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 (Vm) and intracellular calcium (Cai) 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 "Cai/Vm uncoupling" (33.22 [95% CI, 22-48.4] ms vs. 6.6 [95% CI, 0-14.85] ms, P < 0.01). The reduction of Cai/Vm uncoupling was attributable to less prolonged Ca2+ decay constant and suppression of diastolic Cai 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 Cai/Vm 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."

• Authors: Masayuki Takahashi, Hisashi Yokoshiki, Hirofumi Mitsuyama, Masaya Watanabe, Taro Temma, Rui Kamada, Hikaru Hagiwara, Yumi Takahashi, Toshihisa Anzai
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 320 Issue 4 Pg. H1456-H1469 (04 01 2021) ISSN: 1522-1539 [Electronic] United States
• PMID: 33635168 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine
• Anti-Arrhythmia Agents
• Potassium Channel Blockers
• Small-Conductance Calcium-Activated Potassium Channels
• Apamin
• 1-Naphthylamine

Topics

• 1-Naphthylamine (analogs & derivatives, pharmacology)
• Action Potentials (drug effects)
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Apamin (pharmacology)
• Arrhythmias, Cardiac (etiology, metabolism, physiopathology, prevention & control)
• Calcium Signaling (drug effects)
• Cardiac Pacing, Artificial
• Cardiomegaly (complications, drug therapy, metabolism, physiopathology)
• Disease Models, Animal
• Heart Rate (drug effects)
• Hypoxia (complications, drug therapy, metabolism, physiopathology)
• Isolated Heart Preparation
• Male
• Potassium Channel Blockers (pharmacology)
• Rats, Inbred SHR
• Small-Conductance Calcium-Activated Potassium Channels (antagonists & inhibitors, metabolism)
• Time Factors