The time-course for aging-associated effects on vascular reactivity to U46619, a stable analog of thromboxane A2 (TXA2), was studied in aorta from female senescence-accelerated prone mice (SAMP8), a murine model of accelerated senescence. Furthermore, we evaluated the contribution of nitric oxide (NO) and prostanoids in contractile responses to U46619.Methods
3, 6 and 10 months old senescent-resistant mice (SAMR1, n=21) and senescent-prone mice (SAMP8, n=21) were used. Vascular rings from thoracic aorta were mounted for isometric recording of tension and concentration-response curves to U46619 (10-9 – 10 7M) were performed in the absence and in the presence of NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10-4M) and/or the unspecific cyclooxigenase inhibitor indomethacin (10-5M). A segment of aorta from each mouse was frozen for immunofluorescence and protein expression analysis.Results
Maximal contraction to U46619 was markedly higher in SAMP8 at all ages. In SAMR1, increases were seen at 10 months, while SAMP8 displays augmented contraction at 6-months, which was further increased at 10-months. L-NAME enhanced U46619 contractions in both 6-month-old groups, although the increase was higher on vessels from SAMR1 at this age. Indomethacin equally increased U46619 contractions in both 3-month-old groups, suggesting the production of vasodilator prostaglandin in young animals. In contrast, at 6 and 10 months indomethacin decreased U46619 contractions in both groups, indicating an aging-associated swap to a release of contractile prostanoids in aorta. After the co-incubation of segments with L-NAME and indomethacin response to U46619 reached control values.Conclusions
Ageing decreased NO and increased contractile prostanoids in response to U46619 in female aorta. Cyclooxigenase stimulation increases contractile prostanoids and decreases NO in response to thromboxane A2 in aorta from aged female mice.