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  • 1
    Online Resource
    Online Resource
    Impaired activation of ATP-sensitive K + channels in endocardial myocytes from left ventricular hypertrophy
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 293, No. 6 ( 2007-12), p. H3643-H3649
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 293, No. 6 ( 2007-12), p. H3643-H3649
    Abstract: ATP-sensitive K + (K ATP ) channels are essential for maintaining the cellular homeostasis against metabolic stress. Myocardial remodeling in various pathologies may alter this adaptive response to such stress. It was reported that transmural electrophysiological heterogeneity exists in ventricular myocardium. Therefore, we hypothesized that the K ATP channel properties might be altered in hypertrophied myocytes from endocardium. To test this hypothesis, we determined the K ATP channel currents using the perforated patch-clamp technique, open cell-attached patches, and excised inside-out patches in both endocardial and epicardial myocytes isolated from hypertrophied [spontaneous hypertensive rats (SHR)] vs. normal [Wistar-Kyoto rats (WKY)] left ventricle. In endocardial cells, K ATP channel currents ( I K,ATP ), produced by 2 mM CN − and no glucose at 0 mV, were significantly smaller ( P 〈 0.01), and time required to reach peak currents after onset of K ATP channel opening (Time onset to peak ) was significantly longer (319 ± 46 vs. 177 ± 37 s, P = 0.01) in the SHR group ( n = 9) than the WKY group ( n = 13). However, in epicardial cells, there were no differences in I K,ATP and Time onset to peak between the groups (SHR, n = 12; WKY, n = 12). The concentration-open probability-response curves obtained during the exposure of open cells and excised patches to exogenous ATP revealed the impaired K ATP channel activation in endocardial myocytes from SHR. In conclusion, K ATP channel activation under metabolic stress was impaired in endocardial cells from rat hypertrophied left ventricle. The deficit of endocardial K ATP channels to decreased intracellular ATP might contribute to the maladaptive response of hypertrophied hearts to ischemia.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.01357.2006
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 2
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    Online Resource
    SK channel blockade prevents hypoxia-induced ventricular arrhythmias through inhibition of Ca 2+ /voltage uncoupling in hypertrophied hearts
    American Physiological Society ; 2021
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 320, No. 4 ( 2021-04-01), p. H1456-H1469
    Details
    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
    URL: Article
    DOI: 10.1152/ajpheart.00777.2020
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Ca 2+ /calmodulin-dependent protein kinase II increases the susceptibility to the arrhythmogenic action potential alternans in spontaneously hypertensive rats
    American Physiological Society ; 2014
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 307, No. 2 ( 2014-07-15), p. H199-H206
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 307, No. 2 ( 2014-07-15), p. H199-H206
    Abstract: Action potential duration alternans (APD-ALT), defined as long-short-long repetitive pattern of APD, potentially leads to lethal ventricular arrhythmia. However, the mechanisms of APD-ALT in the arrhythmogenesis of cardiac hypertrophy remain undetermined. Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is known to modulate the function of cardiac sarcoplasmic reticulum and play an important role in Ca 2+ cycling. We thus aimed to determine the role of CaMKII in the increased susceptibility to APD-ALT and arrhythmogenesis in the hypertrophied heart. APD was measured by high-resolution optical mapping in left ventricular (LV) anterior wall from normotensive Wistar-Kyoto (WKY; n = 10) and spontaneously hypertensive rats (SHR; n = 10) during rapid ventricular pacing. APD-ALT was evoked at significantly lower pacing rate in SHR compared with WKY (382 ± 43 vs. 465 ± 45 beats/min, P 〈 0.01). These changes in APD-ALT in SHR were completely reversed by KN-93 (1 μmol/l; n = 5), an inhibitor of CaMKII, but not its inactive analog, KN-92 (1 μmol/l; n = 5). The magnitude of APD-ALT was also significantly greater in SHR than WKY and was completely normalized by KN-93. Ventricular fibrillation (VF) was induced by rapid pacing more frequently in SHR than in WKY (60 vs. 10%; P 〈 0.05), which was also abolished by KN-93 (0%, P 〈 0.05). Western blot analyses indicated that the CaMKII autophosphorylation at Thr287 was significantly increased in SHR compared with WKY. The increased susceptibility to APD-ALT and VF during rapid pacing in hypertrophied heart was prevented by KN-93. CaMKII could be an important mechanism of arrhythmogenesis in cardiac hypertrophy.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00387.2012
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2014
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Small-conductance Ca 2+ -activated K + channel activation deteriorates hypoxic ventricular arrhythmias via CaMKII in cardiac hypertrophy
    American Physiological Society ; 2018
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 315, No. 2 ( 2018-08-01), p. H262-H272
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 315, No. 2 ( 2018-08-01), p. H262-H272
    Abstract: The molecular and electrophysiological mechanisms of acute ischemic ventricular arrhythmias in hypertrophied hearts are not well known. We hypothesized that small-conductance Ca 2+ -activated K + (SK) channels are activated during hypoxia via the Ca 2+ /calmodulin-dependent protein kinase II (CaMKII)-dependent pathway. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) as a model of cardiac hypertrophy. The inhibitory effects of SK channels and ATP-sensitive K + channels on electrophysiological changes and genesis of arrhythmias during simulated global hypoxia (GH) were evaluated. Hypoxia-induced abbreviation of action potential duration (APD) occurred earlier in ventricles from SHRs versus. WKY rats. Apamin, a SK channel blocker, prevented this abbreviation in SHRs in both the early and delayed phase of GH, whereas in WKY rats only the delayed phase was prevented. In contrast, SHRs were less sensitive to glibenclamide, a ATP-sensitive K + channel blocker, which inhibited the APD abbreviation in both phases of GH in WKY rats. SK channel blockers (apamin and UCL-1684) reduced the incidence of hypoxia-induced sustained ventricular arrhythmias in SHRs but not in WKY rats. Among three SK channel isoforms, SK2 channels were directly coimmunoprecipitated with CaMKII phosphorylated at Thr 286 (p-CaMKII). We conclude that activation of SK channels leads to the APD abbreviation and sustained ventricular arrhythmias during simulated hypoxia, especially in hypertrophied hearts. This mechanism may result from p-CaMKII-bound SK2 channels and reveal new molecular targets to prevent lethal ventricular arrhythmias during acute hypoxia in cardiac hypertrophy. NEW & NOTEWORTHY We now show a new pathophysiological role of small-conductance Ca 2+ -activated K + channels, which shorten the action potential duration and induce ventricular arrhythmias during hypoxia. We also demonstrate that small-conductance Ca 2+ -activated K + channels interact with phosphorylated Ca 2+ /calmodulin-dependent protein kinase II at Thr 286 in hypertrophied hearts.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00636.2017
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2018
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Small-conductance Ca 2+ -activated K + current is upregulated via the phosphorylation of CaMKII in cardiac hypertrophy from spontaneously hypertensive rats
    American Physiological Society ; 2015
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 309, No. 6 ( 2015-09-15), p. H1066-H1074
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 309, No. 6 ( 2015-09-15), p. H1066-H1074
    Abstract: Left ventricular hypertrophy is associated with an increased risk of ventricular arrhythmias. However, the underlying molecular basis is poorly understood. It has been reported that small-conductance Ca 2+ -activated K + (SK) channels are involved in the pathogenesis of ventricular arrhythmias in heart failure. The present study aimed to test the hypothesis that SK channel activity is increased via the Ca 2+ /calmodulin-dependent protein kinase II (CaMKII)-dependent pathway in hypertensive cardiac hypertrophy. Normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) were used. Whole cell membrane currents were recorded in isolated ventricular myocytes by the patch-clamp method, and apamin-sensitive K + current ( I KAS ), which is inhibited by apamin (100 nM), an SK channel blocker, was evaluated. I KAS at 40 mV was present in SHRs, whereas it was hardly detectable in WKY rats (0.579 ± 0.046 vs. 0.022 ± 0.062 pA/pF, both n = 6, P 〈 0.05). I KAS was almost completely abolished by 1 μM KN-93, a CaMKII inhibitor, in SHRs. Optical recordings of left ventricular anterior wall action potentials revealed that apamin prolonged the late phase of repolarization only in SHRs. Western blot analysis of SK channel protein isoforms demonstrated that SK2 was significantly increased in SHRs compared with WKY rats (SK2/GAPDH: 0.66 ± 0.07 vs. 0.40 ± 0.02, both n = 6, P 〈 0.05), whereas SK1 and SK3 did not differ between groups. In addition, autophosphorylated CaMKII was significantly increased in SHRs (phosphorylated CaMKII/GAPDH: 0.80 ± 0.06 vs. 0.58 ± 0.06, both n = 6, P 〈 0.05) despite a comparable total amount of CaMKII between groups. In conclusion, SK channels are upregulated via the enhanced activation of CaMKII in cardiac hypertrophy in SHRs.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00825.2014
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2015
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    ATP-sensitive K + channels in pancreatic, cardiac, and vascular smooth muscle cells
    American Physiological Society ; 1998
    In:  American Journal of Physiology-Cell Physiology Vol. 274, No. 1 ( 1998-01-01), p. C25-C37
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 274, No. 1 ( 1998-01-01), p. C25-C37
    Abstract: ATP-sensitive K + (K ATP ) channels are therapeutic targets for several diseases, including angina, hypertension, and diabetes. This is because stimulation of K ATP channels is thought to produce vasorelaxation and myocardial protection against ischemia, whereas inhibition facilitates insulin secretion. It is well known that native K ATP channels are inhibited by ATP and sulfonylurea (SU) compounds and stimulated by nucleotide diphosphates and K + channel-opening drugs (KCOs). Although these characteristics can be shared with K ATP channels in different tissues, differences in properties among pancreatic, cardiac, and vascular smooth muscle (VSM) cells do exist in terms of the actions produced by such regulators. Recent molecular biology and electrophysiological studies have provided useful information toward the better understanding of K ATP channels. For example, native K ATP channels appear to be a complex of a regulatory protein containing the SU-binding site [sulfonylurea receptor (SUR)] and an inward-rectifying K + channel (K ir ) serving as a pore-forming subunit. Three isoforms of SUR (SUR1, SUR2A, and SUR2B) have been cloned and found to have two nucleotide-binding folds (NBFs). It seems that these NBFs play an essential role in conferring the MgADP and KCO sensitivity to the channel, whereas the K ir channel subunit itself possesses the ATP-sensing mechanism as an intrinsic property. The molecular structure of K ATP channels is thought to be a heteromultimeric (tetrameric) assembly of these complexes: K ir 6.2 with SUR1 (SUR1/K ir 6.2, pancreatic type), K ir 6.2 with SUR2A (SUR2A/K ir 6.2, cardiac type), and K ir 6.1 with SUR2B (SUR2B/K ir 6.1, VSM type) [i.e., (SUR/K ir 6. x) 4 ]. It remains to be determined what are the molecular connections between the SUR and K ir subunits that enable this unique complex to work as a functional K ATP channel.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.1998.274.1.C25
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1998
    detail.hit.zdb_id: 1477334-X
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Conduction and refractory disorders in the diabetic atrium
    American Physiological Society ; 2012
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 303, No. 1 ( 2012-07-01), p. H86-H95
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 303, No. 1 ( 2012-07-01), p. H86-H95
    Abstract: Diabetes mellitus (DM) is an independent risk of atrial fibrillation. However, its arrhythmogenic substrates remain unclear. This study sought to examine the precise propagation and the spatiotemporal dispersion of the action potential (AP) in the diabetic atrium. DM was induced by streptozotocin (65 mg/kg) in 8-wk-old male Wister rats. Optical mapping and histological analysis were performed in the right atrium (RA) from control ( n = 26) and DM ( n = 27) rats after 16 wk. Rate-dependent alterations of conduction velocity (CV) and its heterogeneity and the spatial distribution of AP were measured in RA using optical mapping. The duration of atrial tachyarrhythmia (AT) induced by rapid atrial stimulation was longer in DM (2.4 ± 0.6 vs. 0.9 ± 0.3 s, P 〈 0.05). CV was decreased, and its heterogeneity was greater in DM than control. Average action potential duration of 80% repolarization (APD 80 ) at pacing cycle length (PCL) of 200 ms from four areas within the RA was prolonged (53 ± 2 vs. 40 ± 3 ms, P 〈 0.01), and the coefficient of variation of APD 80 was greater in DM than control (0.20 ± 0.02 vs. 0.15 ± 0.01%, P 〈 0.05). The ratio of APD 80 at PCL shorter than 200 ms to that at 200 ms was smaller ( P 〈 0.001), and the incidence of APD alternans was higher in DM than control (100 vs. 0%, P 〈 0.001). Interstitial fibrosis was greater and connexin 40 expression was lower in DM than control. The remodeling of the diabetic atrium was characterized as follows: greater vulnerability to AT, increased conduction slowing and its heterogeneity, the prolongation of APD, the increase in spatial dispersion and frequency-dependent shortening of APD, and increased incidence of APD alternans.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00010.2012
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2012
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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