Stroke, Vol 24, 427-434, Copyright © 1993 by American Heart Association
HA Kontos and EP Wei
BACKGROUND AND PURPOSE: Methylene blue and 6-anilino,5,8-quinolinedione
(LY83583) are used extensively to block activation of guanylate cyclase.
Both agents generate oxygen radicals. Therefore, it appeared profitable to
investigate whether the generation of oxygen radicals by these agents is
responsible for the blockade of responses to nitrodilators that act via
activation of guanylate cyclase to relax vascular smooth muscle and cause
vasodilation. METHODS: We tested in anesthetized cats equipped with cranial
windows responses to topical application of nitroglycerin, nitroprusside,
and adenosine before and during topical application of methylene blue (5
microM). Responses to the vasoactive agents were tested during application
of methylene blue after permeabilization of the cell membrane with a
detergent to allow methylene blue to enter vascular smooth muscle.
Responses were also tested in the presence of superoxide dismutase,
catalase, deferoxamine, or dimethyl sulfoxide to scavenge reactive products
of oxygen metabolism or to eliminate catalytic iron. In additional
experiments we tested the effects of topical application of nitroprusside
or adenosine before and after application of LY83583. The responses to the
vasoactive agents were also tested in the presence of superoxide dismutase,
catalase, or dimethyl sulfoxide in addition to LY83583. We also tested
responses to calcitonin gene-related peptide before and in the presence of
LY83583 with or without superoxide dismutase. RESULTS: Methylene blue
eliminated the arteriolar dilation in response to nitroprusside and
nitroglycerin after permeabilization of the cell membrane with a detergent
but not before. The responses to adenosine were unaffected. The blockade
induced by methylene blue was reversed by superoxide dismutase, catalase,
or dimethyl sulfoxide but not by deferoxamine. LY83583 blocked responses to
nitroprusside but not to adenosine. The blockade was eliminated by
superoxide dismutase, catalase, or dimethyl sulfoxide. LY83583 blocked the
vasodilation induced by calcitonin gene-related peptide. This blockade was
reversed by superoxide dismutase. CONCLUSIONS: Methylene blue and LY83583
prevent the activation of soluble guanylate cyclase by nitrodilators or by
calcitonin gene-related peptide by generating oxygen radicals. The mediator
of this response is the hydroxyl radical. Methylene blue does not enter the
vascular smooth muscle of cerebral arterioles unless the cell membrane is
permeabilized.
ARTICLES
Hydroxyl radical-dependent inactivation of guanylate cyclase in cerebral arterioles by methylene blue and by LY83583
Department of Medicine, Medical College of Virginia, Richmond 23298.
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