Apamin Does Not Inhibit Human Cardiac Na+ Current, L-type Ca2+ Current or Other Major K+ Currents

Background: Apamin is commonly used as a small-conductance Ca2+-activated K+ (SK) current inhibitor. However, the specificity of apamin in cardiac tissues remains unclear. Objective: To test the hypothesis that apamin does not inhibit any major cardiac ion currents. Methods: We studied human embryonic kidney (HEK) 293 cells that expressed human voltage-gated Na+, K+ and Ca2+ currents and isolated rabbit ventricular myocytes. Whole-cell patch clamp techniques were used to determine ionic current densities before and after apamin administration. Results: Ca2+ currents (CACNA1c+CACNB2b) were not affected by apamin (500 nM) (data are presented as median [25 th percentile; 75 th percentile] (from -16 [-20;-10] to -17 [-19;-13] pA/pF, P = NS), but were reduced by nifedipine to -1.6 [-3.2;-1.3] pA/pF (p = 0.008). Na+ currents (SCN5A) were not affected by apamin (from -261 [-282;-145] to -268 [-379;-132] pA/pF, P = NS), but were reduced by flecainide to -57 [-70;-47] pA/pF (p = 0.018). None of the major K+ currents (I-Ks, I-Kr, I-K1 and I-to) were inhibited by 500 nM of apamin (KCNQ1+KCNE1, from 28 [20; 37] to 23 [18; 32] pA/pF; KCNH2+KCNE2, from 28 [24; 30] to 27 [24; 29] pA/pF; KCNJ2, from -46 [-48;-40] to -46 [-51;-35] pA/pF; KCND3, from 608 [505; 748] to 606 [454; 684]). Apamin did not inhibit the I-Na or I-CaL in isolated rabbit ventricular myocytes (I-Na, from -67 [-75;-59] to -68 [-71;-59] pA/pF; I-CaL, from -16 [-17;-14] to -14 [-15;-13] pA/pF, P = NS for both). Conclusions: Apamin does not inhibit human cardiac Na+ currents, L-type Ca2+ currents or other major K+ currents. These findings indicate that apamin is a specific SK current inhibitor in hearts as well as in other organs.