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NCX is an important determinant for premature ventricular activity in a drug-induced model of Andersen-Tawil syndrome Radwanski PB; Poelzing SCardiovasc Res 2011[Oct]; 92 (1): 57-66AIMS: Andersen-Tawil syndrome (ATS1)-associated ventricular arrhythmias are initiated by premature ventricular activity (PVA) resulting from diastolic Ca(2+) (Ca(D)) accumulation. We hypothesized that relatively high Na(+)-Ca(2+) exchanger (NCX) expression coupled with slower Ca(2+) uptake may constitute an arrhythmogenic substrate during drug-induced ATS1 (DI-ATS1). METHODS AND RESULTS: DI-ATS1 was induced with 10 micromol/L BaCl(2) and 2 mmol/L [K(+)](o). Ca(2+) transients and action potentials were optically mapped from Langendorff-perfused guinea pig ventricles. Intracellular Ca(2+) handling was modulated by either direct NCX inhibition with 5 micromol/L KB-R7943 or by sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) inhibition with cyclopiazonic acid (CPA). During DI-ATS1, PVA was more frequent in left ventricular (LV)-base (LVB) vs. LV-apex (LVA) (2.2 +/- 0.8 vs. 0.6 +/- 0.3 PVA/10 min), consistent with greater Ca(D) (1.65 +/- 0.13 vs. 1.42 +/- 0.09 normalized-Ca(D) units) and western blot-assessed NCX protein expression (81.2 +/- 30.9%) in LVB relative to LVA. Further, regions of high NCX (LVB) evidenced a shorter PVA coupling interval relative to regions of low NCX expression (LVA, 67.7 +/- 3.5 vs. 78.5 +/- 3.6%). Inhibiting NCX during DI-ATS1 lowered the incidence of ventricular tachycardias (VTs, 0 vs. 25%) and PVA (1.5 +/- 0.4 vs. 4.3 +/- 1.4 PVA/10 min), but it did not affect PVA coupling intervals in LVB nor LVA (70.8 +/- 4.3 vs. 73.8 +/- 2.5%). Conversely, inhibition of SERCA2a with CPA, thereby increasing the role of NCX in Ca(2+) handling, significantly increased the incidence of VTs and PVA relative to DI-ATS1 alone, while decreasing the PVA coupling interval in all regions. CONCLUSION: PVA preferentially occurs in regions of enhanced NCX expression with relatively slower Ca(2+) uptake and during perfusion of CPA which further reduces sarcoplasmic reticular Ca(2+) uptake.|Action Potentials[MESH]|Andersen Syndrome/chemically induced/*physiopathology[MESH]|Animals[MESH]|Arrhythmias, Cardiac/*etiology[MESH]|Calcium/metabolism[MESH]|Cytosol/metabolism[MESH]|Electrocardiography[MESH]|Guinea Pigs[MESH]|Heart Ventricles/*physiopathology[MESH]|Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & inhibitors/physiology[MESH]|Sarcoplasmic Reticulum/metabolism[MESH]|Sodium-Calcium Exchanger/antagonists & inhibitors/*physiology[MESH] |
