Increased sarcolemmal Na+/H+ exchange activity in hypertrophied myocytes from dogs with chronic atrioventricular block

Marcel M G J Van Borren,Jan H Ravesloot,Marc A Vos,Marien J C Houtman,Gudrun Antoons

doi:10.3389/fphys.2013.00322

Abstract

Dogs with compensated biventricular hypertrophy due to chronic atrioventricular block (cAVB), are more susceptible to develop drug-induced Torsade-de-Pointes arrhythmias and sudden cardiac death. It has been suggested that the increased Na+ influx in hypertrophied cAVB ventricular myocytes contribute to these lethal arrhythmias. The increased Na+ influx was not mediated by Na+ channels, in fact the Na+ current proved reduced in cAVB myocytes. Here we tested the hypothesis that increased activity of the Na+/H+ exchanger type 1 (NHE-1), commonly observed in hypertrophic hearts, causes the elevated Na+ influx. Cardiac acid-base transport was studied with a pH-sensitive fluorescent dye in ventricular myocytes isolated from control and hypertrophied cAVB hearts; the H+ equivalent flux through NHE-1, Na+-HCO−3 cotransport (NBC), Cl−/OH− exchange (CHE), and Cl−/HCO−3 exchange (AE) were determined and normalized per liter cell water and corrected for surface-to-volume ratio. In cAVB, sarcolemmal NHE-1 flux was increased by 65 ± 6.3% in the pHi interval 6.3–7.2 and NBC, AE, and CHE fluxes remained unchanged. Accordingly, at steady-state intracellular pH the total sarcolemmal Na+ influx by NHE-1 + NBC increased from 8.5 ± 1.5 amol/μm2/min in normal myocytes to 15 ± 2.4 amol/μm2/min in hypertrophied cAVB myocytes. We conclude that compensated cardiac hypertrophy in cAVB dogs is accompanied with an increased sarcolemmal NHE-1 activity. This in conjunction with unchanged activity of the other acid-base transporters will raise the intracellular Na+ in hypertrophied cAVB myocytes.

Highlights

Patients with left ventricular hypertrophy are at a higher risk to develop ventricular arrhythmias and sudden cardiac death (Bikkina et al, 1993; Oikarinen et al, 2001)
We report that dog ventricular myocytes exhibit Na+/H+ exchanger type 1 (NHE-1), NBC, AE, and Cl−/OH− exchanger (CHE) and that compensated cardiac hypertrophy in complete atrioventricular block (cAVB) dogs is accompanied with an increased sarcolemmal NHE-1 activity
Before studying the differences between normal and hypertrophied cAVB myocytes, we first identified what types of cardiac acid-base transporters are present

Summary

Introduction

Patients with left ventricular hypertrophy are at a higher risk to develop ventricular arrhythmias and sudden cardiac death (Bikkina et al, 1993; Oikarinen et al, 2001). The cAVB dog has compensated biventricular hypertrophy and a high susceptibility for drug-induced Torsade-de-Pointes arrhythmias (Vos et al, 1998) and sudden cardiac death (van Opstal et al, 2001). These potential lethal arrhythmias have been related to increased spatial (Verduyn et al, 1997) and temporal dispersion (Thomsen et al, 2004) of repolarization (Volders et al, 1999; Antoons et al, 2007). The thoigahnNinac+i reiansehdypNear+troinpflhuiexd cAVB rather myocytes has been than impaired Na+

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Discussion

Conclusion