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Center for Perinatal Biology, Departments of Physiology/Pharmacology and Obstetrics and Gynecology, School of Medicine, Loma Linda University, Loma Linda, California 92350
The present study was designed to test the
hypothesis that in cerebral arteries of the fetus, ATP-sensitive
(KATP) and Ca2+-activated K+
channels (KCa) 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
KATP-channel opener pinacidil and the
KCa-channel opener NS 1619 significantly inhibited
NE-induced tension [negative logarithm of the half-maximal 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 KCa-channel blocker iberiotoxin
(10
7 to 106 M) resulted in increased
tension and [Ca2+]i in both adult and fetal
MCA, although the KATP-channel blocker glibenclamide
(107 to 3 × 105 M) failed to do so.
Of interest, administration of 107 M iberiotoxin totally
eliminated vascular contraction and increase in
[Ca2+]i seen in response to 105
M ryanodine. In precontracted fetal cerebral arteries, activation of
the KATP and KCa 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, KATP and the
KCa 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., KCa-channel inhibition,
resulting in increased tension and [Ca2+]i,
whereas KATP-channel inhibition showed no such effect. In addition, the KCa 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.
cerebrovascular circulation; vascular smooth muscle; sympathetic nervous system; norepinephrine; intracellular calcium; potassium channels; fetus; adult
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