Browsing by Author "Guo, Shuai"

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Concomitant SK current activation and sodium current inhibition cause J wave syndrome
(2018-11-15)
Chen, Mu
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Xu, Dong-Zhu
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Wu, Adonis Z.
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Guo, Shuai
;
Wan, Juyi
The mechanisms of J wave syndrome (JWS) are incompletely understood. Here, we showed that the concomitant activation of small-conductance calcium-activated potassium (SK) current (I-KAS) and inhibition of sodium current by cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) recapitulate the phenotypes of JWS in Langendorff-perfused rabbit hearts. CyPPA induced significant J wave elevation and frequent spontaneous ventricular fibrillation (SVF), as well as sinus bradycardia, atrioventricular block, and intraventricular conduction delay. I-KAS activation by CyPPA resulted in heterogeneous shortening of action potential (AP) duration (APD) and repolarization alternans. CyPPA inhibited cardiac sodium current (I-Na) and decelerated AP upstroke and intracellular calcium transient. SVFs were typically triggered by short-coupled premature ventricular contractions, initiated with phase 2 reentry and originated more frequently from the right than the left ventricles. Subsequent I-KAS blockade by apamin reduced J wave elevation and eliminated SVF. beta-Adrenergic stimulation was antiarrhythmic in CyPPA-induced electrical storm. Like CyPPA, hypothermia (32.0 degrees C) also induced J wave elevation and SVF. It facilitated negative calcium-voltage coupling and phase 2 repolarization alternans with spatial and electromechanical discordance, which were ameliorated by apamin. These findings suggest that I-KAS activation contributes to the development of JWS in rabbit ventricles.
Ondansetron blocks wild-type and p.F503L variant small conductance C2+-activated K+ channels
(2018-08-01)
Ko, Jum-Suk
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Guo, Shuai
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Hassel, Jonathan
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Celestino-Soper, Patricia
;
Lynnes, Ty C.
Apamin-sensitive small-conductance Ca2+ activated K+ (SK) current (I-KAS) is encoded by Ca2+ -activated K+ channel subfamily N (KCNN) genes. I-KAS importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that I-KAS inhibition contributes to drug-induced long QT syndrome (diLQTS), we screened for KCNN variants among patients with diLQTS, determined the properties of heterologously expressed wild-type (WI) and variant KCNN channels. and determined if the 5-HT3 receptor antagonist ondansetron blocks I-KAS. We searched 2,306.335 records in the Indiana Network for Patient Care and found 11 patients with diLQTS who had DNA available in the Indiana Biobank. DNA sequencing discovered a heterozygous KCNN2 variant (p.F503L) in a 52-yr-old woman presenting with corrected QT interval prolongation at baseline (473 ms) and further corrected QT interval lengthening (601 ms) after oral administration of ondansetron. That patient was also heterozygous for the p.S38G and p.P2835S variants of the QT-controlling genes KCNEI and ankyrin 2, respectively. Patch-clamp experiments revealed that the p.F503L KCNN2 valiant heterologously expressed in human embryonic kidney (HEK)-293 cells augmented Ca2+ sensitivity, increasing I KAS density. The fraction of total F503L-KCNN2 protein retained in the membrane was higher than that of WT KCNN2 protein. Ondansetron at nanomolar concentrations inhibited WI and p.F503L SK2 channels expressed in HEK-293 cells as well as native SK channels in ventricular cardiomyocytes. Ondansetron-induced I-KAS inhibition was also demonstrated in Langendorff-perfused murine hearts. In conclusion, the heterozygous p.F5031. KCNN2 variant increases Ca2+ sensitivity and I-KAS density in transfected HEK-293 cells. Ondansetron at therapeutic (i.e., nanomolar) concentrations is a potent I-KAS blocker. NEW & NOTEWORTHY We showed that ondansetron, a 5-HT3 receptor antagonist, blocks small-conductance Ca2+-activated K+ (SK) current. Ondansetron may be useful in controlling arrhythmias in which increased SK current is a likely contributor. However, its SK-blocking effects may also facilitate the development of druginduced long QT syndrome.
Sex-specific activation of SK current by isoproterenol facilitates action potential triangulation and arrhythmogenesis in rabbit ventricles
(2018-09-15)
Chen, Mu
;
Yin, Dechun
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Guo, Shuai
;
Xu, Dong-Zhu
;
Wang, Zhuo
Sex has a large influence on cardiac electrophysiological properties. Whether sex differences exist in apamin-sensitive small conductance Ca2+-activated K+ (SK) current (I-KAS) remains unknown. We performed optical mapping, transmembrane potential, patch clamp, western blot and immunostaining in 62 normal rabbit ventricles, including 32 females and 30 males. I-KAS blockade by apamin only minimally prolonged action potential (AP) duration (APD) in the basal condition for both sexes, but significantly prolonged APD in the presence of isoproterenol in females. Apamin prolonged APD at the level of 25% repolarization (APD(25)) more prominently than APD at the level of 80% repolarization (APD(80)), consequently reversing isoproterenol-induced AP triangulation in females. In comparison, apamin prolonged APD to a significantly lesser extent in males and failed to restore the AP plateau during isoproterenol infusion. I-KAS in males did not respond to the L-type calcium current agonist BayK8644, but was amplified by the casein kinase 2 (CK2) inhibitor 4,5,6,7-tetrabromobenzotriazole. In addition, whole-cell outward I-KAS densities in ventricular cardiomyocytes were significantly larger in females than in males. SK channel subtype 2 (SK2) protein expression was higher and the CK2/SK2 ratio was lower in females than in males. I-KAS activation in females induced negative intracellular Ca2+-voltage coupling, promoted electromechanically discordant phase 2 repolarization alternans and facilitated ventricular fibrillation (VF). Apamin eliminated the negative Ca2+-voltage coupling, attenuated alternans and reduced VF inducibility, phase singularities and dominant frequencies in females, but not in males. We conclude that beta-adrenergic stimulation activates ventricular I-KAS in females to a much greater extent than in males. I-KAS activation plays an important role in ventricular arrhythmogenesis in females during sympathetic stimulation.