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Myocardial Na+,K(+)-ATPase in tachycardia induced cardiomyopathy
F G Spinale1, C Clayton, R Tanaka
1Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425.
Insights
This study reveals that pacing-induced cardiomyopathy in pigs significantly reduces sodium-potassium adenosine triphosphatase (Na+,K(+)-ATPase) activity and glycoside binding. This dysfunction impairs the heart
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Na+,K(+)-ATPase is crucial for myocyte homeostasis and cardiac function.
- Cardiac glycosides like digitalis enhance heart contractility by inhibiting Na+,K(+)-ATPase.
- The impact of cardiomyopathy on Na+,K(+)-ATPase activity and glycoside binding is not well understood.
Purpose of the Study:
- To investigate changes in left ventricular (LV) function, Na+,K(+)-ATPase activity, and glycoside binding in a pig model of dilated cardiomyopathy.
- To assess the impact of reduced Na+,K(+)-ATPase function on the heart's response to ouabain.
Main Methods:
- Dilated cardiomyopathy was induced in pigs via 3 weeks of rapid pacing (supraventricular tachycardia).
- LV function was assessed using echocardiography and catheterization.
- Na+,K(+)-ATPase activity was measured via potassium-dependent p-nitrophenol-phosphatase activity.
- [3H]-ouabain binding assays determined glycoside receptor density (Bmax) and affinity (KD).
- Immunohistochemistry examined Na+,K(+)-ATPase distribution in LV tissue.
- Cardiac response to ouabain was evaluated in control and cardiomyopathy groups.
Main Results:
- Pacing-induced cardiomyopathy led to significantly decreased LV fractional shortening and increased LV diastolic dimension and pressure.
- Na+,K(+)-ATPase activity, Bmax, and KD were significantly reduced in pigs with cardiomyopathy compared to controls.
- Immunohistochemistry revealed a patchy, rather than uniform, sarcolemmal distribution of Na+,K(+)-ATPase in cardiomyopathy hearts.
- While isoforms alpha2 and alpha3 distribution remained unchanged, the overall Na+,K(+)-ATPase function was impaired.
- Cardiomyopathy hearts showed a blunted response to ouabain compared to control hearts.
Conclusions:
- Pacing-induced dilated cardiomyopathy in pigs is associated with significant reductions in Na+,K(+)-ATPase activity and altered glycoside binding.
- The impaired Na+,K(+)-ATPase function and distribution may contribute to the reduced inotropic response to cardiac glycosides observed in heart failure.
- These findings highlight the importance of Na+,K(+)-ATPase integrity for effective cardiac glycoside therapy.
Abstract:
Na+,K(+)-ATPase is a major determinant of myocyte homeostasis and excitation-contraction. Cardiac glycosides such as digitalis and ouabain increase the inotropic state of the heart through the inhibition of Na+,K(+)-ATPase. While cardiac glycosides are commonly used in the setting of congestive heart failure, optimal therapy would depend upon an intact Na+,K(+)-ATPase system. Changes in Na+,K(+)-ATPase activity and glycoside receptor density with the development of cardiomyopathy have not been well defined. Accordingly, left ventricular (LV) function and Na+,K(+)-ATPase activity and glycoside binding were examined in 7 pigs with dilated cardiomyopathy and in 7 controls. Dilated cardiomyopathy was produced by pacing induced supraventricular tachycardia (SVT) for 3 weeks at 240 bpm. Left ventricular function was examined by simultaneous echocardiography and catheterization. Left ventricular fractional shortening significantly decreased with SVT (34 +/- 2 vs. 10 +/- 2%, P less than 0.05) and LV diastolic dimension and pressure significantly increased (3.8 +/- 0.3 vs. 5.1 +/- 0.4 cm, and 8 +/- 2 vs. 27 +/- 2 mmHg, respectively, P less than 0.05) as compared to controls. Na+,K(+)-ATPase activity was assayed as potassium dependent p-nitrophenol-phosphatase activity. Glycoside receptor density (Bmax) and affinity (KD) was determined using [3H]-ouabain binding assays. Na+,K(+)-ATPase activity, Bmax, and KD all significantly fell from control values with SVT induced cardiomyopathy (0.64 +/- 0.06 vs. 0.45 +/- 0.12 micrograms pNP/mg/h, 5.5 +/- 0.4 vs. 1.9 +/- 0.4 pmol/mg, and 15 +/- 3 vs. 9 +/- 3 nM, respectively, P less than 0.05). The distribution of Na+,K(+)-ATPase in LV sections taken from control and SVT hearts were examined using immunohistochemical techniques. A patchy distribution of Na+,K(+)-ATPase along the sarcolemma in SVT sections was observed as opposed to a more uniform distribution in control myocytes. There was no observable change in the relative content and distribution of the Na+,K(+)-ATPase isoforms alpha 2 and alpha 3 in the SVT sections as compared to controls. In an additional set of experiments, changes in LV as well as isolated myocyte responsiveness to ouabain were examined. Left ventricular fractional shortening and peak dP/dt were measured following administration of 20-60 micrograms/Kg of ouabain in control (n = 3) and SVT (n = 3) pigs. In the control group, 40 micrograms/Kg caused a 25% in LV fractional shortening and a 60% increase in peak dP/dt from baseline. Cumulative doses of 60 micrograms/Kg in the control pigs resulted in over a 75% increase in peak dP/dt from baseline values.(ABSTRACT TRUNCATED AT 400 WORDS)