Opening of calcium-activated potassium channels improves long-term left-ventricular function after coronary artery
Friederike Behmenburg1, Nina Hölscher1, Ulrich Flögel2
1Department of Anesthesiology, University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
Insights
Preconditioning with NS1619, a BKCa-channel opener, significantly improved cardiac function and reduced infarct size in mice four weeks after myocardial ischemia/reperfusion injury.
Area of Science:
- Cardiovascular Research
- Mitochondrial Physiology
- Pharmacology
Background:
- Mitochondrial calcium-activated potassium channels (BKCa) activation is known to reduce infarct size following myocardial ischemia/reperfusion (I/R) injury.
- The long-term effects of targeting BKCa channels on cardiac performance post-I/R remain largely uninvestigated.
Purpose of the Study:
- To investigate the long-term impact of BKCa channel preconditioning on cardiac function and infarct size after myocardial I/R injury.
- To evaluate the efficacy of NS1619, a BKCa channel opener, in improving cardiac performance and reducing myocardial scar in a mouse model.
Main Methods:
- C57BL/6 mice were randomized into two groups: NS1619 preconditioning (1μg/g bw) or vehicle control, 10 minutes before 45 minutes of myocardial ischemia.
- Cardiac function and volumes were assessed using transthoracic echocardiography at one and four weeks post-reperfusion.
- Cardiac MRI and histological analysis (AZAN staining) were performed at four weeks to evaluate ejection fraction, volumes, and infarct scar size.
Main Results:
- NS1619 preconditioning significantly improved ejection fraction at one week (45% vs 36%) and four weeks (46% vs 33%) post-I/R.
- Echocardiography and MRI revealed reduced end-diastolic and end-systolic volumes in the NS1619 group compared to controls at four weeks.
- Histological analysis showed a 25% reduction in myocardial infarct scar size in the NS1619 group after four weeks.
Conclusions:
- Preconditioning with NS1619, by opening BKCa channels, effectively improves long-term cardiac performance after myocardial I/R injury.
- Targeting BKCa channels with NS1619 demonstrates a significant cardioprotective effect, reducing infarct size and enhancing recovery of cardiac function.
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.
