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 μ M ), NS‐398 (a preferential COX‐2 inhibitor; 1 μ M ), SQ‐29548 (a thromboxane‐receptor antagonist; 1 μ M ), nor valeryl‐salicylate (VAS, a preferential inhibitor of COX‐1; 3 m M ). In aged rats, ACh caused a biphasic response characterized by a first phase of relaxation (0.01–1 μ M ACh), followed by a contraction (3–100 μ M 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 2α 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 2α 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.British Journal of Pharmacology (2000) 131 , 804–810; doi: 10.1038/sj.bjp.0703632