Role of Sodium-Calcium Exchanger in Modulating the Action Potential of Ventricular Myocytes From Normal and Failing Hearts

Abstract

Abstract-Increased Na ϩ -Ca 2ϩ exchange (NCX) activity in heart failure and hypertrophy may compensate for depressed sarcoplasmic reticular Ca 2ϩ uptake, provide inotropic support through reverse-mode Ca 2ϩ entry, and/or deplete intracellular Ca 2ϩ stores. NCX is electrogenic and depends on Na ϩ and Ca 2ϩ transmembrane gradients, making it difficult to predict its effect on the action potential (AP). Here, we examine the effect of [Na ϩ ] i on the AP in myocytes from normal and pacing-induced failing canine hearts and estimate the direction of the NCX driving force using simultaneously recorded APs and Ca 2ϩ transients. AP duration shortened with increasing [Na ϩ ] i and was correlated with a shift in the reversal point of the NCX driving force. At [Na ϩ ] i Ն10 mmol/L, outward NCX current during the plateau facilitated repolarization, whereas at 5 mmol/L [Na ϩ ] i , NCX had a depolarizing effect, confirmed by partially inhibiting NCX with exchange inhibitory peptide. Exchange inhibitory peptide shortened the AP duration at 5 mmol/L [Na ϩ ] i and prolonged it at [Na ϩ ] i Ն10 mmol/L. With K ϩ currents blocked, total membrane current was outward during the late plateau of an AP clamp at 10 mmol/L [Na ϩ ] i and became inward close to the predicted reversal point for the NCX driving force. The results were reproduced using a computer model. These results indicate that NCX plays an important role in shaping the AP of the canine myocyte, helping it to repolarize at high [Na ϩ ] i , especially in the failing heart, but contributing a depolarizing, potentially arrhythmogenic, influence at low [Na Key Words: heart failure Ⅲ Na ϩ -Ca 2ϩ exchanger Ⅲ reversal potential Ⅲ Ca 2ϩ transients T he Na ϩ -Ca 2ϩ exchanger (NCX) catalyzes the electrogenic exchange of Na ϩ for Ca 2ϩ across the cardiac sarcolemma and is reversible, operating in either forward (Ca 2ϩ -efflux) or reverse (Ca 2ϩ -influx) modes, depending on the prevailing electrochemical driving forces for Ca 2ϩ and Na ϩ . This complex dependence on transmembrane ion and voltage gradients, which are both rapidly changing during the cellular action potential (AP), makes predictions about the overall influence of NCX current (I NCX ) on excitation-contraction coupling challenging. NCX is the primary Ca 2ϩ extrusion mechanism in the heart 1,2 and is required to remove the increment of Ca 2ϩ entering the myocyte via Ca 2ϩ channels on each beat, 3 but the timing of the transition from reverse-mode exchange (outward I NCX ) to forward-mode exchange (inward I NCX ) has been difficult to determine. Because the membrane impedance during the AP plateau of large mammals (including humans) is high, the net direction of current flow through NCX is likely to be a fundamental determinant of AP duration (APD).Early investigations into the net effect of I NCX on the AP demonstrated that it contributed net inward current and prolonged the AP in the rat. 4 than that reported by intracellular Ca 2ϩ dyes. In the failing heart, where SR function is impaired, a greater dependence on NCX for...

Excitation-contraction coupling and mitochondrial energetics

“…During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212]. In this context, the elevation of [Na + ] i in cardiac failure and hypertrophy may be regarded as a beneficial and compensatory mechanism [94].…”

“…Decreased SR Ca 2+ -ATPase activity is partly compensated by increased expression and activity of the NCX [16,65,93,146,178,190] The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na [58,121,[203][204][205]. During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212] Are defects in EC coupling linked to energy starvation in heart failure?Besides defects in EC coupling, the failing heart is energy-starved [99,187,211]. The total cellular levels of PCr, but also NAD and adenine nucleotides, are reduced in patients with heart failure [11,99,188].…”

Cyclic Nucleotide Phosphodiesterase PDE1C1 in Human Cardiac Myocytes

“…The effects of PDE1 inhibition on cAMP content in intracellular compartments of cardiac myocytes are likely to differ from those of PDE3 inhibition, perhaps with more favorable sequelae. In animal models, inhibition of cGMP hydrolysis through PDE5 inhibition has been shown to prevent and reverse hypertrophic responses to pressure overload and ␤-adrenergic receptor stimulation and to reduce infarct area size and myocyte apoptosis in injured myocardium (51)(52)(53)(54)(55)(56)(57)(58)(59). PDE1 inhibition might elicit similar benefits.…”

Optimization of an In Silico Cardiac Cell Model for Proarrhythmia Risk Assessment

“…As suggested in previous studies the sodium potassium pump (Lancaster and Sobie, 2016;Britton et al, 2017) and the sodium calcium exchanger (Armoundas et al, 2003;Nagy et al, 2004) play an important role in EAD generation. Simulations of hypothetical drugs by Lancaster and Sobie (2016) show that both the sodium potassium pump and sodium calcium exchanger were ranked as having the greatest influence on TdP risk, above IKs, IK1, and Ito (but excluding IKr, ICaL, and INa).…”