AGING DIFFERENTIALLY AFFECTS DIRECT AND INDIRECT ACTIONS OF ENDOTHELIN-1 IN PERFUSED MESENTERIC-ARTERIES OF THE RAT

The effects of age on the vascular action of endothelin-1 were studied in mesenteric resistance arteries of 4, 9 and 27 month old Fischer 344 rats. Third order branches (about 200 μm in diameter) of mesenteric resistance arteries were dissected free and mounted on glass cannulae in organ chambers. Changes in intraluminal diameter of the perfused and pressurized vessels were continuously measured with a video dimension analyzer. Endothelin-1 (10-14 - 3 x 10-8 M) caused contractions that were augmented after removal of the endothelium. The inhibitory effects of the endothelium were greater in young than in old rats. The sensitivity of vascular smooth muscle to endothelin-1 decreased with age, while the maximal response was maintained. In contrast, the contractions to noradrenaline were unaffected by aging. Threshold concentrations of endothelin-1 potentiated the contractions evoked by low and moderate concentrations of noradrenaline (10-7 - 10-6 M) in old, but not in young, rats. Endothelium-dependent relaxations to acetylcholine inhibited maximal contractions to endothelin-1 and this effect decreased with age. In contrast, the relaxations to the nitric oxide donor, 3-morpholinosydnonimine (SIN-1; the active metabolite of molsidomine), did not differ in the three age groups. Aging specifically decreases the direct contractile effects of endothelin-1 and the inhibitory effects of the endothelium against these contractions, while the indirect (potentiating) effects of the peptide become more pronounced.