Abstract
Objective To investigate the effect of calcium-sensing receptor (CaSR) inhibition on the vulnerability of ventricular arrhythmia (VA) in a rat model of chronic heart failure (CHF) . Methods A total of 48 male rats were randomized to receive saline (control group) , isoproterenol (ISO) (CHF group) and ISO + NPS2143 (a specific inhibitor of CaSR) (treatment group) for 2 weeks. Two weeks later, the cardiac function of three groups was assessed by echocardiography. In the whole Langendorff-perfused hearts, the monophasic action potential was recorded from left anterior basic ventricle. The programmed electrical stimulation was used to determine the thresholds of action potential duration (APD) alternans and VA and constructed the APD restitution (APDR) curves in each group.The calcium transient (CaT) was measured by loading with fura-2 AM in isolated cardiomyocytes. The expression of CaSR, inositol 1, 4, 5-trisphosphate receptors (IP3R) and protein kinase C (PKC) was detected by western-blotting. Results Compared with the control group, the protein expression of CaSR, IP3R and PKC, APD90, the maximal slope (Smax) of APDR curve and the diastolic intercellular Ca2+ level were significantly increased (allP<0.05) , while the CaT amplitude and the APD alternans and VA thresholds were markedly reduced in the CHF group (allP<0.05) . Additionally, compared with the CHF group, the protein expression of IP3R and PKC, APD90, the Smaxof APDR curve and the diastolic intercellular Ca2+ level were significantly decreased (allP<0.05) , while the CaT amplitude and the APD alternans and VA thresholds were markedly increased in the treatment group (allP<0.05) . There was no significant difference in the CaSR expression between CHF and treatment groups. Conclusion Inhibition of CaSR could reduce the vulnerability of VA in rats with CHF, which could be the potential therapeutic target of CHF associated VA. Key words: Calcium-sensing receptor; Chronic heart failure; Ventricular arrhythmia
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