J. Weyne

Effects of carbon dioxide, bicarbonate and pH on lactate and pyruvate in the brain of rats

SummaryThe influence of acute changes inPaCO2on lactate concentration in brain and blood was studied in hypercapnic and hypocapnic rats. Lactate in brain increases markedly whenPCO2is acutely decreased by severe hyperventilation. Compared with the observations in normal rats, the lactate response to an intense hypocapnia was decreased in animals maintained 24 hours in hypoxic alkalosis and increased after 24 hours hypercapnia. The results are discussed in relation to the hypothesis that the lactate concentration response in brain in these conditions is related to local pH. Incubation studies of brain tissue, in whichPCO2or (and) [HCO3−] were varied, show that lactate and pyruvate concentration and glucose consumption increase while the lactate/pyruvate ratio decreases when the pH of the incubation fluid is augmented. In an iso-pH system, lactate and pyruvate concentration, glucose consumption and L/P ratio increase with increasing [HCO3−]. The possible mechanisms and the possible importance of these metabolic variations are discussed.

Effect ofPCO2, bicarbonate and lactate on the isometric contractions of isolated soleus muscle of the rat

SummaryIsometric contractions of isolated soleus muscles of 3 weeks old rats show a potentiation of the maximal twitch tension when thePCO2 is increased, or when the [HCO3−] is increased with a reciprocal decrease in [Cl−]. The reverse response is observed on decrease of thePCO2 and on decrease of the [HCO3−] with a reciprocal increase in [Cl−].The addition of lactate ions results in a potentiation of the maximal twitch, whether accompanied by a reciprocal decrease in [HCO3−] or in [Cl−].The maximal tetanic tension is augmented by rising thePCO2, by increasing the [HCO3−] with simultaneous lowering of [Cl−], or by the addition of lactate ions.

Experimental thromboembolic stroke studied by positron emission tomography : immediate versus delayed reperfusion by fibrinolysis

Acute obstruction of the middle cerebral artery (MCA) was obtained by injecting a single autologous blood clot into the internal carotid artery of dogs. The technique induced very reproducible unilateral ischemic lesions in the MCA territory; hemorrhagic transformation of the lesions was often seen. The hemodynamic and metabolic effects of blood clot embolism were studied in 35 dogs with positron emission tomography (PET) and the 15O steady-state technique, and compared with a control group of seven intact animals. In the acute phase, the involved brain tissue still had a nearly normal oxygen consumption (–11%) despite the lowered tissue perfusion (–20%) caused by the vascular obstruction. The lowered oxygen availability was compensated by an increased oxygen extraction ratio (+11%). Twenty-four hours after the insult, the hemodynamic situation had barely changed, and the ischemic event had evolved into a brain infarct in which oxygen consumption was clearly lowered (–25%) and accompanied by a significant lowering (–22%) of the oxygen extraction ratio compared with the acute situation. Therapeutic thrombolysis by local administration of streptokinase (500,000 IU), starting 30 min after the insult, was not able to salvage any brain tissue or to ameliorate tissue perfusion despite angiographically confirmed clot lysis. However, when fibrinolytic therapy was started within the first 5 min after the insult, hemispheric blood flow was normalized, and most of the threatened brain tissue was salvaged, as was indicated by its normalized oxygen consumption and oxygen extraction ratio. Early fibrinolysis was accompanied by definite clinical improvement and substantial reduction in the severity of the morphological lesions that were never hemorrhagic.

Influence of changes in the acid-base composition of the ventricular system on cerebral blood flow in cats

SummaryIn ventriculo-cisternal perfusion experiments performed in mechanically ventilated cats maintained under nitrous oxide anesthesia, the bicarbonate concentration of the ventricular perfusion fluid was decreased (from 21 to 4 mmol/l) or increased (from 21 to 84 mmol/l) during time intervals ranging from 45 to 120 min. The blood flow was measured in the caudate nucleus with two different methods: in a first series of experiments the temperature difference was continuously measured between a heated thermojunction and a reference junction, both devices being placed symmetrically in the right and left caudate nucleus (heat clearance method), while in a second series of experiments, the local blood flow was estimated from the rate of clearance of133Xenon injected in micro-amounts (8–10 μl) into the caudate nucleus. A decrease in the bicarbonate concentration of the ventricular perfusion fluid increased the blood flow in the caudate nucleus, estimated by both methods, while an increase in the bicarbonate concentration produced the opposite effect. The same alterations in the bicarbonate concentration of the ventricular perfusion fluid produced no detectable change in the hemispheric cerebral blood flow, measured by the clearance of133Xenon injected into the carotid system.Finally, the bicarbonate concentration was independently altered in one of the lateral ventricles during bilateral ventricular perfusions, and changes in the blood flow distribution were studied in the caudate nuclei with a particle distribution method (85Sr or141Ce labeled carbonized microspheres injected into the left heart ventricle). A ventricular perfusion, asymmetric with respect to the bicarbonate concentration induced an uneven distribution of the microspheres and hence of the local blood flow between both caudate nuclei. The results of the present experiments clearly argue in favour of a local influence of tissue pH on the blood flow in paraventricular gray matter.

Bicarbonate and Chloride Shifts in Rat Brain During Acute and Prolonged Respiratory Acid-Base Changes

(4 figures) In recent years the bicarbonate concentration ([HCO,]) in cerebrospinal fluid and in brain has attracted much interest. Several authors studied the buffering systems of the central nervous system in conditions of experimental acidosis and alkalosis and discussed the mechanisms of the observed changes. During metabolic acid-base changes in blood it appeared that pH and [HCOJ in cerebrospinal fluid (CSF) are only very slightly influenced in acute conditions (cfr DE BERSAQUES, 1955, for the literature; DE BERSAQUES and LEUSEN, 1954; ROBIN ef al., 1958; LEUSEN, 1965). More prolonged changes in plasma [HCOJ however are eventually reflected to a certain degree in CSF (for literature see MITCHELL et al., 1965, FENCL ef al., 1966 and MITCHELL, 1966) and variations in [HCOJ in CSF are compensated by changes in the chloride concentration ([Cl-I). Total brain tissue also showed only very small changes in [HCOJ after 6 hours non-respiratory changes in the bicarbonate concentration of blood plasma in the rat (SIESJO, 1964, 1965; SIESJO and PONTBN, 1966a and b). These authors conclude that the chloride ion equilibrated between plasma and brain tissue under the conditions of the experiment. More rapid changes are observed on the other hand in the bicarbonate concentration of CSF during respiratory changes in the acid-base equilibrium. These changes which are rather moderate in acute conditions, become progressively more pronounced with time.

PET studies of changes in cerebral blood flow and oxygen metabolism after unilateral microembolization of the brain in anesthetized dogs.

Cerebral blood flow and oxygen metabolism have been measured with the steady—state oxygen‐15 technique and positron emission tomography in anesthetized dogs. Regional microembolization was induced by infusing Sephadex particles (diameter, 40 μm) into one of the common carotid arteries. In the first series of experiments, 2.5 mg Sephadex was infused, and the dogs were examined within 3–4 hours after embolization. In a second series 0.55 mg Sephadex was infused, and the dogs were examined either in the first 3–4 hours or 24–48 hours after embolization. Cerebral blood flow, oxygen extraction ratio, and cerebral oxygen utilization were measured at 3 Pco2 levels. In the acute experiments, cerebral oxygen utilization in the embolized hemisphere was 6 (0.55 mg Sephadex) and 25% (2.5 mg Sephadex) lower than on the contralateral side. While cerebral blood flow was symmetrically distributed in normocapnia and hypocapnia, it was 9 (0.55 mg Sephadex) and 35% (2.5 mg Sephadex) lower in the embolized hemisphere during hypercapnia. In normocapnia and hypocapnia the lower oxygen utilization in the embolized hemisphere was characterized by a lower oxygen extraction ratio, and in hypercapnia by an unchanged (0.55 mg Sephadex) or by a higher (2.5 mg Sephadex) extraction ratio. The different effect on oxygen extraction ratio in the control and embolized hemispheres resulted in images of uncoupling between perfusion and oxygen demand that varied according to the Pco2. The experiments also showed a fall in cerebral blood flow in the embolized hemisphere after 3–4 hours, indicating delayed hypoperfusion. After 24–48 hours, blood flow was about 10% higher in the embolized hemisphere, and this was observed at the 3 Pco2 levels, while the oxygen extraction ratio was systematically lower. Oxygen utilization in the embolized hemisphere was depressed to practically the same extent as in acute experiments. It can be concluded that between 4 and 24 hours after microembolization the cerebral microcirculation shows important changes, with installation of luxury perfusion in the face of an unchanging decreased oxygen metabolism. (Stroke 1987;18:128–137)

The CSF/blood potential and the regulation of the bicarbonate concentration of CSF during acidosis in the cat

Abstract The bicarbonate concentration in plasma and cerebrospinal fluid, and the potential difference between cisternal CSF and blood were measured in anaesthetized cats. Administration of CO2 (5%) with the respiratory gas mixture during 1 hour produced a shift of the CSF potential towards a less positive value and an increase in plasma and CSF bicarbonate concentration. A combined acidosis realized simultaneously by inhalation of 5 % CO2 and infusion of hydrochloric acid, produced a decrease in the CSF/blood PD, a decrease in plasma [HCO3] and an increase in CSF [HSO3]. It is concluded that alterations in plasma [HCO3−] and in the potential difference between cisternal CSF and blood do not contribute in the cat to the increase in CSF [HCO3−] observed one hour after the simultaneous administration of CO2 and HCl.

Streptokinase treatment versus calcium overload blockade in experimental thromboembolic stroke.

Thromboembolic brain ischemia was produced in dogs using an autologous blood clot model. The effect of postembolic treatment with flunarizine and streptokinase on hemispheric cerebral metabolic rate for oxygen (CMRO2), oxygen extraction ratio (OER), and cerebral blood flow (CBF) was studied by positron emission tomography (oxygen-15 technique) 24 hours after the insult. We studied five groups of experimental dogs and compared them with a control group of nonembolized dogs. Group I received no treatment, Group II was treated locally with 500,000 IU streptokinase starting 30 minutes after the insult, Group III received streptokinase locally 30 minutes after the insult and 0.1 mg/kg i.v. flunarizine immediately after the insult and 2 hours later, Group IV received flunarizine as Group III, and Group V was orally pretreated with 0.5 mg/kg/day flunarizine during 2 weeks preceding embolization. Compared with the contralateral hemisphere, in the embolized hemisphere a significant reduction of CMRO2 (-25% to -40%) and CBF in normocapnia (-35%) and hypercapnia (-50%) was observed in Groups I, II, and V. In Groups III and IV, CMRO2, OER, and CBF of the embolized hemisphere were within the normal range during normocapnia and hypercapnia; the extent of the ischemic lesions was markedly less than in the other groups of experimental dogs. We conclude that flunarizine treatment after experimental thromboembolic stroke had a favorable influence on brain tissue. Chronic preventive flunarizine treatment failed to have a beneficial effect.

Progesterone-transforming enzyme activity in the hypothalamus of the male rat.

The aim of the present study was to assess the activities of the progesterone (Pr) transforming enzyme systems 3alpha-oxidoreductase (3alpha-OR), 5alpha-reductase (5alpha-R) and 20alpha-oxidoreductase (20alpha-OR) in the hypothalamus of the male rat, at different stages of sexual maturation and following castration and adrenalectomy. Special attention was paid to transformation to 3alpha-reduced compounds previously shown to inhibit FSH synthesis and secretion. Homogenates of hypothalamic tissue were incubated with 14C-progesterone. Pr-metabolites were isolated, identified by gas chromatography/mass-spectrometry (GC/MS) and measured by liquid scintillation counting (LSC). In adult rats a ratio of 6:2.5:1 for 5alpha-R:3alpha-OR:20alpha-OR enzyme- activities was found. The hypothalamic 5alpha-R and particularly 3alpha-OR activities were considerably higher before puberty (10-20 day old rats) than in adulthood. Adrenalectomy in adult rats resulted in an increased activity of the three enzyme systems. No significant changes were seen following castration. Among the isolated metabolites, 3alpha-hydroxy-pregn-4-en-20-one (3alpha-Pr) and 3alpha-hydroxy-5alpha-pregnane-20-one (5alpha,3alpha-Pr) were identified. Conversion to both these neurosteroids was considerably higher during prepuberty than in adulthood. The finding that before puberty the hypothalamus has a markedly increased capacity to convert Pr to 3alpha-reduced compounds, such as 3alpha-Pr, known to effectively inhibit FSH release, warrants further research into the mechanisms regulating the hypothalamic formation of biologically active Pr derivatives and their role in the regulation of gonadotropin secretion.

Glutamate and glutamine in the brain: Influence of acute Pco2 changes in normal rats and in rats under sustained hypercapnia or hypocapnia

Abstract The effect of Pco 2 on the concentration of glutamate and glutamine in the brain was studied in anesthetized and curarized rats. Brain glutamate was found to decrease gradually as a function of increasing Pco 2 while glutamine showed the inverse relationship. Identical observations were made in rats maintained 24 hours in an atmosphere of 13 % CO 2 in air (hypercapnia) or 10 % O 2 in nitrogen (hypoxemic hypocapnia) before the experiment.