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.
Johanson
C E
CE
Department of Clinical Neurosciences, Brown University/Rhode Island Hospital, Providence 02903.
Palm
D E
DE
Dyas
M L
ML
Knuckey
N W
NW
D000086:Acetazolamide / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002552:Cerebral Ventricles / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D002831:Choroid Plexus / Q000187:drug effects / Q000378:metabolism; D002946:Cisterna Magna; D004976:Ethacrynic Acid / Q000494:pharmacology*; D005665:Furosemide / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D002712:Chlorides; D005665:Furosemide; D004976:Ethacrynic Acid; D000086:Acetazolamide