Mechanism of CO2 response in cerebral arteries of the newborn pig: Role of phospholipase, cyclooxygenase, and lipoxygenase pathways

Abstract

The role of phospholipase, lipoxygenase, and cyclooxygenase pathways in the mechanism of the cerebrovascular response to CO2 and H+ was investigated in newborn piglets. Responsiveness of pial arterioles, 48-206 μm diameter, to inhalation of 6% CO2 and to suffusion of acidic cerebrospinal fluid (CSF, pH = 6.84), adenosine (10-4 M), or theophylline (10-2 M) was studied using a closed cranial window. Pial arteriolar diameter was measured using intravital microscopy. Phospholipase inhibitors quinacrine hydrochloride (10-4 M in CSF) and p-bromophenacyl bromide (10-4 M in CSF) abolished the CO2 vasodilation from Δdiameter = 27 ± 5% and 28 ± 3% during baseline to 0 ± 4% and -1 ± 1% following the respective inhibitors. Following administration of the cyclooxygenase inhibitor indomethacin (5 mg/kg i.v.), the CO2 response was converted from vasodilation, 31 ± 6%, to constriction, -4 ± 1% (p < 0.001), while the lipoxygenase inhibitor nordihydroguaiaretic acid (2 mg/kg i.v. or 10-4 M in CSF) augmented the pial arteriolar response to CO2 from 21 ± 4% to 34 ± 7% (p < 0.005). Topical application of superoxide dismutase (40 units/ml CSF) plus catalase (40 units/ml CSF) also appeared to augment the CO2 response. Suffusion of the cortical surface with acidic CSF at constant PCO2 increased pial arteriolar diameter by 11 ± 2% that was also abolished by indomethacin. Vasodilatory responses to topical adenosine and theophylline were not affected by indomethacin, suggesting specificity for H+ ion-related vasodilation. The data support a role for arachidonic acid metabolism and production of vasoactive prostaglandins mediating the cerebrovascular response to hypercapnia in the newborn piglet. A mechanism by which extracellular H+ may influence cell membrane function and activate phospholipase to release arachidonic acid is suggested.