KATPchannel inhibition blunts electromechanical decline during hypoxia in left ventricular working rabbit hearts.
Heart function is critically dependent upon the balance of energy production and utilization. Sarcolemmal ATP-sensitive potassium channels (KATPchannels) in cardiac myocytes adjust contractile function to compensate for the level of available energy. Understanding the activation of KATPchannels in working myocardium during high-stress situations is crucial to the treatment of cardiovascular disease, especially ischaemic heart disease. Using a new optical mapping approach, we measured action potentials from the surface of excised contracting rabbit hearts to assess when sarcolemmal KATPchannels were activated during physiologically relevant workloads and during gradual reductions in myocardial oxygenation. We demonstrate that left ventricular pressure is closely linked to KATPchannel activation and that KATPchannel inhibition with a low concentration of tolbutamide prevents electromechanical decline when oxygen availability is reduced. As a result, KATPchannel inhibition probably exacerbates a mismatch between energy demand and energy production when myocardial oxygenation is low.



Sarcolemmal ATP-sensitive potassium channel (KATPchannel) activation in isolated cells is generally understood, although the relationship between myocardial oxygenation and KATPactivation in excised working rabbit hearts remains unknown. We optically mapped action potentials (APs) in excised rabbit hearts to test the hypothesis that hypoxic changes would be more severe in left ventricular (LV) working hearts (LWHs) than Langendorff (LANG) perfused hearts. We further hypothesized that KATPinhibition would prevent those changes. Optical APs were mapped when measuring LV developed pressure (LVDP), coronary flow rate and oxygen consumption in LANG and LWHs. Hearts were paced to increase workload and perfusate was deoxygenated to study the effects of myocardial hypoxia. A subset of hearts was perfused with 1 μm tolbutamide (TOLB) to identify the level of AP duration (APD) shortening attributed to KATPchannel activation. During sinus rhythm, APD was shorter in LWHs compared to LANG hearts. APD in both LWHs and LANG hearts dropped steadily during deoxygenation. With TOLB, APDs in LWHs were longer at all workloads and APD reductions during deoxygenation were blunted in both LWHs and LANG hearts. At 50% perfusate oxygenation, APD and LVDP were significantly higher in LWHs perfused with TOLB (199 ± 16 ms; 92 ± 5.3 mmHg) than in LWHs without TOLB (109 ± 14 ms, P = 0.005; 65 ± 6.5 mmHg, P = 0.01). Our results indicate that KATPchannels are activated to a greater extent in perfused hearts when the LV performs pressure-volume work. The results of the present study demonstrate the critical role of KATPchannels in modulating myocardial function over a wide range of physiological conditions.
Department of Biomedical Engineering, The George Washington University, Washington, DC, USA.
Kara
K
Garrott
Department of Biomedical Engineering, The George Washington University, Washington, DC, USA.
Sarah
S
Kuzmiak-Glancy
Department of Biomedical Engineering, The George Washington University, Washington, DC, USA.
Anastasia
A
Wengrowski
Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL, USA.
Hanyu
H
Zhang
Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL, USA.
Jack
J
Rogers
Department of Biomedical Engineering, The George Washington University, Washington, DC, USA.
Matthew W
0000-0003-2756-5055
MW
Kay
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology; D006321:Heart / Q000503:physiopathology*; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D054086:KATP Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D011817:Rabbits; D012039:Regional Blood Flow / Q000502:physiology; D016277:Ventricular Function, Left / Q000502:physiology*
D054086:KATP Channels; D010100:Oxygen
KATP channel; action potential; electromechanical; energetics; optical mapping; oxygenation