Combined effects of carbonic anhydrase inhibitor and adenosine A1 receptor antagonist on hemodynamic and tubular function in the kidney.
BACKGROUND
Carbonic anhydrase inhibitors (CAI) reduce proximal reabsorption, activating tubuloglomerular feedback (TGF) and reducing glomerular filtration rate (GFR). Adenosine A(1) receptors (A(1)R) mediate the TGF response and stimulate proximal reabsorption.


METHODS
Clearance and micropuncture studies were performed in Wistar rats to determine whether blockade of A(1)R (KW3902 0.3 mg/kg i.v.) would prevent CAI (benzolamide 5 mg/kg i.v.) from lowering GFR, whether CAI and KW3902 exert additive effects on sodium excretion, and to what extent such interactions depend on events in the glomerulus, proximal tubule, or distal nephron.


RESULTS
KW3902 raised GFR and prevented CAI from lowering GFR. KW3902 and CAI caused additive diuresis and natriuresis. KW3902 and CAI increased lithium clearance, but their effects were redundant. CAI increased the dependence of proximal reabsorption on active chloride transport. KW3902, alone, did likewise, but to a lesser extent than CAI. Adding KW3902 to CAI lessened the shift toward active chloride transport.


CONCLUSIONS
The data reveal that A(1)R mediate glomerular vascular resistance whether or not TGF is activated, that additive effects of CAI and KW3902 on salt excretion occur, in part, because KW3902 inhibits reabsorption downstream from the macula densa, and that KW3902 likely inhibits proximal reabsorption by interfering with apical sodium-hydrogen exchange.
Miracle
Cynthia M
CM
Division of Nephrology-Hypertension, University of California, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA. cmiracle@ucsd.edu
Rieg
Timo
T
Blantz
Roland C
RC
Vallon
Volker
V
Thomson
Scott C
SC
D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D001574:Benzolamide / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D004232:Diuretics / Q000494:pharmacology; D004357:Drug Synergism; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007684:Kidney Tubules / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology*; D008094:Lithium / Q000652:urine; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000652:urine; D014661:Vasoconstriction / Q000187:drug effects*; D014970:Xanthines / Q000494:pharmacology*
D058916:Adenosine A1 Receptor Antagonists; D002257:Carbonic Anhydrase Inhibitors; D004232:Diuretics; D014970:Xanthines; C073525:rolofylline; D008094:Lithium; D012964:Sodium; D001574:Benzolamide