Increased activity of membrane-associated nucleoside diphosphate kinase and inhibition of cAMP synthesis in failing human myocardium.
OBJECTIVE
Chronic heart failure is associated with a decreased responsiveness of the heart to beta-adrenergic receptor agonists. We recently demonstrated a receptor-independent activation of G proteins and modulation of cardiac adenylyl cyclase activity by sarcolemmal membrane-associated nucleoside diphosphate kinase. We wondered whether changes in the activity of nucleoside diphosphate kinase occur in heart failure and contribute to or compensate for the impairment in myocardial receptor-mediated cAMP generation.


METHODS
Sarcolemmal membranes were purified from non-failing and failing human left ventricular myocardium. The protein level and activity of nucleoside diphosphate kinase were quantified. The influence of nucleoside diphosphate kinase on adenylyl cyclase activity was determined by measuring the effect of GDP on adenylyl cyclase activity in the absence and presence of nucleoside diphosphate kinase inhibitors.


RESULTS
The amount and activity of nucleoside diphosphate kinase in sarcolemmal membranes from failing hearts (n=13) were increased 3- to 4-fold compared to levels in membranes from non-failing myocardium (n=5). This increase in sarcolemmal nucleoside diphosphate kinase activity resulted in a 50% inhibition of adenylyl cyclase activity over a range of GDP and ATP concentrations.


CONCLUSIONS
The amount and activity of nucleoside diphosphate kinase are increased in sarcolemmal membranes of failing human myocardium, resulting in a substantial receptor-independent inhibition of adenylyl cyclase activity.
Lutz
S
S
University of Heidelberg, Department of Cardiology, Bergheimer Strasse 58, D-69115, Heidelberg, Germany.
Mura
R
R
Baltus
D
D
Movsesian
M
M
Kübler
W
W
Niroomand
F
F
D015720:5'-Nucleotidase / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000242:Cyclic AMP / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000494:pharmacology; D006333:Heart Failure / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009701:Nucleoside-Diphosphate Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012508:Sarcolemma / Q000201:enzymology / Q000378:metabolism
D006153:Guanosine Diphosphate; D000242:Cyclic AMP; D009701:Nucleoside-Diphosphate Kinase; D015720:5'-Nucleotidase; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases