[Proton nuclear magnetic resonance in the pharmacologic study of cerebral edema]. / Intérêt de la résonance magnétique nucléaire du proton dans l'étude pharmacologique de l'oedème cérébral.

Wistar male rats have been orally administered 2 mg X kg-1j-1 of triethyltin (TET) chloride for 5 consecutive days. The result was a cerebral edema which constituted a reproducible and useful experimental model for pharmacological screening of drugs used in ageing. Water content modifications and clinical behaviour for 11 days from the beginning of experiment have been linked to T1 and T2 proton relaxation times measured by nuclear magnetic resonance (1H-NMR). The observation of 3 central nervous system structures, which differ in white matter content, has lead to the conclusion that NMR is a more sensitive technique to follow up the edema evolution than the water content measurement alone; it has also allowed to discriminate intra from extra-cellular edema (osmotic and TET edema), and has proved the action of two drugs which are used in aging process treatment on the TET edema (dihydroergotoxine 2 X 10 mg X kg-1j-1 and (--) eburnamonine 2 X 50 mg X kg-1j-1). In the future the mastery of this technology will be used to study other nuclei (Na, K, P) which will bring more physiopathological informations and to pharmacological investigations of the brain by NMR tomography or focalised NMR.

Experimental approach of activity and mechanism(s) of action of drugs used in cerebral metabolic insufficiency. Application to 1-eburnamonine.

The authors described an experimental approach, specially using oral administration, of drugs used in cerebral metabolic insufficiencies and its application to l-eburnamonine (l-EB). Administered orally, l-EB: (1) significantly increased the cerebral consumption of [14C]- deoxyglucose in normoxic mice; (2) decreased the fall in cerebral energy charge (ECP) of rats after an acute normobaric hypoxia, and (3) stimulated the glycolysis of red blood cells (RBC) in healthy volunteers (repeated administrations) as demonstrated by important increases in 2,3-DPG and ATP, i.e., in factors involved in the bioavailability of oxygen (oxygen transport activity and RBC deformability). The results therefore demonstrate oral activity of l-EB in animals and man. They are in agreement with previous data showing cerebral metabolic stimulant and antihypoxic effects following parenteral administration, in animals. They allow to propose that l-EB acts both at cerebral and extracerebral levels and constitute objective biochemical proof of the activity of l-EB in man. The study of new drugs may be done using the same experimental approach.

[Effect of ascorbic acid during acute iterative anoxia, hypothesis of an anti-oxidizing mechanism of action in comparison with the effect of hydroquinone]. / Influence de l'acide ascorbique dans l'anoxie aiguë itérative, hypothèse d'un méchanisme d'action anti-oxydant par comparaison avec l'hydroquinone.

Some of the problems which appear during senescence, are said to be caused by cerebral oxygen deficiency and various experiments have been set up to try to imitate this particular aspect of the ageing process. We have already studied the action of many drugs with regard to acute repeated anoxia. Our work has given us clear evidence of the activity of ascorbic acid, which delays the moment of electroencephalographic silence in rats and decreases the latent period up to the reappearance of electrical activity. In order to pinpoint the mechanism of action, we compared the influence of lysine aceto-salicylate with that of hydroquinone. Very small doses of the latter drug produce a marked effect and lead us to put forward the hypothesis that it may be anti-oxydising. However, although all the drugs which proved effective in these experiments may be grouped together (despite their varying pharmacological profiles) and described as "anabiotic" drugs, it is not possible to revert to a single mechanism of action for the group as a whole.

Activity of some drugs on the electroencephalogram of curarized rats during acute and iterative hypercapnic anoxia Hypotheses on mechanisms of action.

The present study is related to the activity of some drugs in a test of acute and iterative hypercapnic anoxia in curarized rats. The interpretation of the results is based on the values of cerebral resistance to anoxia and on the duration of post-anoxic recovery and cerebral electric silence, i.e. the duration of "nul" electroencephalogram. Results obtained allow us to put forward some hypotheses about mechanisms of action. Cerebral or systemic vasodilation or vasoconstriction both seem to be excluded. Membrane activity as well as an increase in cerebral blood perfusion pressure or an impact at the level of the brain neurotransmitters may be taken into consideration. Furthermore, it is possible that extracerebral phenomena (cardiovascular, respiratory, within the blood cells for example) could interact with cerebral phenomena. It would be necessary to undertake further, more extensive studies if we wish to evaluate the potential interest of the experimental model used and the way in which the drugs proposed as treatment for cerebrovascular diseases or ageing processes work.

Cerebral metabolic and hemodynamic activities of l-eburnamonine in the anesthetized dog. A comparison with vincamine.

1. The cerebral metabolic and hemodynamic activities of l-eburnamonine (l-E) were investigated in anesthetized dogs and compared with those of vincamine (Vi). 2. The injection of l-E (2 mg/kg i.v.) increased vertebral, carotid and femoral blood flows (VBF, CBF, FBF) while corresponding resistances decreased. aortic blood flow (A0 BF) and systolic ejection volume (SEV) increased. Cerebral O2 and glucose consumption (CMRO2, CMRG) increased as did the O2 extraction coefficient and the O2 supply. This last increase was due to the simultaneous increase of VBF, hemoglobin (Hb) and arterial pO2.

Effects of some coronary vasodilator drugs on collateral hemodynamics after chronic myocardial ischemia in the anesthetized dog: appropriate or inappropriate redistribution?

These effects of dipyridamole, carbochromen, pentaerythritol tetranitrate (PETN), papaverine and ethaverine on collateral hemodynamics were investigated in anesthetized dogs 5 weeks after experimental coronary occlusion. The retrograde pressure, flow and resistance (RP, RF and RR) and the pressure, flow and resistance of the nonoccluded artery (CP, CF and CR) were measured; the pressure, flow and resistance ratios, i.e., the circulatory relationships which appeared between areas localized on both sides of the well-developed collateral channels, were calculated. Dipyridamole and carbochromen provoked an inappropriate and long-lasting redistribution to the detriment of ischemic areas: RF and RP decreased, whereas CF increased; RP/CP and RF/CF decreased; RR/CR increased. PETN provoked a redistribution in favor of ischemic areas: RF increased and RR decreased; RP/CP and RF/CF increased; RR/CR decreased. These main effects of PETN appeared after a first short period during which the changes in normal and ischemic areas were almost identical. Like PETN, papaverine and ethaverine provoked an appropriate redistribution during a second period. These results are discussed in terms of the selectivity of coronary dilator action on large or small vessels. The methodology used appears to be adequate to evaluate the activities of various drugs on a well-developed collateral coronary circulation.

Cerebral metabolic, hemodynamic and antihypoxic properties of l-eburnamonine.

l-Eburnamonine--16-oxoeburnane--assumes experimental cerebral 'oxygenator' and antihypoxic properties which appear more pronounced than those of vincamine. In anesthetized dogs, l-eburnamonine increases the cerebral oxygen supply and the cerebral oxygen consumption, without cerebral vasodilation; l-eburnamonine improves the cerebral capillary circulation, as observed on the rheoencephalogram. l-Eburnamonine inhibits the effects of hypobaric hypoxia in mice (increase of survival time) and in rats (inhibition of amnesic effects of hypoxia). l-Eburnamonine decreases the electroencephalographic consequences of the acute and iterative asphyxic anoxia in curarized rats and, by means of the protection of the cerebral cortex, inhibits the postischemic increase of thalamic somesthetic evoked potentials in curarized cats. Further studies are necessary to precise the mechanisms involved in these 'cerebral protective' properties of l-eburnamonine.

[Influence of age on the modifications of cerebral electrogenesis in the curarized rat induced by acute and repeated asphyxic anoxia]. / Influence de l'âge sur les modifications de l'électrogenèse cérébrale du rat curarisé induites par l'anoxie asphyxique aiguë et itérative.

In curarized rats, acute and iterative asphyxic anoxia produced large modifications of the cerebral electrogenesis, whose intensity could be evaluated, during each anoxia, by measurements of three parameters : the resistance to anoxia, the post-asphyxic recuperation and the cerebral electric silence. Comparative trials, carried out on animals of the same stock, showed that the cerebral sensibility towards anoxia was very different according to their age : maximal sensibility in 2 or 28 months old rats, minimal sensibility between 8 to 15 months. These results are discussed in terms of choice of animal material and specially of the age of rats used for study of the cerebral anoxia, as well as for the study of cerebral anti- hypoxic drugs.

[Modifications by 1-eburnamonine and vincamine on 2,3-diphosphoglycerate blood levels in the presence or absence of histotoxic hypoxia produced by potassium cyanide in the awake rat]. / Modifications par la 1-éburnamonine et la vincamine du taux sanguin de 2,3-diphosphoglycérate en présence ou en l'absence de l'hypoxie histotoxique provoquée par le cyanure de potassium chez le rat éveillé.

The influence of 1-éburnamonine (1-E) and vincamine (Vi) on 2,3-disphosphoglycerate (2,3-DPG) blood level was investigated in awake rats when cyanide (KCN) induced hypoxia was present or not. Used alone, KCN, 1-E and Vi (i.p. route) increased 2,3-DPG blood level. Used with KCN, 1-E or Vi produced a very more important increase of 2,3-DPG than that observed when both drugs were used alone. In all cases, the observed increase was attributed to red cells 2,3-DPG since hematocrite, red-cells count and hemoglobin level were unmodified. The results suggest that the KCN induced increase of 2,3-DPG constitutes a response to hypoxia. On the contrary, that of 1-E or Vi seems to be the result of a metabolic stimulation and could explain in part their antihypoxic properties previously described at cerebral level.

[Effect of L-eburnamonine on bronchial respiratory resistance in the anesthetized guinea pig. Comparison with vincamine]. / Action de la l'éburnamonine sur la résistance des bronches à l'insufflation chez le cobaye anesthésié. Comparaison avec la vincamine.

In anesthetized guinea pigs, i.v. injection of l-eburnamonine (l-E) induced a moderate constriction of bronchia. This bronchoconstriction was partially antagonized by atropine and brompheniramine and nearly completely inhibited by papaverine; methysergide was devoid of antagonistic activity. It was suggested that the contractive activity of l-E is complex and not specific. Similar results were obtained with vincamine (Vi) but vincamine's bronchoconstriction was not completely inhibited by papaverine. Furthermore, the bronchoconstrictor activity of Vi was more important and more durable than that of l-E.

[Study of the effect of ethaverine and papaverine on post-ischemic arrhythmias in the awake dog]. / Etude des effets de l'éthavérine et de la papavérine sur les dysrythmies post-ischémiques chez le chien éveillé.

Influence of ethaverine was compared to papaverine on the development of dysrhythmias observed in the unanesthetized dog following coronary ligation. Papaverine generally induced the reappearance of ectopic beats. In most cases, ethaverine induced the normalization of the electrocardiogram. This favourable effect of ethaverine distinguished it from papaverine; however it was moderate, transient and weaker than that of classical antidysrhythmic drugs. According to these results and those of previous experimental data, ethaverine seems to be devoid of "malignant properties".

[Study of the antihypoxic effect of eburnamonine in acute and recurrent anoxia on the cerebral electric activity in curarized rats. Comparison with vincamine]. / Etude de la protection exercée par la l-éburnamonine vis-à-vis de l'anoxie asphyxique alguë et itérative sur l'activité électrique cérébrale du rat curarisé. Comparaison avec la vincamine.

Using venous infusion (0.25 mg/kg min.), l-eburnamonine decreases the electroencephalographic modifications induced by acute asphyxic anoxia in curarized rats. This activity appears when the total dose administrated before the first asphyxia is approximatively 5 mg/kg. In such conditions, its protective activity is precocious and long lasting. In the same experimental conditions, vincamine assumes a protective activity only during a short time. The results are discussed in terms of selectivity of the method used and in terms of cerebral antihypoxic properties of l-eburnamonine.

[Comparative activity of ethaverine and papaverine on the effective refractory period of the isolated guinea pig atrium]. / Activité comparée de l'éthavérine et de la papavérine sur la période réfractaire effective de l'oreillette isolée de cobaye.

From lower concentrations (from 10(-7) to 10(-5) M) ethaverine reduces the maximal following frequency (MFF) of isolated guinea-pig's right atrium during its electrical driving at increasing frequencies. On the other hand, papaverine assumes a variable effect according to its concentration: increase (10(-7) M) or decrease (10(-6) M) of MFF. Modifications of MFF are related with those of atrial effective refractory period (ERP). These results show that ethaverine induces a lengthening of ERP whereas papaverine reduces or increases ERP. These observations are discussed comparatively with previous personal data on anesthetized dogs (Lacroix et al.) and with local anesthetic properties of ethaverine.

[Effects of a beta-adrenolytic and a diuretic vis-à-vis hyper-reninemia induced by isoprenaline in anesthetized dogs. Value of beta blocking-diuretic interaction]. / Effets d'un adrénolytique bêta et d'un diurétique vis-à-vis de l'hyperréninémie provoquée par l'isoprénaline chez le chien anesthésié. Intérêt de l'interaction bêta-bloquant-diurétique.

Intravenous injection of isoproterenol increases plasma renin activity (PRA) in anesthetized dogs. S. 464, a new beta adrenergic blocking agent, injected five minutes before isoproterenol, inhibits plasma renin hyperactivity. On the other hand, teclothiazide, a thiazide diuretic, induces no significant modification of the isoproterenol-induced increase of PRA. The combination of both compounds (five parts of S. 464, one part of diuretic), assumes the same inhibitory effects as S. 464 alone. These results and other experimental data (antihypertensive and diuretic activities) are discussed and explain the interest of such an association as a rational therapy of arterial hypertensive disorders.

[Action of 3-beta adrenolytics on plasma renin activity measured by radioimmunology in genetically hypertensive rats]. / Action de trois adrénolytiques bêta sur l'activité rénine plasmatique mesurée par radio-immunologie chez le rat génétiquement hypertendu.

Spontaneously hypertensive rats (SHR) have basal levels of plasma renin activity (PRA) lower than the ones observed in normal Sprague Dawley rats. Three beta blocking agents are orally administered to unanesthetized spontaneously hypertensive and normotensive rats. Propranolol and S 464 reduce PRA in spontaneously hypertensive and normotensive control rats. Pindolol do not lower PRA in normotensive rats but increases levels of PRA in spontaneously hypertensive rats. These results are discussed.