Inhibiting NCX delays the early onset of Ca alternans in myocytes from spontaneously hypertensive rats (SHR).

Spontaneously hypertensive rats (SHR) are more susceptible to cardiac alternans, a precursor to arrhythmias. Ca alternans is a beat-to-beat oscillation in Ca transient amplitude at constant stimulation frequency. We previously found that the early onset of alternans in SHR hearts is associated with prolonged sarcoplasmic reticulum (SR) Ca release refractoriness, primarily influenced by SR Ca load and RyR2 sensitivity. The Na/Ca exchanger (NCX) is critical for regulating intracellular Ca. In SHR myocytes, elevated intracellular Na and Ca levels and prolonged action potential duration along with structural changes in T-tubules, where NCX is primarily located, could alter NCX function. The effect of NCX on Ca alternans is complex: enhanced NCX activity may hasten Ca decay, offering protection, but also reduce SR Ca content, potentially promoting alternans. This study aimed to investigate NCX's role in alternans in SHR hearts using pharmacological and computational approaches. ORM-10962, a selective NCX inhibitor, increased Ca transient amplitude and SR Ca content in SHR myocytes, but had no effect on normotensive myocytes, suggesting preferential forward mode activation in SHR. The inhibitor delayed alternans onset and normalized SR Ca release refractoriness. These findings were confirmed by the computational model. Further experiments showed that blocking of NCX's reverse mode had no impact on Ca alternans in SHR myocytes. The results suggest that NCX hyperactivity in SHR myocytes prevents the necessary increase in SR Ca load to overcome the prolonged refractoriness. The findings highlight NCX inhibition as a potential therapeutic strategy to prevent Ca alternans and reduce arrhythmic risk in hypertensive conditions.