Severity: Warning
Message: file_get_contents(https://...@pubfacts.com&api_key=b8daa3ad693db53b1410957c26c9a51b4908&a=1): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
Line Number: 176
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 176
Function: file_get_contents
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 250
Function: simplexml_load_file_from_url
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 1034
Function: getPubMedXML
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3152
Function: GetPubMedArticleOutput_2016
File: /var/www/html/application/controllers/Detail.php
Line: 575
Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
Line: 489
Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
Line: 316
Function: require_once
Missense mutations in calmodulin (CaM)-encoding genes are associated with life-threatening ventricular arrhythmia syndromes. Here, we investigated a role of cardiac K channel dysregulation in arrhythmogenic long QT syndrome (LQTS) using a knock-in mouse model heterozygous for a recurrent mutation (p.N98S) in the gene (Calm1). Single-cell patch-clamp technique and whole-heart optical voltage mapping were used to assess action potentials and whole-cell currents. Ventricular action potential duration (APD) at baseline was similar between genotypes. The β-adrenergic agonist isoproterenol prolonged APD in myocytes and isolated perfused hearts from Calm1, but not wild-type (Calm1), mice. Current density-voltage relationships for the small-conductance calcium-activated K (SK) current and the inward rectifier K current did not significantly differ between Calm1 and Calm1 ventricular cardiomyocytes ± isoproterenol. Peak densities of other voltage-gated K currents were significantly larger in Calm1 versus Calm1 cells at voltages ≥40 mV both without and with isoproterenol. Isoproterenol reduced outward K currents more in Calm1 versus Calm1 myocytes. Dialysis of Calm1 cardiomyocytes with exogenous wild-type or N98S-CaM protein (5 μmol/l) via the pipette respectively increased and eliminated SK currents. The specific SK channel inhibitor apamin did not significantly alter APD of Calm1 or Calm1 hearts ± isoproterenol. Thus, dysregulation of SK or voltage-gated K channels does not contribute to the β-adrenergic-induced LQTS of Calm1 mice, possibly because cardiomyocyte content of endogenous N98S-CaM and/or its affinity for CaM binding domains may be too low to modulate channel properties. The larger K current inhibition by isoproterenol may delay Calm1 myocyte repolarization at low intracellular [ATP].
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Source |
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http://dx.doi.org/10.1152/ajpheart.00470.2024 | DOI Listing |
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