscles from rats and guinea pigs during transient acidosis and PKC activation by recording developed force (DF), action potential characteristics, and electrical conductance (stimulus-response interval). Two protocols were used, with or without HOE 642 (10(-5) mol/L): papillary muscle was exposed (i) for 15 min to a glucose-free, nonoxygenated HEPES buffer containing lactate (20 mmol/L) (pH 6.8) followed by 15 min recovery or (ii) to a PKC activator (phorbolmyristate acetate (PMA) (10(-9) mol/L)) for 30 min. The DF after acidification remained significantly decreased in the NHE-blocked papillary muscles. During recovery from acidosis, papillary muscles exposed to HOE 642 remained at a higher electrical resistance. The present study shows that post-acidotic continued depression of DF and change in tissue electrophysiological properties might occur as a result of blocking the NHE. During infarct development, the tissue-protecting effect of NHE blockade has been well documented. When acidosis or reduced contractile function is present, however, blocking NHE by HOE 642 might not improve the situation.

Cariporide (HOE642) attenuates lactic acidosis induced pulmonary vein arrhythmogenesis

“…In this study, similar to the findings of previous studies (Dhein et al 1998;Sundset et al 2003), lactic acidosis increased the SRI, which is an indicator of conduction through tissues. Intercellular uncoupling was proposed to be due to the reduced intracellular Na + availability and impairs impulse propagation (Cascio et al 2005).…”

“…Similar to findings in this study, cariporide did not alter the spontaneous activity, APA, or AP duration in cardiomyocytes (Gryshchenko et al 2002;Sundset et al 2003), but, it had significant effects on the RMP and SRI in the PV and LA. In earlier studies, cariporide was found to reverse or prevent cellular uncoupling and improve the SRI in both atria and ventricular cells via its action on Na + /H + exchanger and also by preventing ATP depletion (Cascio et al 2005;Dhein et al 1998;Sundset et al 2003).…”

“…Since lactic acidosis significantly alters Ca 2+ regulation and activates the reverse mode of Na + /Ca 2+ exchanger, it is possible that lactic acidosis may increase PV arrhythmogenesis and contribute to the genesis of AF. Cariporide (HOE-642), a potent selective Na + /H + exchanger blocker, was found to prevent ischemic injury and prevent or reduce cardiac dysfunction and ventricular tachy-arrhythmias (van Borren et al 2004). Jayachandran et al found that cariporide prevented ischemia-and tachycardiainduced electrical remodeling in canine atria (Jayachandran et al 2000).…”

Bradykinin induced sustained anti–adrenergic actions in guinea pig heart muscle involves PKC

“…Intracellular pH may interact with [Ca 2' ] i , and thereby contractility. Intracellular changes in pH related to regulation of and inhibition of Na/H exchange cannot be excluded (19). In the present study we have not identified the mechanism responsible for the early inhibitory response although a role for protein kinase C seems to be unlikely.…”

RNA-Seq Analyses Reveal Roles of the HVCN1 Proton Channel in Cardiac pH Homeostasis

“…The effects of HVCN1 proton channel deletion on other proton channels/exchangers and proton-coupled transporters/antiporters were investigated. The sodium-hydrogen exchanger 1 ( NHE1 ) has been reported to regulate intracellular pH in cardiomyocytes ( Sundset et al, 2003 ). Our RNA-seq revealed that NHE1 was upregulated in HVCN1 null hearts.…”