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Effect of calcium entry blockers in models of brain hypoxia

  • A. Wauquier
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 40)

Summary

The present paper summarizes experimental evidence on the protection against brain hypoxia using calcium entry blockers in a variety of animal models. It appears that they are not a homogeneous class of pharmacological substances. This is partly due to the fact that the models used do not measure one particular causal factor related to hypoxia. The reasons for the final brain hypoxia are often multiple, originating from ischaemia (cardiovascular effects), respiratory problems, hypothermia, etc. However, the final outcome, independent of the original causes might be cellular toxicity by transmembrane calcium influx beyond physiological limits. Further studies are required to determine whether the protective action of calcium entry blockers resides primarily in their action on cerebral vessels and/or neurons. In view of the postulated role for calcium entry as the trigger of the events leading to cellular toxicity, it might be that calcium entry blockers will become important tools in preventing neuronal damage. Further emphasis will have to be given to physiologically controlled models of hypoxia and studies combining various techniques, including direct measures of ion fluxes through the membrane in order to achieve the final goal: brain protection.

Keywords

Hypobaric Hypoxia Spreading Depression Brain Hypoxia Calcium Entry Blocker Retention Deficit 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Résumé

Le présent dossier résume les preuves expérimentales sur la protection contre l’hypoxie cérébrale, basée sur l’utilisation de bloqueurs de l’entrée de calcium chez une série d’animaux-modèles. Il en ressort que ceux-ci ne constituent pas une classe homogène de substances pharmacologiques. Ceci est dû en partie au fait que les modèles utilisés ne mesurent pas un facteur causal particulier lié à l’hypoxie. Les causes de l’hypoxie cérébrale engendrée sont souvent multiples, trouvant leur source dans l’ischémie (effets cardio-vasculaires), les problèmes respiratoires, l’hypothermie, etc. Cependant, le résultat final, indépendamment des causes initiales, peut être une toxicité cellulaire due à un influx de calcium transmembraneux passant outre les limites physiologiques. De nouvelles études sont nécessaires afin de préciser si l’action protectrice des bloqueurs d’entrée de calcium réside principalement dans leur action sur les vaisseaux cérébraux et/ou au niveau neuronal. Compte tenu que le rôle admis de l’entrée de calcium consiste à déclencher les circonstances conduisant à une toxicité cellulaire, il se pourrait que les bloqueurs de l’entrée de calcium deviennent d’importants instruments dans la prévention de la détérioration neuronale. Il faudra mettre l’accent sur les modèles d’hypoxie contrôlés physiologiquement et sur des études combinant diverses techniques englobant des mesures directes des flux d’ions au niveau de la membrane afin d’atteindre le but final, à savoir une protection cérébrale.

Resumen

Se resume la evidencia experimental, en cuanto a la protección contra hipoxia del cerebro, usando inhibidores de la penetración intracelular de Ca2+, en una variedad de modelos animales. Estas substancias farmacológicas no parecen ser una clase homogénea. Esto es parcialmente debido al hecho de que los modelos empleados no dependen de un solo y específico factor causante de hipoxia. Las razones de la hipoxia cerebral final son a menudo múltiples, teniendo su origen en isquemia (efectos cardiovasculares) problemas respiratorios, hipotermia etc. Sin embargo, el resultado final, independiente de las causas originales, puede ser toxicidad celular por entrada transmembranosa de calcio más allá de los límites fisiológicos. Se requieren más estudios para saber si la acción protectora de los inhibidores de la penetración intracelular de Ca2+ reside esencialmente en su acción en vasos cerebrales y/o al nivel de las neuronas. Dado el papel supuesto que juega el acceso de calcio como provocador de los acontecimientos que conducen a la toxicidad celular, podría ser que los inhibidores de la-penetración intracelular del calcio se hicieran importantes instrumentos que impiden la lésión neurónica. Se necesitará más insistencia en modelos de hipoxia controlados fisiológicamente y estudios que combinan técnicas distintas, incluyendo directas medidas de flujos de iones a nivel de la membrana para poder alcanzar el objetivo final: la protección del cerebro.

Zusammenfassung

Die Studie faßt das experimentelle Beweismaterial über den Schutz vor Gehirnhypoxie, das nach Gabe von Kalziumeinstromhemmern in verschiedenen Tiermodellen gesammelt wurde, zusammen. Die Arzneimittelgruppe ist in dieser Hinsicht nicht homogen. Dies ist teilweise darauf zurückzuführen, daß die verwendeten Modelle sich nicht auf die Messung des gleichen hypoxieauslösenden Faktors beziehen. Die Gründe für die resultierende Hirnhypoxie sind öfters vielfach: Ischämie (kardiovaskuläre Wirkungen), Atemschwierigkeiten, Hypothermie usw. Unabhängig von den auslösenden Ursachen kann jedoch das Endergebnis in einer durch Kalziumeinstrom hervorgerufenen Zelltoxizität bestehen, die eine umfassendere als nur physiologische Auswirkung hat. Weitere Untersuchungen müssen zeigen, ob die Schutzwirkung von Kalziumeinstromhemmern hauptsächlich auf die Beeinflussung der Hirngefäße und/oder des Neuronalbereichs zurückzuführen ist. Im Hinblick auf die für Kalzium postulierte Rolle als Auslöser von Ereignissen, die zu Zelltoxizität führen, ist anzunehmen, daß Kalziumeinstromhemmer bei der Vorbeugung von Neuronalschäden in Zukunft eine wichtige Schutzrolle spielen werden. Um das Endziel, d.h. den Hirnschutz zu erreichen, sind weitere, physiologisch kontrollierte Hypoxiemodelle ebenso wie Versuche, in denen verschiedene Techniken, u.a. solche, welche die lonenströme auf Membranebene direkt beeinflussen, kombiniert erforderlich.

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© Martinus Nijhoff Publishers, The Hague 1984

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  • A. Wauquier

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