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 Ba 2+ (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 pD 2 for 5-HT in adult (from 7.15 to 7.49), but not in fetal, arteries. Conversely, glibenclamide attenuated the pD 2 for 5-HT in fetal (from 7.02 to 6.71), but not in adult, arteries. Iberiotoxin enhanced the pD 2 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 pD 2 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.