A. Murray Harper

Upper Limit of Autoregulation of Cerebral Blood Flow in the Baboon

The upper limit of autoregulation of cerebral blood flow was studied in ten young baboons. Blood pressure was increased by infusing angiotensin, and cerebral blood flow was measured by the intracarotid 133xenon injection method. Autoregulation was maintained until blood pressure was 30–40% above resting values. At this blood pressure level, cerebrovascular resistance reached a maximum. Any additional increase in blood pressure resulted in an increase in cerebral blood flow and a decrease in cerebrovascular resistance; this situation is designated the “breakthrough of autoregulation.” In four baboons subjected to unilateral sympathetic denervation, autoregulation of cerebral blood flow was studied bilaterally; no difference in the upper limit of autoregulation was found between the intact and the sympathectomized hemisphere. The breakthrough of autoregulation supposedly plays an important role in the pathogenesis of acute hypertensive encephalopathy. The old concept of hypertensive cerebral vasospasm has been revised in recent years, and it is now generally recognized that acute hypertensive encephalopathy is caused by focal overdistention of brain arterioles with lesions of the blood-brain barrier. However, whether this condition is associated with a high cerebral blood flow in the clinical syndrome has not been investigated.

THE INTER‐RELATIONSHIP BETWEEN aPco2 AND BLOOD PRESSURE IN THE REGULATION OF BLOOD FLOW THROUGH THE CEREBRAL CORTEX

The importance of the arterial carbon dioxide tension and the artcrial blood pressure in the regulation of cerebral blood flow is well recognised. However, there is a need to determine quantitatively the flow response over a wide range of arterial carbon dioxide tensions and systemic blood pressures, and in particular to determine the interplay of these two factors in the control of the cerebral circulation. This paper reports the effect of varying the systemic blood yressures in normocapnic and hypercapnic dogs and of varying the arterial carbon dioxide tensions in normotensive and hypotensive dogs on thc Mood-flow through the cerebral cortex.

Effects of 5‐hydrooxytryptamine on pial arteriolar calibre in anaesthetized cats

1. The responses of individual pial arterioles and small arteries to perivascular injections of 5‐hydroxytryptamine were studied in anaesthetized cats.

Prostaglandin-induced effects in the primate cerebral circulation.

The effects of intracarotid infusions of prostaglandins E2 and F2alpha on cerebral blood flow (CBF) and oxygen consumption (CMRO2), and on extracranial blood flow, have been studied in anaesthetisex baboons. The 133Xe clearance method was used for measuring CBF, whilst extracranial blood flow was assessed by both the local tissue injection of 133Xe and external carotid artery flowmetry. Both PGF2alpha and PGE2 (10(-7) and 10(-6) g/kg/min) reduced both CBF and CMRO2. Spasm of the internal carotid artery with PGE2 was noted at the higher dose. Following osmotic opening of the blood-brain barrier by the hypertonic urea technique, the effects of small doses of PGE2 and CBF and CMRO2 were greatly potentiated. PGE2 greatly increased extracranial blood flow. Hence, both PGE2 and PGF2alpha reduce CBF and CMRO2, whilst PGE2 greatly increases extracranial blood flow.

Local Cerebral Glucose Utilisation Following Indoleamine- and Piperazine-Containing 5-Hydroxytryptamine Agonists

Abstract: Substances with varying structural components have been shown to have 5‐hydroxytryptamine (5‐HT)‐like properties in the CNS. In this study, putative 5‐HT agonists with indoleamine moeities—lysergic acid diethylamide (LSD) and 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeODMT)—and with piperazine moeities—quipazine (Quip) and 6‐chloro‐2‐(1‐piperazinyl)pyrazine (6‐CPP) were administered to rats. Local cerebral glucose utilisation was measured using the [14C]2‐deoxyglucose autoradiographic technique. It was found that in most cerebral structures, these substances produced dose‐dependent reductions in glucose utilisation. However, Quip and 6‐CPP increased glucose utilisation in specific areas of the diencephalon (e.g., nucleus reuniens) and produced a biphasic effect in some but not all extrapyramidal structures (e.g., ventromedial caudate nucleus). No such increases in local cerebral glucose utilisation were measured following LSD or 5‐MeODMT administration. These results indicate that although similarities exist between the effects of indoleamine‐ and piperazine‐containing 5‐HT agonists on local cerebral glucose utilisation there are also significant differences in the overall patterns of response produced.

THE EFFECT OF SEROTONIN ON CEREBRAL AND EXTRACEREBRAL BLOOD FLOW WITH POSSIBLE IMPLICATIONS IN MIGRAINE

Serotonin (1 μg/kg/min) was infused into the internal or the external carotid artery in anaesthetised baboons. Blood flow through the carotid arteries was measured by electromagnetic flow probes. Cerebral blood flow was measured by the 133Xenon clearance method. Temporal muscle blood flow was measured from the clearance of 133Xenon following local injection into the muscle. The following results of the infusion of Serotonin were noted: 1) The blood flow through the external carotid artery and the temporal muscle increased by several hundred per cent. 2) The blood flow through the internal carotid artery was reduced by 57 %. 3) The cerebral blood flow was reduced by 17 % at normocapnia but by twice this figure at hypercapnia.

Osmotic opening of the blood-brain barrier: value in pharmacological studies on the cerebral circulation

Contiguous endothelial cells in the cerebral circulation are joined together by tight junctions and this feature is believed to be the structural basis for the bloodbrain barrier. These tight junctions are present at the level of the cerebral arterioles as well as the capillaries18,2% Cerebrovascular smooth muscle is therefore separated from the circulation by this blood-brain barrier, and the poor reactivity of the cerebral circulation to systemic agents may be related, in part, to the inability of these agents to cross the blood-brain barrier. The tight junctions between adjacent endothelial cells may be reversibly opened by the intracarotid infusions of hypertonic solutions, combined with either temporary or permanent occlusion of the carotid artery 14,16. These procedures permit the passage of molecules as large as horseradish peroxidase (MW 40,000) into the cerebral interstitial fluid, as confirmed by electron microscopic and functional studies on the bloodbrain barried, 2°,2a. As pointed out by Rapoport 15, osmotic opening of the bloodbrain barrier would facilitate entry into the brain of drugs normally excluded and could prove most useful in physiological and pharmacological studies on the cerebral circulation. However, the previously published techniques are unacceptable for studies of the cerebral circulation because the carotid clamping necessary will result in a reactive hyperemia. Furthermore, it is necessary to ensure that osmotic disruption of the blood-brain barrier by itself does not affect blood flow through the brain before the technique can be applied to cerebral circulatory investigations. The object of this investigation was to open the blood-brain barrier osmotically, without occluding blood flow to the brain, and to assess the effects of this procedure on cerebral blood flow, on the physiological responsiveness of the cerebral circulation, and on cerebral metabolism.

Adenosine response on pial arteries, influence of CO2 and blood pressure

The television image-splitting technique was used to study the influence of arterialpCO2 and blood pressure on the dilatatory response of pial arterioles to topically applied adenosine in chloralose anaesthetised cats. At normocapnia (pCO2≃35 mm Hg) 10−5 adenosine caused pial arteriole dilatation of 29.2 ±2.7% (S.E.M.). This was significantly reduced to 14.5±1.6% (P<0.001) atpCO2 25 mm Hg and to 8.5±1.6% (P<0.001) atpCO2 48 mm Hg. Lowering the blood pressure to 65–85 mm Hg had no significant effect on the adenosine response, but raising the blood pressure to 140–160 mm Hg significantly reduced the adenosine response to 22.1±1.8% (P<0.05). The response was independent of vessel size except at hypertension where vessels<150 μm were significantly more reactive than the larger vessels (P<0.01). These results indicate that adenosine induced vasodilatation of pial arterioles shows little change in the face of alterations in vessel tone induced by altering blood pressure, but is markedly decreased by the combination of changing perivascular pH and vascular resistance through moderate changes in arterialpCO2. The importance of these results in assessing the role of adenosine as a cerebral vasodilator is discussed.The television image-splitting technique was used to study the influence of arterial pCO2 and blood pressure on the dilatatory response of pial arterioles to topically applied adenosine in chloralose anaesthetised cats. At normocapnia (pCO2 congruent to 35 mm Hg) 10(-5) adenosine caused pial arteriole dilatation of 29.2 +/- 2.7% (S.E.M.). This was significantly reduced to 14.5 +/- 1.6% (P < 0.001) at pCO2 25 mm Hg and to 8.5 +/- 1.6% (P O 0.001) at pCO2 48 mm Hg. Lowering the blood pressure to 65--85 mm Hg had no significant effect on the adenosine response, but raising the blood pressure to 140--160 mm Hg significantly reduced the adenosine response to 22.1 +/- 1.8% (P < 0.005). The response was independent of vessel size except at hypertension where vessels < 150 micrometer were significantly more reactive than the larger vessels (P < 0.01). These results indicate that adenosine induced vasodilatation of pial arterioles shows little change in the face of alterations in vessel tone induced by altering blood pressure, but is markedly decreased by the combination of changing perivascular pH and vascular resistance through moderate changes in arterial pCO2. The importance of these results in assessing the role of adenosine as a cerebral vasodilator is discussed.

BLOOD FLOW AND OXYGEN UPTAKE OF THE CEREBRAL CORTEX OF THE DOG DURING ANAESTHESIA WITH DIFFERENT VOLATILE AGENTS

The oxygen uptake of the brain is reduced during barbiturate anaesthesia and the degree of reduction is proportional to the depth of anaesthesia (Cleichmann, Znguar, Lassen, Lubbers, Siesjo & Thews 1962, Himwich, Homburger, Maresca & IIimwich 1947, Sokoloff 1969). Sokoloff (1963) suggested that “it is likely that most general anaesthetic agents have similar effects ( i .e . similar to the barbiturates) on the cerebral circulation and metabolism”. The following experiments were designed to test this hypothesis.

Serotonin Depression of Local Cerebral Glucose Utilisation after Monoamine Oxidase Inhibition

The major catabolic enzyme for serotonin, monoamine oxidase (MAO), is present in the endothelium of cerebral vessels. We report the effects of the intracarotid administration of serotonin on local cerebral glucose utilisation in rats following MAO inhibition with the drug clorgyline. It was found that saline, clorgyline, or serotonin alone produced no significant changes in glucose utilisation. Following the infusion of clorgyline, the administration of serotonin produced significant decreases in glucose utilisation in cortical areas of between 12 and 33% and in the caudate nucleus of 16%.