The primary goal of this project is the treatment of experimental hydrocephalus by the constant infusion of a pharmacological agents (S) into the cerebral ventricles. This project will evluate new halogenated cardiotonic steroids as to the magnitude and reversibility of their inhibitory effect on choroid plexus Na+, K+ activated (transport) ATPase as well as on the intraventricular accretion of cerebrospinal fluid in the normal and abnormal animal. The in vitro effect of inhibitors will be measured as % inhibition of released Pi from ATP added to rabbit and dog choroid plexus. The dose-response relationship and the side effect of these agents and other non-ATPase binding secretory inhibitors (such as distal loop diuretics and agents effecting cellular respiration) will be studied acutely in dog using a ventriculo-cisternal perfusion system. By means of dye-dilution (Dextran) in transit through the ventricular system, the effect of various concentrations of inhibitors will be measured. The potential transient cardiovascular effects (hypertension and cardiac arrhythmias) will be evaluated and treated as required with alpha and beta receptor blocking agents. The best therapeutic agents (lowest concentration with minimal side effects) will be used to treat hydrocephalus in the chronic awake dog model by means of an implanted infusion system. This system, in conscious unrestrained hydrocephalic dogs, will infuse the inhibitors(s) at a concentration and rate based on prior acute in vivo and in vitro experiments. The proposed studies are significant because they may lead to a useful means of treating a common human condition with inherently lower mortality and morbidity than now exists by any now available surgical treatment scheme.
