Cyclo-oxygenase-1 and-2 contribution to endothelial dysfunction in ageing

1 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. 2 In young rats, acetylcholine (ACh) caused a complete relaxation which was not affected by indomethacin (0.3 muM), NS-398 (a preferential COX-2 inhibitor; 1 muM), SQ-29548 (a thromboxane-receptor antagonist; 1 muM), nor valeryl-salicylate (VAS, a preferential inhibitor of COX-1; 3 mM). 3 In aged rats, ACh caused a biphasic response characterized by a first phase of relaxation (0.01-1 muM ACh), followed by a contraction (3 - 100 muM 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 EC50 values in young and aged rats. 4 In aged rats, the ACh-stimulated release of prostacyclin, prostaglandin F-2 alpha 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-2 alpha were smaller than in older animals and remained unaffected by NS-398. 5 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. 6 These data demonstrate the active contribution of COX-1 and -2 in endothelial dysfunction associated with ageing.