Renal Function in a Rat Model of Analgesic Nephropathy: Effect of Chloroquine

Abstract

The antimalaria drug chloroquine is often taken against a background of analgesic nephropathy caused by nonsteroidal antiinflammatory 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. SpragueDawley rats (n ϭ 6 -8/group) were treated with paracetamol (500 mg kg Ϫ1 day Ϫ1 ) for 30 days in drinking water to induce analgesic nephropathy; control rats received normal tap water. Under intraval anesthesia (100 mg kg Ϫ1 ) 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 Ϫ1 ), N -nitro-L-arginine methyl ester (L-NAME, nitric-oxide synthase inhibitor, 60 g kg Ϫ1 h Ϫ1 ) 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 Ͻ 0.05), sodium excretion (p Ͻ 0.001), and urine osmolality (p Ͻ 0.001), but no change in urine flow rate compared with untreated animals. Chloroquine administration in paracetamol treated rats induced a significant reduction (p Ͻ 0.05) in urine flow rate and a significant increase in plasma vasopressin (p Ͻ 0.001). These effects were blocked by coadministration of L-NAME and thus seem to be mediated by a pathway involving nitric oxide. However, these responses contrast 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.

Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury

“…Chloroquine has also been reported to interfere with ERK-mediated TNF-␣ upregulation in vitro (43), but the relative contribution of this pathway to sepsis in vivo is not known. Chloroquine also may have direct renal effects, including increases in urine flow, sodium excretion, and glomerular filtration rate (2,3), that might contribute to protection of tubular damage induced by CLP; whether these are related to TLRs or other actions is unknown. Nevertheless, the concordance between TLR9 deficiency and chloroquine administration on almost all measured outcomes (survival, renal injury, cytokine levels) suggests that chloro- quine is functioning in this model in large part via inhibition of splenic TLR9.…”

Renal Action of Acute Chloroquine and Paracetamol Administration in the Anesthetized, Fluid-Balanced Rat

“…day Ϫ1 for 30 days (Ahmed et al, 2003b). This treatment regime did not produce gross renal histological changes associated with clinical nephropathy, such as papillary necrosis and interstitial nephritis, but it did reduce the urinary concentrating ability of the animals.…”

“…The response to chloroquine of rats with analgesic nephropathy was markedly different from that in untreated animals. The diuresis, natriuresis, and increase in GFR seen with chloroquine alone were all reversed when chloroquine was infused in rats that had previously been treated with paracetamol (Ahmed et al, 2003b). This could be attributable to either the acute inhibitory effect of paracetamol on prostaglandin synthesis (Hardman et al, 2001) or long-term loss of urine-concentrating ability arising through papillary necrosis and interstitial nephritis, which are typical of analgesic nephropathy (Henrich, 1998).…”

“…We could not distinguish between these two possible mechanisms in the previous study (Ahmed et al, 2003b), because animals continued to receive paracetamol in their drinking water up until the time that renal function was assessed. Paracetamol has a plasma half-life of 2 to 4 h, being inactivated in the liver (Hardman et al, 2001), and its excretion rate is markedly reduced by renal impairment (Prescott et al, 1989), so it is highly likely that paracetamol remained in the circulation of these animals during the measurement of their renal function.…”

“…In the same study (Ahmed et al, 2003b), we also assessed the effect of chronic paracetamol treatment on the renal actions of chloroquine. The response to chloroquine of rats with analgesic nephropathy was markedly different from that in untreated animals.…”