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 responsiven ess of the heart to beta -adrenergic receptor agonists. We recently demonst rated a receptor-independent activation of G proteins and modulation of car diac adenylyl cyclase activity by sarcolemmal membrane-associated nucleosid e diphosphate kinase. We wondered whether changes in the activity of nucleo side diphosphate kinase occur in heart failure and contribute to or compens ate for the impairment in myocardial receptor-mediated cAMP generation. Met hods: Sarcolemmal membranes were purified from non-failing and failing huma n left ventricular myocardium. The protein level and activity of nucleoside diphosphate kinase were quantified. The influence of nucleoside diphosphat e kinase on adenylyl cyclase activity was determined by measuring the effec t of GDP on adenylyl cyclase activity in the absence and presence of nucleo side diphosphate kinase inhibitors. Results: The amount and activity of nuc leoside diphosphate kinase in sarcolemmal membranes from failing hearts (n= 13) were increased 3- to 4-fold compared to levels in membranes from non-fa iling 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. Conclusion: The amount and acti vity of nucleoside diphosphate kinase are increased in sarcolemmal membrane s of failing human myocardium, resulting in a substantial receptor-independ ent inhibition of adenylyl cyclase activity. (C) 2001 Elsevier Science B.V. All rights reserved.