Opening of calcium-activated potassium channels improves long-term left-ventricular function after coronary artery occlusion in mice.

BACKGROUND: Opening of mitochondrial calcium-activated potassium channels (BKCa ) reduces infarct size after myocardial ischemia/reperfusion injury (I/R). It is unknown if targeting BKCa -channels improves cardiac performance in the long-term after I/R.

METHODS: Experiments were conducted in compliance with institutional and national guidelines in C57BL/6 mice (n=7-8/group). Animals were randomized into two groups. Preconditioning was induced by intraperitoneal application of NS1619 (NS, 1μg/g bw) 10min before ischemia, control animals (Con) received the vehicle. All animals underwent 45min of myocardial ischemia and four weeks of reperfusion. Transthoracal Echocardiography (TTE) was conducted one and four weeks after ischemia (TTEW1/TTEW4) and additionally a cardiac MRI was done in week four. At the end of experiments the infarction scar was determined by AZAN staining.

RESULTS: TTE revealed that NS1619 improved ejection fraction one week (Con: 36±4%, NS: 45±4%; P<0.05) and four weeks after I/R (Con: 33±11%, NS: 46±8%; P<0.05). Preconditioning with NS1619 reduced end-diastolic volume at both time points (TTEW1: Con: 60±12μl, NS: 45±8μl; TTEW4: Con: 82±31μl, NS: 44±8μl; each P<0.05) and increased fractional shortening after four weeks (TTEW4: Con: 12±6%, NS: 24±8%; P<0.05). MRI-analysis after four weeks confirmed the echocardiographic results. NS1619 increased ejection fraction by 45% (MRI: Con: 29±6%, NS: 42±9%; P<0.05 vs. Con) and reduced end-diastolic and -systolic volume (EDV, ESV) compared to control (MRI: EDV: Con: 110±19μl, NS: 88±16μl; ESV: Con: 79±19μl, NS: 53±18μl; each P<0.05). Preconditioning reduced infarction scar after four weeks by 25% (Con: 12±3%, NS: 9±2%; P<0.05).

CONCLUSIONS: Preconditioning by opening of BKCa -channels with NS1619 improves cardiac performance after four weeks of reperfusion and reduces myocardial infarction scar.