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Alterations in ATP-sensitive potassium channel sensitivity to ATP in failing human hearts
S I Koumi1, R L Martin, R Sato
1Department of Medicine, Northwestern University Medical School, Chicago, Illinois, USA.
Insights
Congestive heart failure alters ATP-sensitive potassium channels (I[K(ATP)]) in human hearts. These channels are less sensitive to ATP inhibition in heart failure patients, impacting cardiac function.
Area of Science:
- Cardiology
- Molecular Physiology
- Ion Channel Research
Background:
- Preexisting heart disease, particularly congestive heart failure (HF), may influence the function of ATP-sensitive potassium channels (I[K(ATP)]) in the human heart.
- Understanding these alterations is crucial for developing targeted therapies for cardiac conditions.
Purpose of the Study:
- To characterize and compare the properties of I[K(ATP)] in cardiac myocytes from patients with HF and healthy donors.
- To investigate the functional impact of HF on I[K(ATP)] activity and ATP sensitivity.
Main Methods:
- Utilized the patch-clamp technique to record I[K(ATP)] in isolated atrial myocytes from HF patients and healthy donors.
- Induced metabolic inhibition using cyanide and 2-deoxyglucose to assess channel response and action potential duration.
- Analyzed single-channel properties, conductance, gating, and ATP sensitivity (IC50).
Main Results:
- Action potential shortening during metabolic inhibition was significantly greater and occurred sooner in HF myocytes compared to controls.
- Whole-cell current responses to metabolic inhibition were also enhanced and accelerated in HF.
- While single-channel kinetics were similar, I[K(ATP)] in HF myocytes showed reduced sensitivity to ATP inhibition (higher IC50) than in donor myocytes.
Conclusions:
- Cardiac I[K(ATP)] channels in human HF exhibit largely similar single-channel characteristics but reduced ATP sensitivity compared to healthy controls.
- This altered ATP sensitivity of I[K(ATP)] may contribute to the pathophysiology of congestive heart failure.
Abstract:
Little is known about the involvement of preexisting heart disease on characteristics of ATP-sensitive K+ channels [I[K(ATP)]] in human heart. We have characterized I[K(ATP)] in isolated cardiac myocytes from patients with congestive heart failure (HF) and compared these channel characteristics with those from donor hearts (healthy control) using the patch-clamp technique. During metabolic inhibition induced by treatment with cyanide (1 mM) and 2-deoxyglucose (10 mM), action potential shortening occurred in atrial myocytes isolated from both HF and donors, but this response was significantly greater and sooner in HF than in donors. The action potential duration at 90% repolarization was 24.7 +/- 4.1% (n = 15) of control in HF, whereas it was 58.7 +/- 5.9% (n = 10, P < 0.001) of control in donors measured at 30-min metabolic inhibition. The shortening of the action potential was partially reversed by glibenclamide (0.5 microM) in both groups. Consistent with the action potential measurements, the whole cell membrane current response to metabolic inhibition, evaluated by the differential current measurement, was sooner and greater in HF than in donors. Single-channel atrial I[K(ATP)] from both HF and donors, recorded in the excised inside-out patch configuration, exhibited bursting opening, conductance, and gating behaviors that did not differ between the two groups. However, the concentration of ATP at half-maximal inhibition of the channel in HF was greater (131.0 microM) than in donors (26.1 microM). We conclude that I[K(ATP)] in cardiac myocytes from patients with HF has channel characteristics substantially similar to those in donors, but that the channel is less sensitive to ATP inhibition in HF than in donors.