TY - JOUR

T1 - Activation of big conductance Ca(2+)-activated K (+) channels (BK) protects the heart against ischemia-reperfusion injury

AU - Bentzen, Bo Hjorth

AU - Osadchii, Oleg

AU - Jespersen, Thomas

AU - Hansen, Rie Schultz

AU - Olesen, Søren-Peter

AU - Grunnet, Morten

N1 - Keywords: ATP-Binding Cassette Transporters; Animals; Cells, Cultured; Humans; Indoles; KATP Channels; Large-Conductance Calcium-Activated Potassium Channels; Male; Mitochondria, Heart; Myocardial Contraction; Myocardial Reperfusion Injury; Oocytes; Potassium Channels, Inwardly Rectifying; Rats; Receptors, Drug; Tetrazoles; Thiourea; Ventricular Function; Xenopus laevis

PY - 2009

Y1 - 2009

N2 - Activation of the large-conductance Ca(2+)-activated K(+) channel (BK) in the cardiac inner mitochondrial membrane has been suggested to protect the heart against ischemic injury. However, these findings are limited by the low selectivity profile and potency of the BK channel activator (NS1619) used. In the present study, we address the cardioprotective role of BK channels using a novel, potent, selective, and chemically unrelated BK channel activator, NS11021. Using electrophysiological recordings of heterologously expressed channels, NS11021 was found to activate BK alpha + beta1 channel complexes, while producing no effect on cardiac K(ATP) channels. The cardioprotective effects of NS11021-induced BK channel activation were studied in isolated, perfused rat hearts subjected to 35 min of global ischemia followed by 120 min of reperfusion. 3 microM NS11021 applied prior to ischemia or at the onset of reperfusion significantly reduced the infarct size [control: 44.6 +/- 2.0%; NS11021: 11.4 +/- 2.0%; NS11021 at reperfusion: 19.8 +/- 3.3% (p < 0.001 for both treatments compared to control)] and promoted recovery of myocardial performance. Co-administration of the BK-channel inhibitor paxilline (3 microM) antagonized the protective effect. These findings suggest that tissue damage induced by ischemia and reperfusion can be reduced by activation of cardiac BK channels.

AB - Activation of the large-conductance Ca(2+)-activated K(+) channel (BK) in the cardiac inner mitochondrial membrane has been suggested to protect the heart against ischemic injury. However, these findings are limited by the low selectivity profile and potency of the BK channel activator (NS1619) used. In the present study, we address the cardioprotective role of BK channels using a novel, potent, selective, and chemically unrelated BK channel activator, NS11021. Using electrophysiological recordings of heterologously expressed channels, NS11021 was found to activate BK alpha + beta1 channel complexes, while producing no effect on cardiac K(ATP) channels. The cardioprotective effects of NS11021-induced BK channel activation were studied in isolated, perfused rat hearts subjected to 35 min of global ischemia followed by 120 min of reperfusion. 3 microM NS11021 applied prior to ischemia or at the onset of reperfusion significantly reduced the infarct size [control: 44.6 +/- 2.0%; NS11021: 11.4 +/- 2.0%; NS11021 at reperfusion: 19.8 +/- 3.3% (p < 0.001 for both treatments compared to control)] and promoted recovery of myocardial performance. Co-administration of the BK-channel inhibitor paxilline (3 microM) antagonized the protective effect. These findings suggest that tissue damage induced by ischemia and reperfusion can be reduced by activation of cardiac BK channels.

U2 - 10.1007/s00424-008-0583-5

DO - 10.1007/s00424-008-0583-5

M3 - Journal article

C2 - 18762970

VL - 457

SP - 979

EP - 988

JO - Pflügers Archiv - European Journal of Physiology

JF - Pflügers Archiv - European Journal of Physiology

SN - 0031-6768

IS - 5

ER -