The present studies were conducted to examine the role of cerebrovascular
guanylate cyclase in hypoxic cerebral vasodilatation. In arteries mounted in vitro for measurements of isometric tension, 20 min of
hypoxia (bath
oxygen partial pressure, approximately 15 Torr) significantly increased
cyclic GMP levels from 16 to 32, from 15 to 25 and from 20 to 38 pmol/g in rabbit common carotid, internal carotid and basilar arteries. These increases were blocked either by pretreatment with 3 microM
methylene blue, or by removal of the vascular endothelium.
Methylene blue also significantly delayed hypoxic relaxation in the basilar and internal carotid arteries, and blocked transient hypoxic vasoconstriction in the common carotid. Together, these in vitro results demonstrate that vascular cytosolic
guanylate cyclase participates in an endothelium-dependent manner in the direct effects of
hypoxia on cerebral arteries, and that the nature of this participation varies significantly between arteries. When
methylene blue (20 mg/kg) was administered in vivo, however, it had no effect on the magnitude of hypoxic cerebral vasodilatation as determined by both local (mass spectrometry) and global (venous outflow) methods of blood flow measurement. This latter finding suggests that: 1) large and small cerebral arteries may differ significantly in terms of either endothelial function or sensitivity to
methylene blue; or 2) feedback regulation of other mechanisms of hypoxic cerebral vasodilatation compensate for the effects of
guanylate cyclase inhibition. Additional experiments using other inhibitors of cytosolic
guanylate cyclase and/or vessels isolated from the cerebral microcirculation will be necessary to distinguish between these possibilities.