Cerebral artery K(ATP)- and K(Ca)-channel activity and contractility: Changes with development

The present study was designed to test the hypothesis that in cerebral arteries of the fetus, ATP-sensitive (K(ATP)) and Ca²⁺-activated K⁺ channels (K(Ca)) play an important role in the regulation of intracellular Ca²⁺ concentration ([Ca²⁺](i)) and that this differs significantly from that of the adult. In main branch middle cerebral arteries (MCA) from near-term fetal (~140 days) and nonpregnant adult sheep, simultaneously we measured norepinephrine (NE)-induced responses of vascular tension and [Ca²⁺](i) in the absence and presence of selective K⁺-channel openers/blockers. In fetal MCA, in a dose-dependent manner, both the K(ATP)-channel opener pinacidil and the K(Ca)-channel opener NS 1619 significantly inhibited NE-induced tension [negative logarithm of the halfmaximal inhibitory concentration (pIC₅₀) = 5.0 ± 0.1 and 8.2 ± 0.1, respectively], with a modest decrease of [Ca²⁺](i). In the adult MCA, in contrast, both pinacidil and NS 1619 produced a significant tension decrease (pIC₅₀ = 5.1 ± 0.1 and 7.6 ± 0.1, respectively) with no change in [Ca²⁺](i). In addition, the K(Ca)-channel blocker iberiotoxin (10^-7 to 10^-6 M) resulted in increased tension and [Ca²](i) in both adult and fetal MCA, although the K(ATP)-channel blocker glibenclamide (10^-7 to 3 x 10^-5 M) failed to do so. Of interest, administration of 10^-7 M iberiotoxin totally eliminated vascular contraction and increase in [Ca²⁺](i) seen in response to 10^-5 M ryanodine. In precontracted fetal cerebral arteries, activation of the K(ATP) and K(Ca) channels significantly decreased both tension and [Ca²⁺](i), suggesting that both K⁺ channels play an important role in regulating L-type channel Ca²⁺ flux and therefore vascular tone in these vessels. In the adult, K(ATP) and the K(Ca) channels also appear to play an important role in this regard; however, in the adult vessel, activation of these channels with resultant vasorelaxation can occur with no significant change in [Ca²⁺](i). These channels show differing responses to inhibition, e.g., K(Ca)-channel inhibition, resulting in increased tension and [Ca²⁺](i), whereas K(ATP)-channel inhibition showed no such effect. In addition, the K(Ca) channel appears to be coupled to the sarcoplasmic reticulum ryanodine receptor. Thus differences in plasma membrane K⁺-channel activity may account, in part, for the differences in the regulation of contractility of fetal and adult cerebral arteries.