Vascular bed heterogeneity in age-related endothelial dysfunction with respect to NO and eicosanoids.
1. Endothelial dysfunction has been described with ageing but the mechanisms responsible have not been clearly elucidated and might be different from one vessel to the other. This study assesses the relative contribution of endothelial nitric oxide (NO) and cyclo-oxygenase (COX) metabolites in relaxation to acetylcholine with ageing in the aorta and the small mesenteric artery of the rat. 2. In the aorta and branch II or III of superior mesenteric artery (SMA), endothelium-dependent relaxation to acetylcholine was not different between 12 - 14 (adult) and 32-week-old rats whereas it was reduced at 70 - 100 (old) weeks of age. 3. Despite an increased endothelial NO-synthase protein expression, the NO-synthase inhibitor, N(G)-nitro-L-arginine-sensitive component of relaxation decreased with ageing. 4. In old rats, exposure to the COX inhibitor, indomethacin, but not the selective COX-2 inhibitor, NS-398, potentiated response to acetylcholine. The thromboxane A(2)/prostaglandin H(2) receptor antagonist, GR 32191B enhanced relaxation to acetylcholine in aorta but it had no effect in SMA. Furthermore, acetylcholine increased thromboxane B(2) production (enzymeimmunoassay) in aorta but not in SMA. Finally, Western blot analysis showed enhanced expression of COX-1 and 2 in the two arteries with ageing. 5. These results suggest that the decrease in acetylcholine-induced relaxation with ageing involves reduced NO-mediated dilatation and increased generation of vasoconstrictor prostanoids most likely from COX-1. They also point out vascular bed heterogeneity related to the nature of prostanoids involved between the aorta (i.e., thromboxane A(2)) and the SMA (unidentified) arteries even though increased expression of COX occurs in both vessels.
Matz
R L
RL
Laboratoire de Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, UMR CNRS 7034, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch Cedex, France.
de Sotomayor
M A
MA
Schott
C
C
Stoclet
J C
JC
Andriantsitohaina
R
R
D000109:Acetylcholine / Q000378:metabolism; D000375:Aging / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001011:Aorta; D001794:Blood Pressure; D015153:Blotting, Western; D001835:Body Weight; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015777:Eicosanoids / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D007527:Isoenzymes / Q000032:analysis; D008297:Male; D008565:Membrane Proteins; D008638:Mesenteric Arteries; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000032:analysis; D052250:Nitric Oxide Synthase Type III; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013929:Thromboxane B2 / Q000378:metabolism; D014664:Vasodilation
D015777:Eicosanoids; D007527:Isoenzymes; D008565:Membrane Proteins; D009569:Nitric Oxide; D013929:Thromboxane B2; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D000109:Acetylcholine