Renal Function in a Rat Model of Analgesic Nephropathy: Effect of Chloroquine MOHAMED H. AHMED, NICK ASHTON, and RICHARD J. BALMENT School of Biological Sciences, University of Manchester, Manchester, United Kingdom Received November 21, 2002; accepted December 18, 2002 ABSTRACT The antimalaria drug chloroquine is often taken against a back- ground of analgesic nephropathy caused by nonsteroidal anti- inflammatory drugs such as paracetamol (acetaminophen). Chloroquine has marked effects on the normal kidney and stimulates an increase in plasma vasopressin via nitric oxide. The aim of this study was to determine the renal action of chloroquine in a model of analgesic nephropathy. Sprague- Dawley rats (n = 6 – 8/group) were treated with paracetamol (500 mg kg -1 day -1 ) for 30 days in drinking water to induce analgesic nephropathy; control rats received normal tap water. Under intraval anesthesia (100 mg kg -1 ) rats were infused with 2.5% dextrose for 3 h to equilibrate and after a control hour they received either vehicle, chloroquine (0.04 mg h -1 ), N  - nitro-L-arginine methyl ester (L-NAME, nitric-oxide synthase in- hibitor, 60 g kg -1 h -1 ) or combined chloroquine and L-NAME over the next hour. Plasma was collected from a parallel group of animals for vasopressin radioimmunoassay. Long-term paracetamol treatment resulted in a decrease in glomerular filtration rate (p  0.05), sodium excretion (p  0.001), and urine osmolality (p  0.001), but no change in urine flow rate com- pared with untreated animals. Chloroquine administration in paracetamol treated rats induced a significant reduction (p  0.05) in urine flow rate and a significant increase in plasma vasopressin (p  0.001). These effects were blocked by coad- ministration of L-NAME and thus seem to be mediated by a pathway involving nitric oxide. However, these responses con- trast with the chloroquine-induced diuresis previously observed in untreated rats, possibly reflecting paracetamol inhibition of renal prostaglandin synthesis and consequent moderation of vasopressin’s action. Paracetamol (known as acetaminophen in the United States) is one of the most commonly used nonsteroidal anti- inflammatory drugs (NSAIDs) (Hardman et al., 2001). It is a rapid, reversible, noncompetitive inhibitor of cyclooxygenase activity and thus products of the arachidonic acid cascade. In addition to its analgesic properties, paracetamol also has direct actions on the kidney. Colletti et al. (1999) demon- strated that administration of paracetamol to dogs fed either a normal or low sodium diet (renal prostaglandin-dependent state) resulted in a decrease in renal blood flow, glomerular filtration rate (GFR), and prostaglandin E 2 (PGE 2 ) excretion. In the isolated perfused rat kidney, administration of parac- etamol resulted in a decrease in GFR and PGE 2 (Trumper et al., 1998). Similarly, in normal human volunteers treated with paracetamol for 3 days, a reduction in urinary PGE 2 and sodium excretion was observed. In addition, paracetamol in- duced a delay in the onset of diuresis after an acute water load (Prescott et al., 1989). Paracetamol also exerts acute and chronic nephrotoxic ef- fects. Acute ingestion of large doses (10 –15 g) is character- ized by necrosis and damage to the proximal tubule. How- ever, it is recognized from both clinical and experimental studies that much lower doses (500 –1000 mg) can produce renal damage, especially in patients with hepatic disease or those taking enzyme inducer drugs (carabamazepine and phenytoin) or in the malnourished (Blantz, 1996). Chronic ingestion of paracetamol results in analgesic nephropathy. This is defined as habitual ingestion of an analgesic, which after an insidious onset, leads to renal papillary necrosis and chronic interstitial nephritis with progressive renal failure (Henrich, 1998). Epidemiological studies show that long- term regular consumption of paracetamol increases the rel- ative risk of chronic renal disease to 3.2 (Sandler et al., 1989), whereas the odds ratio for end stage renal disease was 2.1 for the heaviest annual intake of paracetamol and 2.4 for cumu- lative lifetime intake of more than 5000 tablets containing paracetamol (Perneger et al., 1994). Burrell et al. (1990) found that paracetamol (380 mg kg -1 b.wt. day -1 ) and aspi- rin (230 mg kg -1 b.wt. day -1 ) given for 21 weeks to female Fischer-344 rats resulted in papillary necrosis and impaired ability to concentrate urine, although a lower dose of parac- Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.102.047233. ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; GFR, glomerular filtration rate; PGE 2 , prostaglandin E 2 ; L-NAME, N  -nitro-L- arginine methyl ester; ANOVA, analysis of variance; SNK, Student-Newman-Keuls; AVP, vasopressin; HETE, hydroxyeicosatetraenoic acid. 0022-3565/03/3051-123–130$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 305, No. 1 Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 47233/1051090 JPET 305:123–130, 2003 Printed in U.S.A. 123 at ASPET Journals on September 10, 2016 jpet.aspetjournals.org Downloaded from