Abstract
Acetazolamide (AZ) is a carbonic anhydrase inhibitor with diuretic actions at the proximal tubule. Clinical use of AZ is limited, in part, because of the urinary potassium loss and decrease of renal hemodynamic function that accompanies the drug. There is recent interest in A1 adenosine receptor (A1AR) antagonists, a novel class of diuretic agents that do not cause loss of potassium or tubuloglomerular feedback- (TGF) mediated reductions of renal hemodynamics. We tested whether the A1AR antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) could attenuate the adverse effects normally associated with use of AZ. Renal blood flow (RBF) and urine output were measured during two consecutive 40-min periods in anesthetized rats. In the first period, vehicle or DPCPX was infused. DPCPX alone increased urine output and sodium excretion but did not significantly alter potassium output or RBF. In the second period, the initial infusion of vehicle or DPCPX was continued, and either AZ or its vehicle was administered. AZ alone increased urinary excretion of both sodium and potassium and decreased RBF. DPCPX significantly attenuated the AZ-induced increase of potassium excretion by 50% but did not blunt the renal hemodynamic response to AZ. In a separate study, angiotensin II type 1 (AT1) receptor blockade also failed to blunt the renal hemodynamic response to AZ. In summary, A1AR antagonists may be useful diuretic agents alone or in combination with other conventional diuretic agents. The decrease of RBF that occurred in response to carbonic anhydrase inhibition was not attenuated by either A1AR blockade or AT1 receptor blockade and does not seem to be mediated by a TGF-dependent mechanism.
Footnotes
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Financial support was provided in part by grants from the National Institutes of Health (HL074852) and the American Heart Association (0365380).
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A portion of this work was presented as a poster at the 2004 Renal Week Conference of the American Society of Nephrology; 2004 October 27-November 1; St. Louis, MO.
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doi:10.1124/jpet.105.091462.
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ABBREVIATIONS: GFR, glomerular filtration rate; RBF, renal blood flow; CAI, carbonic anhydrase inhibitor; PT, proximal tubule; TGF, tubuloglomerular feedback; A1AR, A1 adenosine receptor; MABP, mean arterial blood pressure; DPCPX, 1,3-dipropyl-8-cyclopentylxanthine (DP); DMSO, dimethylsulfoxide; Vh, vehicle; AZ, acetazolamide; AT1 receptor, angiotensin II type 1 receptor; ANGII, angiotensin II; ARB, angiotensin AT1 receptor blocker; L158809, 5,7-dimethyl-2-ethyl-3-[[2′-(1H-tetrazol-5yl)[1,1′]-biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine; UV, urine excretion rate; UNaV, urinary excretion rate of sodium; UKV, urinary excretion rate of potassium; ANOVA, analysis of variance; RAS, reninangiotensin system.
- Received June 22, 2005.
- Accepted November 7, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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