Effects of vitamin C and of a cell permeable superoxide dismutase mimetic on acute lipoprotein induced endothelial dysfunction in rabbit aortic rings.
Low density lipoprotein (LDL) inhibits endothelium-dependent relaxation. The mechanism is uncertain, but increased production of superoxide anion O2- with inactivation of endothelium-derived NO and formation of toxic free radical species have been implicated. We investigated effects of the cell permeable superoxide dismutase mimetic manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP), the free radical scavenger vitamin C and arginine (which may reduce O2- formation) on acute LDL-induced endothelial dysfunction in rabbit aortic rings, using LDL prepared by ultracentrifugation of plasma from healthy men and aortic rings from New Zealand white rabbits. LDL (150 microg protein ml(-1) for 20 min) markedly inhibited relaxation of aortic rings (in Krebs' solution at 37 degrees C and pre-constricted to 80% maximum tension with noradrenaline) to acetylcholine 82+/-10% (mean percentage difference between sum of relaxations after each concentration of acetylcholine in the presence and absence of LDL, +/-s.e.mean, n=26, P<0.001) but not to the endothelium-independent agonist nitroprusside. MnTMPyP (10 microM) reduced inhibitory effects of LDL from 124+/-27 to 56+/-17% (n=6, P<0.05). Vitamin C (1 mM) reduced inhibitory effects of LDL from 59+/-8 to 22+/-5% (n=6, P<0.05). Inhibitory effects of LDL were similar in the absence or presence of arginine (84+/-12 vs 79+/-16%, n=14, P=0.55). Effects of L-arginine (10 mM) did not differ significantly from those of D-arginine (10 mM). Acute (20 min) exposure of aortic rings to LDL impairs endothelium-dependent relaxation which can be partially restored by MnTMPyP and vitamin C. This is consistent with LDL causing increased O2- generation.
Fontana
L
L
Department of Clinical Pharmacology, Guy's, King's and St Thomas' School of Biomedical Sciences, St Thomas' Hospital, London, England.
McNeill
K L
KL
Ritter
J M
JM
Chowienczyk
P J
PJ
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000503:physiopathology; D001120:Arginine / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008074:Lipoproteins / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D008875:Middle Aged; D009126:Muscle Relaxation / Q000187:drug effects; D009599:Nitroprusside / Q000494:pharmacology; D011817:Rabbits; D013482:Superoxide Dismutase / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D016166:Free Radical Scavengers; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D008665:Metalloporphyrins; D014665:Vasodilator Agents; D009599:Nitroprusside; C050950:tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex; D001120:Arginine; D013482:Superoxide Dismutase; D000109:Acetylcholine; D001205:Ascorbic Acid