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Center for Perinatal Biology, Departments of Physiology, Pharmacology, and Obstetrics and Gynecology, Loma Linda University, School of Medicine, Loma Linda, California 92350
In vascular smooth muscle, elevation of agonist-induced
intracellular Ca2+ concentration
([Ca2+]i)
occurs via both Ca2+ release from
intracellular stores and Ca2+
influx across the plasma membrane. In the cerebral vasculature of the
fetus and adult the relative roles of these mechanisms have not been
defined. To test the hypothesis that plasma membrane L-type and
receptor-operated Ca2+ channels
play a key role in NE-induced vasoconstriction via alterations in
plasma membrane Ca2+ flux and that
this may change with developmental age, we performed the following
study. In main branch middle cerebral arteries (MCA) from near-term
fetal (~140 days) and nonpregnant adult sheep, we quantified
NE-induced responses of vascular tension and
[Ca2+]i
(by use of fura 2) under standard conditions in response to several
Ca2+ channel blockers and in
response to zero extracellular
Ca2+. In fetal and adult MCA,
maximal NE-induced tensions (g) were 0.91 ± 0.12 (n = 10) and 1.61 ± 0.13 (n = 12), respectively. The pD2 values for
NE-induced tension were both 6.0 ± 0.1, whereas the fetal and adult
maximum responses (%Kmax) were
107 ± 16 and 119 ± 7, respectively. The fetal and adult
pD2 values for NE-induced increase
of
[Ca2+]i
were 6.2 ± 0.1 and 6.4 ± 0.1, respectively, whereas maximum [Ca2+]i
responses were 81 ± 9 and 103 ± 15% of
Kmax, respectively. After
10
5 M NE-induced
contraction, nifedipine resulted in dose-dependent decrease in vessel
tone and
[Ca2+]i
with pIC50 values for
fetal and adult tensions of 7.3 ± 0.1 and 6.6 ± 0.1, respectively (P < 0.01;
n = 4 each), whereas
pIC50 for
[Ca2+]i
responses were 7.2 ± 0.1 and 6.9 ± 0.1, respectively. The
pIC50 values for tension for
diltiazem and verapamil were somewhat lower but showed a similar
relationship. The receptor-operated
Ca2+ channel blocker 2-nitro-4
carboxyphenyl-N,N-diphenyl carbamate showed little effect on NE-induced vessel contractility or
[Ca2+]i.
In the absence of extracellular
Ca2+ for 2 min,
105 M NE resulted in
markedly attenuated responses of adult MCA tension and
[Ca2+]i
to 39 ± 7 and 73 ± 8% of control values
(n = 4). For fetal MCA,
exposure to extracellular Ca2+
concentration resulted in essentially no contractile or
[Ca2+]i
response (n = 4). Similar blunting of
NE-induced tension and [Ca2+]i
was seen in response to 103
M lanthanum ion. These findings provide evidence to suggest that especially in fetal, but also in adult, ovine MCA,
Ca2+ flux via L-type calcium
channels plays a key role in NE-induced contraction. In contrast,
Ca2+ flux via receptor-operated
Ca2+ channels is of less
importance. This developmental difference in the role of
cerebrovascular plasma membrane
Ca2+ channels may be an important
association with increased Ca2+
sensitivity of the fetal vessels.
cerebrovascular circulation; vascular smooth muscle; sympathetic nervous system; norepinephrine; intracellular calcium; calcium channels; fetus; development
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