Published Online
on March 24, 2003

A more recent version of this article appeared on April 8, 2003

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Submitted on December 16, 2002
Revised on February 20, 2003
Accepted on February 21, 2003

Functional Consequences of Endothelial Nitric Oxide Synthase Uncoupling in Congestive Cardiac Failure

Lana J. Dixon MRCP, David R. Morgan MRCP, Sinead M. Hughes MRCP, Lawrence T. McGrath MSc, PhD, Naglaa A. El-Sherbeeny MB, MSc, Rick D. Plumb MRCP, Adrian Devine MSc, William Leahey MSc, G. Dennis Johnston MD, PhD, and Gary E. McVeigh MD, PhD^*

From the Department of Therapeutics and Pharmacology, Queen's University Belfast, Belfast, Northern Ireland.

^* To whom correspondence should be addressed. E-mail: g.mcveigh{at}qub.ac.uk.

Background--Impaired endothelium-mediated vasodilatation (EMVD) in congestive cardiac failure (CCF) has been linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O₂^·-), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, endothelial nitric oxide synthase (eNOS) produces O₂^·-. We studied the functional consequences of eNOS uncoupling in relation to EMVD in patients with CCF.

Methods and Results--We employed the platelet as a compartmentalized ex-vivo model to examine O₂^·- and NO production. When eNOS is functioning normally, incorporation of N-Nitro-L-Arginine methyl ester (L-NAME, 1 mmol/L), results in increased O₂^·- detection, as inhibition of NO production prevents NO scavenging of O₂^·-. This was observed in controls and 9 of the CCF patients, in whom O₂^·- detection increased by 63% and 101%, respectively. In the remaining 9 CCF patients, incorporation of L-NAME reduced O₂^·- production by 39%, indicating O₂^·- production by eNOS uncoupling. Detection of platelet-derived NO was significantly greater in eNOS-coupled platelets compared with the uncoupled group (2.8±1.4 versus 0.9±0.4 pmol/10⁸ platelets, P=0.04). Endothelium-dependent and -independent vasodilator responses to acetylcholine and sodium nitroprusside recorded using venous occlusion plethysmography were significantly impaired in patients exhibiting eNOS uncoupling.

Conclusions--This study provides first evidence that platelet eNOS can become uncoupled in human CCF. Impaired endothelium-dependent and -independent vasodilator responses and diminished platelet-derived NO production occurred in association with enzyme uncoupling.

Key words: nitric oxide synthase • nitric oxide • platelets • acetylcholine • vasodilation

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