Reduced myocardial and systemic L-arginine uptake in heart failure.
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.
Kaye
David M
DM
Baker Heart Research Institute and Heart Centre, Alfred Hospital, Melbourne, Victoria, Australia. david.kaye@baker.edu.au
Parnell
Melinda M
MM
Ahlers
Belinda A
BA
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
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