Maturational modulation of endothelium-dependent vasodilatation in ovine cerebral arteries

Abstract

To address the hypothesis that maturation enhances endothelial vasodilator function in cerebral arteries, relaxant responses to ADP and A-23187 were determined in ovine carotid and cerebral arteries harvested from 25 newborn lambs (3–7 days) and 23 adult sheep. Maturation significantly increased pD2values for A-23187 (newborn range: 4.9 ± 0.3 to 5.4 ± 0.3; adult range: 6.0 ± 0.2 to 7.1 ± 0.2) and the maximal vasodilator response to A-23187 by 10–18%. In contrast, maturation decreased maximum responses to ADP by 5–25% with no change in pD2. The magnitudes of endothelium-dependent relaxation were not affected by 10 μM indomethacin but were virtually abolished by 100 μM NG-nitro-l-arginine methyl ester/l-nitro arginine, indicating that nitric oxide (NO) is the primary endothelium-dependent vasodilator in these arteries. Maturation also modestly decreased endothelial NO synthase (eNOS) abundance in both carotid (32%) and cerebral (26%) arteries. Together, these findings reinforce the view that receptor coupling to endothelial activation is tightly regulated and may offset underlying changes in maximal endothelial vasodilator capacity. This capacity, in turn, appears to increase with postnatal age despite major growth and expansion of endothelial cell size and vascular wall volume. In ovine cerebral arteries, endothelial vasodilator capacity appears completely dependent on eNOS activity but not on cyclooxygenase activity. In turn, eNOS activity appears to be postnatally regulated by mechanisms independent of changes in eNOS abundance alone.