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Departments of Physiology and Pharmacology, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California 92350
Because cerebrovascular cGMP levels vary
significantly during maturation, we examined the hypothesis that the
ability of cGMP to relax cerebral arteries also changes during
maturation. In concentration-response experiments, potassium-induced
tone in basilar arteries was significantly more sensitive to a
nonmetabolizable cell-permeant cGMP analogue
8-(p-chlorophenylthio)-cGMP (8-pCPT-cGMP) in term fetal
[
log one-half maximal concentration (EC50) = 4.4 ± 0.1 M] than in adult (log EC50 = 4.0 ± 0.1 M) ovine basilar arteries. Serotonin-induced tone also
revealed significantly greater sensitivity to the cGMP analogue in
fetal (log EC50 = 4.9 ± 0.1 M) than in adult
(log EC50 = 4.7 ± 0.1 M) basilars. In fura
2-loaded preparations, 8-pCPT-cGMP had no significant effect on
cytosolic calcium concentrations in potassium-contracted arteries but
at 6 µM significantly reduced calcium only in fetal basilars
(
= 33 ± 8%). Higher 8-pCPT-cGMP concentrations reduced
cytosolic calcium in both fetal and adult basilars. Similarly, in both
potassium- and 5-hydroxytryptamine (5-HT)-contracted preparations, low
concentrations of 8-pCPT-cGMP reduced myofilament calcium sensitivity
only in fetal basilars ( = 29 ± 6 and = 42 ± 10%, respectively), whereas higher concentrations reduced calcium
sensitivity in both fetal and adult arteries. In
-escin-permeabilized arteries, equivalent reductions in basal and
agonist-enhanced myofilament calcium sensitivity were produced by much
lower 8-pCPT-cGMP concentrations in fetal (172 and 61 µM,
respectively) than in adult (410 and 231 µM, respectively) basilars.
The mechanisms mediating cGMP-induced vasorelaxation appear similar in
fetal and adult arteries, with the exception that they are much more
sensitive to cGMP in fetal than adult arteries. These age-related
differences in the sensitivity of cytosolic calcium concentration,
basal, and agonist-enhanced myofilament calcium sensitivity to cGMP can
easily explain why both potassium- and 5-HT-induced tone are more
sensitive to cGMP in fetal than adult cerebral arteries.
8-(p-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate; cerebral arteries; cerebrovascular circulation; guanylate cyclase; intracellular calcium concentration
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