Cardiac IK1 underlies early action potential shortening during hypoxia in the mouse heart.
It is established that prolonged hypoxia leads to activation of K(ATP) channels and action potential (AP) shortening, but the mechanisms behind the early phase of metabolic stress remain controversial. Under normal conditions IK1 channels are constitutively active while K(ATP) channels are closed. Therefore, early changes in IK1 may underlie early AP shortening. This hypothesis was tested using transgenic mice with suppressed IK1 (AAA-TG). In isolated AAA-TG hearts AP shortening was delayed by approximately 24 s compared to WT hearts. In WT ventricular myocytes, blocking oxidative phosphorylation with 1 mM cyanide (CN; 28 degrees C) led to a 29% decrease in APD90 within approximately 3-5 min. The effect of CN was reversed by application of 100 microM Ba2+, a selective blocker of IK1, but not by 10 microM glybenclamide, a selective blocker of KATP channels. Accordingly, voltage-clamp experiments revealed that both CN and true hypoxia lead to early activation of IK1. In AAA-TG myocytes, neither CN nor glybenclamide or Ba2+ had any effect on AP. Further experiments showed that buffering of intracellular Ca2+ with 20 mM BAPTA prevented IK1 activation by CN, although CN still caused a 54% increase in IK1 in a Ca2+ -free bath solution. Importantly, both (i) 20 microM ruthenium red, a selective inhibitor of SR Ca2+ -release, and (ii) depleting SR by application of 10 microM ryanodine+1 mM caffeine, abolished the activation of IK1 by CN. The above data strongly argue that in the mouse heart IK1, not KATP, channels are responsible for the early AP shortening during hypoxia.
Piao
Lin
L
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Li
Jingdong
J
McLerie
Meredith
M
Lopatin
Anatoli N
AN
D000200:Action Potentials / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D002118:Calcium / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D002478:Cells, Cultured; D051379:Mice; D032383:Myocytes, Cardiac / Q000502:physiology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
C489461:Kir2.1 channel; D024661:Potassium Channels, Inwardly Rectifying; D002118:Calcium