Maturation alters the contribution of potassium channels to resting and 5HT-induced tone in small cerebral arteries of the sheep

To address the hypothesis that maturation alters the contribution of K-channels to resting and agonist-induced tone in small cerebral arteries, second branch middle cerebral arteries (∼200 μm) were taken from term fetal (139-141 days gestation) and adult sheep, denuded of endothelium, and mounted in myographs. After determination of length-tension relations, the arteries were stretched to 55, 100, and 145% of optimum length. At each level of stretch, contractile responses to 5 mM 4-aminopyridine (4-AP, voltage-sensitive K-channel blocker), 100 nM iberiotoxin (calcium-sensitive K-channel blocker), 10 μM glibenclamide (ATP-sensitive K-channel blocker), or 10 μM Ba²⁺ (inward rectifier K-channel blocker) were recorded. In separate experiments, concentration-response relations were determined for 5-HT in the presence and absence of each of the four K-channel blockers at the same concentrations. Both 4-AP and iberiotoxin produced stretch-dependent contractions of greater magnitude in adult (37% for 4-AP and 43% for iberiotoxin at 100% optimum) than in fetal (5% for 4-AP and 7% for iberiotoxin at 100% optimum) arteries. 4-AP also enhanced the pD₂ for 5-HT in adult (from 7.15 to 7.49), but not in fetal, arteries. Conversely, glibenclamide attenuated the pD₂ for 5-HT in fetal (from 7.02 to 6.71), but not in adult, arteries. Iberiotoxin enhanced the pD₂ for 5-HT in both fetal (from 7.05 to 7.51) and adult (from 7.15 to 7.75) arteries. In addition, iberiotoxin enhanced maximum responses to 5-HT (from 59 to 82%) in adult but not fetal arteries. Finally, 4-AP enhanced the maximum responses to 5-HT in both fetal (from 67 to 85%) and adult (from 59 to 79%) arteries. These results indicate that maturation modulates the contribution of K_V, K_Ca, and K_ATP, but not K_IR channels to basal and/or 5HT-induced cerebrovascular tone, and demonstrate that K_V and K_Ca channels are coupled to stretch-sensitive receptors, and that K_V and K_Ca limit contractile responses to 5-HT. To the extent that changes in pD₂ values reflect changes in agonist-ligand interactions, the data also suggest that K_V, K_Ca, and K_ATP channels may possibly influence ligand-receptor binding for 5-HT.