SK channel blockade prevents hypoxia-induced ventricular arrhythmias through inhibition of Ca2+/voltage uncoupling in hypertrophied hearts

Abstract

Ventricular arrhythmia (VA) is the major cause of death in patients with left ventricular (LV) hypertrophy and/or acute ischemia. We hypothesized that apamin, a blocker of small-conductance Ca²⁺-activated K⁺ (SK) channels, alters Ca²⁺ handling and exhibits anti-arrhythmic effects in ventricular myocardium. Spontaneous hypertensive rats were used as a model of LV hypertrophy. A dual optical mapping of membrane potential (V_m) and intracellular calcium (Ca_i) was performed during global hypoxia (GH) on the Langendorff perfusion system. The majority of pacing-induced VAs during GH were initiated by triggered activities. Pretreatment of apamin (100 nmol/L) significantly inhibited the VA inducibility. Compared with SK channel blockers (apamin and NS8593), non-SK channel blockers (glibenclamide and 4-AP) did not exhibit anti-arrhythmic effects. Apamin prevented not only action potential duration (APD₈₀) shortening (-18.7 [95% confidence interval, -35.2 to -6.05] ms vs. -2.75 [95% CI, -10.45 to 12.65] ms, P = 0.04) but also calcium transient duration (CaTD₈₀) prolongation (14.52 [95% CI, 8.8-20.35] ms vs. 3.85 [95% CI, -3.3 to 12.1] ms, P < 0.01), thereby reducing CaTD₈₀ - APD₈₀, which denotes "Ca_i/V_m uncoupling" (33.22 [95% CI, 22-48.4] ms vs. 6.6 [95% CI, 0-14.85] ms, P < 0.01). The reduction of Ca_i/V_m uncoupling was attributable to less prolonged Ca²⁺ decay constant and suppression of diastolic Ca_i increase by apamin. The inhibition of VA inducibility and changes in APs/CaTs parameters caused by apamin was negated by the addition of ouabain, an inhibitor of Na⁺/K⁺ pump. Apamin attenuates APD shortening, Ca²⁺ handling abnormalities, and Ca_i/V_m uncoupling, leading to inhibition of VA occurrence in hypoxic hypertrophied hearts.NEW & NOTEWORTHY We demonstrated that hypoxia-induced ventricular arrhythmias were mainly initiated by Ca²⁺-loaded triggered activities in hypertrophied hearts. The blockades of small-conductance Ca²⁺-activated K⁺ channels, especially "apamin," showed anti-arrhythmic effects by alleviation of not only action potential duration shortening but also Ca²⁺ handling abnormalities, most notably the "Ca²⁺/voltage uncoupling."

Keywords: calcium signaling; cardiac hypertrophy; ion channel; ischemia; small-conductance Ca2+-activated K+ channels (SK channels); ventricular arrhythmia.