Effects of Anoxia on Cerebral Blood Flow in the Rat Brain: Evidence for a Role of Adenosine in Autoregulation

Abstract

Summary: The purpose of these experiments was to de termine the utility of a new method for monitoring CBF using a venous outflow technique with an extracorporeal circulation and to examine the effects of agents that po tentiate or antagonize the actions of adenosine on the blood flow response to brief periods of anoxia. The re sults demonstrate the ability of the new technique to de tect the increases in CBF in response to anoxia. Caffeine, CBF is able to respond rapidly and appropriately to alterations in arterial blood pressure and brain metabolism. The mechanisms responsible for this autoregulation remain controversial, but a consid erable volume of evidence supports the hypothesis that adenosine plays a significant role in the regu lation of cerebral vascular tone. Adenosine is pro duced in the brain during hypoxia, ischemia, hy potension, and seizures (Berne et aI. , 1974; N ord strom et aI. , 1977; Winn et aI. , 1979 Winn et aI. , , 1980 Schrader et aI. , 1980). When applied directly to ce rebral vessels, adenosine causes vasodilatation (Berne et aI. , 1974;Wahl and Kuschinsky, 1976), though the effects of intraarterially perfused aden osine on CBF vary between species (Buyanski and Rapela, 1969; Berne et aI. , 1974; Heistad et aI. , 1981). The frequent failure of intraarterial adeno sine to affect CBF may be a result of its inability to readily cross the blood-brain barrier (Berne et aI. , 1974).In this study, we have used a venous outt1ow technique to measure CBF and its response to brief periods of anoxia. The method for measuring CBF by cannulation of the retroglenoid (postglenoid) vein was initially described by Gjedde et al. (1975) and by Nilsson and colleagues (Nilsson and Siesjo, 586an adenosine antagonist, reduced the intensity and du ration of the anoxia-induced hyperemia. Dipyridamole and papaverine, inhibitors of adenosine uptake, poten tiated the increase in CBF during anoxia. The results support the hypothesis that adenosine plays an important role in regulating CBF during anoxic episodes. Key Words: Anoxia-Caffeine-Cerebral blood flow-Di pyridamole-Papaverine. 1976; Hardebo et aI. , 1979). Winn et al. (1983) sub sequently adapted the technique for continuous re cording of CBF using an extracorporeal circulation with return of cerebral blood through a femoral vein. We have used this latter adaptation of the technique, which has the advantage of allowing for the continuous recording of a major fraction of the CBF over periods of several hours, during which time manipUlations of blood gases can be conducted in the presence or absence of pharmacological agents. The results of our study offer further evi dence that adenosine is an important regulator of CBF in animals challenged by anoxic episodes. METHODS PreparationCBF measurements were performed on male Sprague Dawley rats (Charles River) (weight 350-400 g). Anes thesia was induced with 2-3% halothane to allow trache otomy, and the animals were then maintained during sur gery on a mixture of nitrogen (70%), oxygen (30%), and methoxyflu...

Increases in Cerebral Cortical Perfusate Adenosine and Inosine Concentrations during Hypoxia and Ischemia

“…The low adenosine levels in normal CSF are, there fore, likely to reflect low levels of adenosine in the interstitial fluid of brain, rather than a loss of aden osine subsequent to entry into the CSF. The con clusion that extracellular adenosine concentrations in the brain of normoxic anesthetized rats may be in the 10-100 nM range is consistent with earlier observations of a failure of adenosine antagonists to affect basal CBF or pial vessel diameter, in the anesthetized rat (Phillis et al, 1984;Morii et al, 1985). This lack of effect of methyl xanthine antago nists on basal CBF suggests that adenosine is not an important factor in the regulation of vessel tone in the normoxic brain of anesthetized animals, and provides an indication that extracellular levels of adenosine are likely to be < 10 -7 M (Morii et al, 1986) under these conditions.…”

Adenosine Receptors and the Nucleoside Transporter in Human Brain Vasculature

“…as brain hypoxia, ischemia, hypoglycemia, and status epilepticus (Berne et al , 1983). Prevention of such removal by nucleoside transport inhibitors such as DPY will potentiate the effects of adeno sine at its receptors in neuronal, glial, and vessel membranes (Berne et al , 1983;Phillis et al, 1984).…”

The role of adenosine in the hyperaemic response of the hepatic artery to portal vein occlusion (the ‘buffer response’)

“…By contrast, the large decrease in 'buffering capacity' with IBMX took place despite an increase in basal PV flow, thus implying a rather greater inhibitory effect of IBMX than previously concluded; the hypotensive effect of IBMX is probably not responsible (see discussion above). DPD did not enhance 'buffering capacity '. Adenosine has been shown to be an important regulator of blood flow in a number of organs (Berne et al, 1983), including the brain (Phillis et al, 1984;Winn et al, 1985), the coronary circulation (Berne, 1963;Leung et al, 1985;Randall & Jones, 1985), skeletal muscle (Berne et al, 1983), the kidney (Osswald, 1988) and the intestine (Granger & Norris, 1980;Lautt, 1986). It has also been shown to control post-occlusion reactive hyperaemia of the HA (Ezzat & Lautt, 1987).…”