title: Reduced myocardial and systemic L-arginine uptake in heart failure.
abstract: Altered nitric oxide (NO) bioavailability has been ascribed an important role in the pathophysiology of congestive heart failure (CHF). In the peripheral vasculature, we recently demonstrated a depression of L-arginine transport in association with pharmacological evidence of reduced endothelial function. In contrast, increased myocardial NO generation has been proposed to account for a component of the reduced myocardial contractility in CHF, although this remains controversial. We determined the whole body clearance rate and cardiac fractional extraction of L-arginine during a steady-state intravenous infusion of [3H]L-arginine (300 nCi/min) in 9 healthy control subjects and 7 patients with moderate to severe CHF. In patients with CHF, there was a 30% reduction in the transcardiac extraction of [3H]L-arginine compared with controls (P<0.05), which was accompanied by a trend toward reduced [3H]L-citrulline release (P=0.06). In conjunction, the systemic clearance rate of [3H]L-arginine was significantly lower in patients with CHF (778+/-148 versus 1278+/-144 mL/min, P<0.05). In association with these biochemical indices, we observed a 38% reduction (P<0.05) in the mRNA expression of the cationic amino acid transporter CAT-1 in ventricular myocardial samples from patients with CHF compared with healthy unused donor myocardium, whereas myocardial NOS enzymatic activity and NOS protein were unchanged. These data indicate the presence of a significant reduction in the myocardial uptake of L-arginine in patients with CHF. Furthermore, this abnormality seems to be part of a systemic downregulation of L-arginine transport.
authors.affiliation: Baker Heart Research Institute and Heart Centre, Alfred Hospital, Melbourne, Victoria, Australia. david.kaye@baker.edu.au
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
authors.forename: Melinda M
authors.initials: MM
authors.lastname: Parnell
authors.forename: Belinda A
authors.initials: BA
authors.lastname: Ahlers
mesh_terms: D001120:Arginine / Q000378:metabolism / Q000493:pharmacokinetics*; D001692:Biological Transport; D001706:Biopsy; D002302:Cardiac Output; D002404:Catheterization; D027201:Cationic Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism; D027202:Cationic Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D002908:Chronic Disease; D002956:Citrulline / Q000032:analysis / Q000096:biosynthesis; D015536:Down-Regulation; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology*; D006352:Heart Ventricles / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007262:Infusions, Intravenous; D007700:Kinetics; D008657:Metabolic Clearance Rate / Q000502:physiology; D008875:Middle Aged; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012016:Reference Values; D014316:Tritium
chemical_list: D027201:Cationic Amino Acid Transporter 1; D027202:Cationic Amino Acid Transporter 2; D012333:RNA, Messenger; D014316:Tritium; D002956:Citrulline; D001120:Arginine; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III