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We studied the role of prostaglandins and free radicals in the induction of the functional and morphological pial arteriolar abnormalities produced by concussive brain injury. Anesthetized cats equipped with a cranial window for the observation of the pial microcirculation were subjected to concussive brain injury using a fluid-percussion device following administration of cyclooxygenase inhibitors (indomethacin or AHR-5850) or the vehicle for the solution of these agents (NaCl or Na2CO3 solution). Pial arterioles from vehicle-treated animals displayed sustained dilation, reduced responsiveness to the vasoconstrictor effect of arterial hypocapnia, and a high density of endothelial lesions. Animals pretreated with cyclooxygenase inhibitors showed less pronounced vasodilation, normal responsiveness to hypocapnia, and a significantly reduced number of lesions. The vasodilation and reduced responsiveness to the vasoconstrictor effects of hypocapnia after brain injury also were inhibited by topical application of free radical scavengers (nitroblue tetrazolium, superoxide dismutase, or mannitol). The vessels from cats pretreated with free radical scavengers also had a lower density of endothelial lesions than controls. The results support the view that the immediate cause of cerebral arteriolar damage in concussive brain injury is the generation of free oxygen radicals associated with increased prostaglandin synthesis.

The appearance of superoxide anion radical in cerebral extracellular space during and after acute hypertension induced by intravenous norepinephrine was investigated in anesthetized cats equipped with cranial windows. Superoxide was detected by demonstrating the presence of superoxide dismutase-inhibitable reduction of nitroblue tetrazolium. The superoxide dismutase-inhibitable rate of reduction of nitroblue tetrazolium was 4.1 +/- 1.61 nM/min per cm2 during hypertension and 4.55 +/- 0.62 nM/min per cm2 one hour after hypertension had subsided. During norepinephrine administration in the absence of hypertension, the superoxide dismutase-inhibitable rate of reduction of nitroblue tetrazolium was 0.44 +/- 0.17 nM/min per cm2. The reduction of nitroblue tetrazolium during hypertension was also inhibited by prior treatment of the brain surface with phenylglyoxal at pH 10, to induce irreversible inhibition of the anion channel. The results show that acute hypertension is associated with the generation of superoxide which enters the extracellular space of the brain via the anion channel. Following hypertension, the sustained vasodilation caused by acute hypertension was inhibited significantly by topical application of superoxide dismutase and catalase, showing that it was due in part to superoxide and other radicals derived from it. The vasodilator response of cerebral arterioles to topical acetylcholine was converted to vasoconstriction following acute hypertension, and restored to vasodilation following topical application of superoxide dismutase and catalase. The results show that superoxide and other radicals generated after acute hypertension interfere with acetylcholine-induced endothelium-dependent vasodilation, probably because they destroy the endothelium-derived relaxant factor.

Acute, severe increases in arterial blood pressure cause sustained cerebral arteriolar dilation, abnormal reactivity to carbon dioxide and to changes in blood pressure, abolition of endothelium-dependent dilation from acetylcholine, discrete morphological lesions of the endothelium and vascular smooth muscle, and breakdown of the blood-brain barrier to plasma proteins. The dilation, abnormal reactivity, and morphological abnormalities are inhibited by pretreatment with cyclooxygenase inhibitors or with free radical scavengers. Superoxide dismutase-inhibitable reduction of nitroblue tetrazolium applied to the brain surface was detectable both during hypertension and one hour after hypertension subsided. Nitroblue tetrazolium reduction is also reduced by inhibitors of the anion channel. The abnormalities seen after hypertension are reproduced by topical application of arachidonate. The results are consistent with the view that acute hypertension induces generation of superoxide anion radical in association with accelerated arachidonate metabolism via cyclooxygenase. This radical enters cerebral extracellular space via the anion channel and gives rise to hydrogen peroxide and hydroxyl radical. All three radicals are capable of causing vasodilation by relaxation of cerebral vascular smooth muscle. The hydroxyl radical is the most likely candidate for vascular wall damage. The significance of this mechanism in chronic experimental hypertension or its relevance to human disease is not known.

There is still considerable controversy regarding the influence of blood viscosity upon CBF. We have measured CBF with microspheres in 23 cats. Autoregulation was disturbed in the left caudate nucleus by microsurgical occlusion of the left middle cerebral artery. Induced hypertension or hypotension was used and i.v. mannitol (1 g/kg) administered. In all cats blood viscosity decreased an average of 16% at 15 minutes and, in 16 cats, increased 10% at 75 minutes post-mannitol. CBF in the right caudate was 79 +/- 6 ml/100g/min, in the left 38 +/- 6 (p less than 0.001). Only minor changes of CBF occurred in areas with presumed normal autoregulation, including the right caudate, in conjunction with pressure or viscosity changes. In the left caudate CBF decreased 21% with hypotension and 18% with higher viscosity, more than on the right (p less than 0.01 and p less than 0.2, respectively). CBF increased in the left caudate 56% with hypertension and 47% with lower viscosity, again much more than on the right (p less than 0.001 and p less than 0.01, respectively). In the other area which is (nearly) exclusively supplied by the middle cerebral artery of the cat, i.e., the ectosylvian cortex, results were similar to those in the caudate nucleus. These results show that viscosity changes must result in compensatory readjustments of vessel diameter, but that these adjustments do not occur where autoregulation to pressure changes is known to be defective. The adjustments to viscosity changes might be called blood viscosity autoregulation of CBF. We hypothesize that pressure autoregulation and blood viscosity autoregulation share the same mechanism.

The responses of cerebral (pial) arterioles to increased venous pressure were examined in anesthetized cats equipped with cranial windows for the observation of the cerebral microcirculation. Increased venous pressure was induced by occlusion of the superior vena cava. Intracranial pressure was kept constant. Increased venous pressure when the window was filled with stationary cerebrospinal fluid caused 9-12% arteriolar dilation. Cerebral arteriolar dilation of equal magnitude (8-12%) was also seen when the space under the cranial window was perfused with fluorocarbon FC-80 equilibrated with 100% nitrogen. Increased venous pressure when the cranial window space was perfused with fluorocarbon equilibrated with 100% oxygen caused a small (5%) but significant arteriolar constriction. These results show that the dominant mechanism of autoregulation in the cerebral arterioles is metabolic, and that it involves an oxygen-sensitive mechanism. Myogenic vasoconstriction is unmasked during venous hypertension when the dominant metabolic mechanism is eliminated by increased local supply of oxygen.