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

Abstract

Chloroquine induces diuresis, natriuresis, and an increase in glomerular filtration rate (GFR) in the rat. These responses are modified in rats with analgesic nephropathy induced by longterm paracetamol (acetaminophen) administration. Here, the effects of acute paracetamol treatment on renal function and the response to chloroquine are reported. Under intraval anesthesia (100 mg kg Ϫ1 ) male Sprague-Dawley rats (n ϭ 6/group) were infused with 2.5% dextrose for 3 h. After a control hour, they received either vehicle, chloroquine (0.04 mg h Ϫ1 ), paracetamol (priming dose of 210 mg kg Ϫ1 followed by 110 mg kg Ϫ1 h Ϫ1 ) or chloroquine and paracetamol over the next hour. Compared with vehicle, chloroquine infusion resulted in increases in GFR (2.4 Ϯ 0.3 versus 4.8 Ϯ 0.6 ml min Ϫ1 ), urine flow (4.2 Ϯ 0.3 versus 10.4 Ϯ 0.7 ml h Ϫ1 ), and sodium excretion (47.7 Ϯ 4.1 versus 171.2 Ϯ 18.6 mol h Ϫ1 ) and a reduction in urine osmolality (223.2 Ϯ 5.9 versus 121.7 Ϯ 23.9 mOsM kg Ϫ1 ). Paracetamol reduced sodium excretion but had no effect on urine flow, GFR, or urine osmolality. When combined, paracetamol blocked the chloroquine-induced diuresis (3.9 Ϯ 0.7 ml h Ϫ1 ) and natriuresis (22.6 Ϯ 8.5 mol h Ϫ1 ), attenuated the increase in glomerular filtration rate (3.5 Ϯ 0.2 ml min Ϫ1 ), and raised urine osmolality (280.0 Ϯ 22.8 mOsM kg Ϫ1 ). The differing effects of acute and long-term paracetamol treatment on basal and chloroquine-mediated renal function suggest that the length of prior exposure to paracetamol, and thus the presence of analgesic nephropathy, is an important determinant of the renal response to chloroquine.

Synthesis and Pharmacological Characterization of Novel Glucagon-like Peptide-2 (GLP-2) Analogues with Low Systemic Clearance

“…We thought it was unlikely that these substitutions would render the peptides highly resistant to proteolysis as point modifications in positions 11 and/or 16 would not be able to prevent enzymatic attack at multiple and very distant potential proteolysis sites, if proteolysis is actually the reason for the high clearance of 1 and 2 (but see the discussion on helicity later). The value of the residual clearance in rats for analogues 72 – 86, < 0.3 mL/min/kg, is much lower than the glomerular filtration rate in these animals, about 9 mL/min/kg . Since the MW of these peptides (<4100) is not sufficiently high to slow down glomerular filtration per se , the low total clearance pointed at a reduced free fraction of the peptides in plasma and to plasma protein binding (PPB) as the cause of their low clearance.…”

“…The value of the residual clearance in rats for analogues 72−86, < 0.3 mL/min/kg, is much lower than the glomerular filtration rate in these animals, about 9 mL/min/ kg. 59 Since the MW of these peptides (<4100) is not sufficiently high to slow down glomerular filtration per se, 60 the low total clearance pointed at a reduced free fraction of the peptides in plasma and to plasma protein binding (PPB) as the cause of their low clearance. We therefore tested selected analogues with low CL for PPB in rat plasma using an ultracentrifugation method (Table 7).…”

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

“…However, a number of marked functional changes were induced. Most notably a reduction in concentrating ability was observed which contrasts with the effects of acute paracetamol infusion in which urine osmolality increased (Ahmed et al, 2002). These observations suggest that the altered renal function displayed by the paracetamol-treated rats reflects subclinical nephropathy rather than an acute action of paracetamol remaining in the circulation.…”