Cardiac Na+/Ca2+ exchange stimulators among cardioprotective drugs

Abstract

We previously reviewed our study of the pharmacological properties of cardiac Na + /Ca 2+ exchange (NCX1) inhibitors among cardioprotective drugs, such as amiodarone, bepridil, dronedarone, cibenzoline, azimilide, aprindine, and benzyl-oxyphenyl derivatives (Watanabe et al. in J Pharmacol Sci 102:7-16, 2006). Since then we have continued our studies further and found that some cardioprotective drugs are NCX1 stimulators. Cardiac Na + /Ca 2+ exchange current (I NCX1) was stimulated by nicorandil (a hybrid ATP-sensitive K + channel opener), pinacidil (a non-selective ATP-sensitive K + channel opener), flecainide (an antiarrhythmic drug), and sodium nitroprusside (SNP) (an NO donor). Sildenafil (a phosphodiesterase-5 inhibitor) further increased the pinacidil-induced augmentation of I NCX1. In paper, here I review the NCX stimulants that enhance NCX function among the cardioprotective agents we examined such as nicorandil, pinacidil, SNP, sildenafil and flecainide, in addition to atrial natriuretic (ANP) and dofetilide, which were reported by other investigators. Keywords Cardiac Na + /Ca 2+ exchanger (NCX1) • Cardiac Na + /Ca 2+ exchange current (I NCX1) • NCX1 stimulator • Patchclamp method • Cardioprotective drug

In silico Identification of Disrupted Myocardial Calcium Homeostasis as Proarrhythmic Trigger in Arrhythmogenic Cardiomyopathy

“…This could be further investigated experimentally in the PKP2-cKO mice. This is in agreement with previous studies reporting a cardioprotective effect of NCX stimulatory drugs like flecainide, although flecainide also is known to modulate RyR2 and the sodium current (Watanabe, 2019). Flecainide was effective in suppressing arrhythmic events through direct modulation of I NCX in Andersen-Tawil syndrome-induced pluripotent stem cells-derived cardiomyocytes (Kuroda et al, 2017).…”

Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

“…Our current study detected the difference, i.e., quinidine reduced the window current, decelerated the recovery from inactivation and deactivation, while amiodarone showed no or opposite effects on those parameters. Besides hERG current, I Na , I Ca-L , I NCX , I to , I Ks , I K1 and I KATP can be inhibited by amiodarone (Supplementary Table 1) (Nishida et al, 2011;Suzuki et al, 2013;Iwamoto et al, 2007;Watanabe, 2019). The inhibition of I Ca-L may shorten APD, while the inhibition of I to , I Ks , I K1 and I KATP can prolong APD.…”

“…These data may help explain why flecainide showed no antiarrhythmic effects in SQT1-hiPSC-CMs and SQT-patients because these effects are different from that of quinidine, ajmaline, ivabradine and mexiletine, which prolonged APD and reduced epinephrine-induced arrhythmic events in SQT1-hiPSC-CMs. Flecainide can inhibit I Na , I Ca-L , I to , I KATP , and enhance I NCX and I K1 but has no effect on I Ks (Supplementary Table 1) (Watanabe, 2019;Wang et al, 1996;Wang et al, 1993;Follmer and Colatsky, 1990;Caballero et al, 2010;Yunoki et al, 2001). The inhibition of I to and I KATP can prolong APD, which may contribute to the APD-prolongation observed in healthy cardiomyocytes (Table 1) (Borchard and Boisten, 1982;Wang et al, 1993).…”

Cardiac efficacy and toxicity of aconitine: A new frontier for the ancient poison

“…Chan and other famous experts in aconite poisoning presented a widely accepted viewpoint that AC induced a positive inotropic effect possibly via prolonging Na + influx during the action potential 33,55 . As described above, Na + accumulation could consequently lead to the reverse mode of Na + ‐Ca 2+ exchange and increased [Ca 2+ ] i , which would enhance the contractility of myocytes 56 …”