Methylene blue inhibits hypoxic cerebral vasodilation in awake sheep

Cerebral vasodilation in hypoxia may involve endothelium-derived relaxing factor-nitric oxide. Methylene blue (MB), an in vitro inhibitor of soluble guanylate cyclase, was injected intravenously into six adult ewes instrumented chronically with left ventricular, aortic, and sagittal sinus catheters. In normoxia, MB (0.5 mg/kg) did not alter cerebral blood flow (CBF, measured with 15-μm radiolabeled microspheres), cerebral O₂ uptake, mean arterial pressure (MAP), heart rate, cerebral lactate release, or cerebral O₂ extraction fraction (OEF). After 1 h of normobaric poikilocapnic hypoxia (arterial PO₂ 40 Torr, arterial O₂ saturation 50%), CBF increased from 51 ± 5.8 to 142 ± 18.8 ml · min^-1 · 100 g^-1, cerebral O₂ uptake from 3.5 ± 0.25 to 4.7 ± 0.41 ml · min^-1 · 100 g^-1, cerebral lactate release from 2 ± 10 to 100 ± 50 μmol · min^-1 · 100 g^-1, and heart rate from 107 ± 5 to 155 ± 9 beats/min (P < 0.01). MAP and OEF were unchanged from 91 ± 3 mmHg and 48 ± 4%, respectively. In hypoxia, 30 min after MB (0.5 mg/kg), CBF declined to 79.3 ± 11.7 ml · min^-1 · 100 g^{- 1} (P < 0.01), brain O₂ uptake (4.3 ± 0.9 ml · min^-1 · 100 g^-1) and heart rate (133 ± 9 beats/min) remained elevated, cerebral lactate release became negative (-155 ± 60 μmol · min^-1 · 100 g^-1, P < 0.01), OEF increased to 57 ± 3% (P < 0.01), and MAP (93 ± 5 mmHg) was unchanged. The sheep became behaviorally depressed, probably because of global cerebral ischemia. These results may be related to interference with a guanylate cyclase-dependent mechanism. However, because the specific vascular effects of MB in vivo are uncertain, other mechanisms, including inactivation of oxygen radicals, may be involved.