Abstract 3912: The Effects of SN-6, a Novel Sodium-Calcium Exchange Inhibitor, on Contractility and Calcium Handling in Isolated Failing Rat Cardiomyocytes
Specific Na+/Ca2+ exchanger (NCX) inhibition is a potential strategy to correct the reduced contractility and depleted sarcoplasmic reticulum (SR) Ca2+ content seen in heart failure. However, selective NCX inhibitors are currently not available. SN-6, a benzyloxyphenyl derivative, has been proposed to be a selective NCX inhibitor, and could be used for this purpose. This study was designed to evaluate the effects of SN-6 on contractility and Ca2+ handling in normal and failing isolated rat cardiomyocytes. Heart failure was induced by permanent coronary artery ligation for 6 weeks. LV ejection fraction assessed by echocardiography was <40%. Sarcomere shortening, induced by field stimulation, was reduced in amplitude with increasing concentrations of SN-6 ((% of control) 1μM SN-6: normal: 75.5±4% (n=10) p<0.001; failing: 87.5±3.5% (n=13) p<0.05). Time course of contractility (time-to-peak and 50% relaxation) was also significantly faster in the presence of SN-6. The amplitude of cytoplasmic Ca2+ transients, monitored using Indo-1, was not altered by low concentrations (0.1 and 1μM) of the drug, suggesting that SN-6 may affect myofilament sensitivity to Ca2+. 10μM SN-6 reduced Ca2+ transient amplitude to 61.5±4% (n=8; p<0.001) and 64.7±5% (n=11; p<0.001) in normal and failing cells, respectively. Diastolic Ca2+ was significantly increased by 1μM SN-6. SR Ca2+ content, assessed by rapid application of caffeine, was reduced in failing cells by 1μM SN-6. SN-6 did not alter the rate of Ca2+ extrusion after application of caffeine, suggesting a predominant outward mode inhibition. Peak L-type Ca2+ current, measured by whole cell patch clamping, was significantly reduced by 1μM SN-6 in both normal (32.6±3.6% (n=5) p<0.001) and failing (42.3±5.2% (n=5) p<0.001) myocytes. Our data suggest that SN-6 impairs contractility and Ca2+ handling in normal and failing cardiomyocytes. SN-6 has limited inhibitory effects on NCX-mediated Ca2+ extrusion, reduces L-type Ca2+ current and myofilament sensitivity to Ca2+. The use of SN-6 in correcting the contractile abnormalities of heart failure is unlikely. Further development for NCX inhibitors must strive towards more selective and targeted blockade of NCX and testing in models of heart failure.