In:
American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 320, No. 4 ( 2021-04-01), p. H1456-H1469
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 Ca 2+ -activated K + (SK) channels, alters Ca 2+ 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 (APD 80 ) 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 (CaTD 80 ) 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 CaTD 80 − APD 80 , 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 Ca 2+ 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, Ca 2+ 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 Ca 2+ -loaded triggered activities in hypertrophied hearts. The blockades of small-conductance Ca 2+ -activated K + channels, especially “apamin,” showed anti-arrhythmic effects by alleviation of not only action potential duration shortening but also Ca 2+ handling abnormalities, most notably the “Ca 2+ /voltage uncoupling.”
Type of Medium:
Online Resource
ISSN:
0363-6135
,
1522-1539
DOI:
10.1152/ajpheart.00777.2020
Language:
English
Publisher:
American Physiological Society
Publication Date:
2021
detail.hit.zdb_id:
1477308-9
SSG:
12
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