The senescence-accelerated prone mouse is a genetic model of hastened aging. We have studied vascular function in quiescent aortas from these animals together with immunohistochemical analyses of endothelial NO synthase and oxidative stress. The thoracic aorta from 6-7 month-old senescence-accelerated prone (SAM-P8) and resistant (SAM-R1) mice was excised and prepared for myographical, histological and biochemical studies. Myographical studies showed that the contractility of SAM-P8 aortas was higher than that of SAM-R1 as determined by KCl. Endothelial function assessed by acetylcholine (dose-response) relaxations showed that SAM-R1 vessels were slightly more sensitive than the SAM-P8. In the presence of L-NAME, all vessels displayed contractions to acetylcholine which were more pronounced in the SAM-R1. Endothelial modulation of smooth muscle contractions was assessed by phenylephrine (dose-response) in the absence or presence of L-NAME. SAM-P8 responses to phenylephrine were stronger than those of SAM-R1. However, in the presence of L-NAME, phenylephrine contractions were markedly more pronounced in SAM-R1 compared to SAM-P8. Vessels treated with indomethacin did not change their responses to acetylcholine or phenylephrine. Standard histology and immunohistochemistry of endothelial NO synthase, revealed no differences between aortas from both mouse strains. In contrast, malondialdehyde accumulation, a marker of oxidative stress, was higher in SAM-P8 vessels. Our present results suggest that the endothelium of SAM-P8 vessels is dysfunctional and lacks a normal capability to counteract smooth muscle contraction. This appears to be due to a malfunction of the NO system. NO production seems to be maintained, but oxidative stress probably accounts for an overdegradation of NO.