Preserved hypocapnic pial arteriolar constriction during hyperammonemia byglutamine synthetase inhibition

Ammonia intoxication, which results in astrocytic edema and glutamine accum ulation, blocks cerebral vasodilation during hypercapnia but not during hyp oxia. Ammonia's effect on blood flow during hypocapnia is unclear, with som e brain regions showing a paradoxical increase in flow. Here, we studied th e responses to hypocapnia of pial arterioles not surrounded by astrocytic e nd feet to avoid mechanical compression by local edema. Blood flow was meas ured by microspheres in pentobarbital sodium-anesthetized rats equipped wit h closed cranial windows that permitted intravital microscopy. The normal p ial arterial constriction in hypocapnia (12 +/- 1%; mean +/- SE) was blocke d (2 +/- 1%) during a 6-h intravenous infusion of ammonium acetate, with so me regions (cerebrum, midbrain) showing increased flow during hypocapnia. A fter pretreatment with methionine sulfoximine (MSO), which inhibits glutami ne synthesis, the normal hypocapnic constrictor response was retained in pi al arterioles (11 +/- 2%) during hyperammonemia. The increase in the calcul ated cerebrovascular resistance also was retained. An analog of MSO that do es not block glutamine synthesis (buthionine sulfoximine) was ineffective i n maintaining hypocapnic reactivity. In a sodium acetate-treated control gr oup, MSO did not alter the pial arteriolar response. Normal vasoconstrictiv e ability was shown during ammonium infusion in response to U-46619, a thro mboxane analog. We conclude that the inhibition of hypocapnic responsivity induced by ammonium is not due to paralysis of the pial arteriolar smooth m uscle or to vascular compression by swollen astrocytes but is in some may d ue to glutamine metabolically produced from the ammonium.