Microdialysis analysis of effects of loop diuretics and acetazolamide on chloride transport from blood to CSF

With the hypothesis that the NaCl cotransporter in mammalian choroid plexus (CP) has a role in CSF formation, we postulated that loop diuretic agents would curtail transport of Cl from blood to CSF. Microdialysis in the cisterna magna of Sprague-Dawley rats was used to assess the ability of furosemide and ethacrynic acid (i.e. loop agents that interfere directly with cotransport) to inhibit 36Cl transport from blood to CSF over a 3-h period. Cl uptake by CSF was quantified as % volume of distribution (Vd) of 36Cl, i.e. 100 x cpm/g CSF divided by cpm/ml plasma. Uptake curves of Vd vs. time were constructed for the various treatments; then, to compare drug effects, the curves were analyzed for: (i) the early slope of uptake (Kin), (ii) the steady-state value for Vd, and (iii) the area-under-curve (AUC). Assessment of the curve parameters collectively revealed that at 5 mg/kg, both furosemide (FUR) and ethacrynic acid (EA) reduced Cl penetration into CSF by one quarter; at 50 mg/kg, these loop agents decreased Cl uptake by about a third. On the other hand, 50 mg/kg of the carbonic anhydrase inhibitor, acetazolamide, reduced Cl uptake into CSF by 55-60%. Thus, NaCl cotransport inhibitors maximally reduced Cl transport in the rat by about 35%; this inhibition was less extensive than that brought about by acetazolamide, which interferes with CSF secretion by a different mechanism.