Dietary L-arginine normalizes endothelin-induced vascular contractions in cholesterol-fed rabbits.
The endothelium regulates vascular function by releasing the vasodilator autacoid nitric oxide (NO) and the vasoconstrictor peptide endothelin-1 (ET-1). Impaired activity of NO as well as excessive activity of ET-1 have been demonstrated in hypercholesterolemia and atherosclerosis. Because dietary L-arginine can restore NO function and improve abnormal endothelium-dependent relaxation in hypercholesterolemic rabbits, we examined the effects of dietary supplementation with L-arginine in cholesterol-fed rabbits on endothelium-dependent vascular relaxation and ET-1-induced vascular contraction, as well as the systemic synthesis of ET-1. Rabbits were initially fed a diet enriched with 1% cholesterol for 4 weeks, followed by 0.5% cholesterol alone or supplemented with 2% L-arginine in drinking water during the next 12 weeks. Cholesterol feeding impaired endothelium-dependent relaxation of rabbit aortic rings ex vivo and increased urinary immunoreactive ET-1 excretion, along with decreased urinary nitrate excretion, an index of NO production. L-Arginine partially restored endothelium-dependent relaxation in parallel to increased urinary nitrate excretion and decreased urinary immunoreactive ET-1 excretion. Selective inhibition of ET-A receptors with BQ123 partially restored endothelium-dependent relaxation in hypercholesterolemic rabbits but had no effect on arterial rings from rabbits supplemented with L-arginine or from control animals. The contractile vascular response of aortic rings to exogenous ET-1 was increased in rabbits fed a high-cholesterol diet; this enhanced contractility to ET-1 was completely reversed by L-arginine. These data suggest that L-arginine restores endothelial function and normalizes the synthesis and vasoconstrictor response to ET-1 in hypercholesterolemia.
Institute of Clinical Pharmacology, Medical School, Hannover, Germany.
L
L
Phivthong-ngam
S M
SM
Bode-Böger
R H
RH
Böger
M
M
Böhme
R P
RP
Brandes
A
A
Mügge
J C
JC
Frölich
D000818:Animals; D001120:Arginine / Q000097:blood / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage*; D003401:Creatine / Q000378:metabolism; D004347:Drug Interactions; D019332:Endothelin-1 / Q000096:biosynthesis / Q000502:physiology* / Q000652:urine; D006937:Hypercholesterolemia / Q000188:drug therapy; D008297:Male; D008657:Metabolic Clearance Rate; D009566:Nitrates / Q000652:urine; D011817:Rabbits; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D002791:Cholesterol, Dietary; D019332:Endothelin-1; D009566:Nitrates; D001120:Arginine; D002784:Cholesterol; D003401:Creatine