Maturation Enhances the Sensitivity of Ovine Cerebral Arteries to the ATP-Sensitive Potassium Channel Activator Lemakalim

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Abstract
A wide variety of previous studies have demonstrated that arterial reactivity and contractility change dramatically during maturation. In light of recent findings that binding sites for glibenclamide, a ligand for ATP-sensitive potassium (KATP) channels, become more abundant with age in many tissues, the present studies examine the hypothesis that maturational changes in vascular reactivity involve changes in arterial electrophysiologic characteristics. To test this hypothesis, we determined the dose-response relation to lemakalim, a selective activator of KATP channels, in isolated endothelium-denuded segments of the second (2B, internal diameter 200 Mm) and fourth (4B, internal diameter 125 μm) branches of middle cerebral arteries taken from newborn (3–7 d old) and adult sheep. At 100 μM, lemakalim completely relaxed serotonin-induced tone in all arteries. However, -Iog ED50 values were 29 to 43 times greater in adult (2B, 7.15 ± 0.38; 4B, 6.61 ± 0.42) than in newborn (2B, 5.52 ± 0.25; 4B, 5.15 ± 0.24) segments. Correspondingly, Hill values were significantly smaller in adults (2B, 0.47 ± 0.17; 4B, 0.71 ± 0.30) than in newborns (2B, 1.40 ± 0.35; 4B, 3.30 ± 0.92). These findings demonstrate that KATP channels are less sensitive to activation in newborn than in adult cerebral arteries. Given the important influence of KATP channels on vascular tone, and their possible role in many cardiovascular responses, the present data suggest that maturational increases in the activity of KATP channels contribute significantly to age-related changes in cerebrovascular contractility.

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