Cyclo-oxygenase-1 and -2 contribution to endothelial dysfunction in ageing.
Experiments were designed to investigate the role of cyclo-oxygenase isoforms in endothelial dysfunction in ageing. Aortic rings with endothelium of aged and young (24 vs 4 month-old) Wistar rats, were mounted in organ chambers for the recording of changes in isometric tension. In young rats, acetylcholine (ACh) caused a complete relaxation which was not affected by indomethacin (0.3 microM), NS-398 (a preferential COX-2 inhibitor; 1 microM), SQ-29548 (a thromboxane-receptor antagonist; 1 microM), nor valeryl-salicylate (VAS, a preferential inhibitor of COX-1; 3 mM). In aged rats, ACh caused a biphasic response characterized by a first phase of relaxation (0.01 - 1 microM ACh), followed by a contraction (3 - 100 microM ACh). Indomethacin, NS-398 and SQ-29548, but not VAS, augmented the first phase. Indomethacin, VAS, NS-398 and SQ-29548 decreased the contractions to high ACh concentrations. Then, the sensitivity to thromboxane receptor activation was investigated with U-46619. The results show comparable EC(50) values in young and aged rats. In aged rats, the ACh-stimulated release of prostacyclin, prostaglandin F(2alpha) and thromboxane A(2) was decreased by either indomethacin, NS-398, VAS or endothelium removal. However, in young animals, the ACh-stimulated release of prostacyclin and prostaglandin F(2alpha) were smaller than in older animals and remained unaffected by NS-398. Aortic endothelial cells from aged - but not young - rats express COX-2 isoform, while COX-1 labelling was observed in endothelial cells from both young and aged rats. These data demonstrate the active contribution of COX-1 and -2 in endothelial dysfunction associated with ageing.
Heymes
C
C
INSERM U-127, Institut Fédératif de Recherche IFR Circulation and University Paris VII, Hôpital Lariboisière, F-75475 Paris cedex 10, France.
Habib
A
A
Yang
D
D
Mathieu
E
E
Marotte
F
F
Samuel
J
J
Boulanger
C M
CM
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004730:Endothelium, Vascular / Q000502:physiology*; D011464:Epoprostenol / Q000378:metabolism; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis / Q000502:physiology; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D007527:Isoenzymes; D008565:Membrane Proteins; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D000109:Acetylcholine