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Department of Physiology and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
This study examined the mechanism by
which cGMP contributes to the vasodilator response to nitric oxide (NO)
in rat middle cerebral arteries (MCA). Administration of a NO donor,
diethylaminodiazen-1-ium-1,2-dioate (DEA-NONOate), or 8-bromo-cGMP
(8-BrcGMP) increased the diameter of serotonin-preconstricted MCA by
79 ± 3%. The response to DEA-NONOate, but not 8-BrcGMP, was
attenuated by iberiotoxin (10
7 M) or a 80 mM
high-K+ media, suggesting that activation of K+
channels contributes to the vasodilator response to NO but not 8-BrcGMP. The effects of NO and cGMP on the vasoconstrictor response to
Ca2+ were also studied in MCA that were permeabilized with
-toxin and ionomycin. Elevations in bath Ca2+ from
10
8 to 10
5 M decreased the diameter of
permeabilized MCA by 76 ± 5%. DEA-NONOate (10
6 M)
and 8-BrcGMP (10
4 M) blunted this response by 60%.
Inhibition of guanylyl cyclase with
1H-[1,2,4]oxadiazole[4,3-a]
quinoxalin-1-one (10
5 M) blocked the inhibitory effect of
the NO donor, but not 8-BrcGMP, on Ca2+-induced
vasoconstriction. 8-BrcGMP (10
4 M) had no effect on
intracellular Ca2+ concentration
([Ca2+]i) in control, serotonin-stimulated,
or
-toxin- and ionomycin-permeabilized vascular smooth muscle cells
isolated from the MCA. These results indicate that the vasodilator
response to NO in rat MCA is mediated by activation of
Ca2+-activated K+ channels via a
cGMP-independent pathway and that cGMP also contributes to the
vasodilator response to NO by decreasing the contractile response to
elevations in [Ca2+]i.
vascular smooth muscle; calcium sensitivity; cytochrome P-450
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