Effects of sodium artesunate, a new antimalarial drug, on renal function.
BACKGROUND
Sodium artesunate is currently used in malaria treatment. Adverse effects of this drug have not been described, probably because they cannot be differentiated from malaria-related effects.


METHODS
The effects on renal function of an acute infusion of sodium artesunate (12 mg/kg body weight) were studied in the rat with clearance techniques. We also evaluate the effect of sodium artesunate on chloride lumen-bath flux (Cl Jlb) in the isolated thick ascending limb of the loop of Henle (TALH) microperfused in vitro.


RESULTS
Acute infusion of artesunate to the rat decreased inulin clearance, despite an increase in renal blood flow. These effects were associated with an increase in urinary excretion of sodium, chloride, potassium, and nitric oxide metabolites (NO(2)/NO(3)). In water-loaded animals, artesunate increased sodium and water distal delivery and decreased free water clearance (C(H(2)O)) factored for sodium and water delivery. Following hypertonic NaCl infusion, artesunate decreased free water excretion (Tc(H(2)O)) corrected by clearance of osmolarity (C(Osm)). In vitro, artesunate 10(-6) and 10(-3) mol/L added to bath solution decreased chloride lumen-bath flux in isolated rabbit TALH in a dose-dependent manner, with the threshold effect at 10(-4) mol/L. This effect was completely blocked by N(G)-nitroL-arginine-metilester (L-NAME) 5 mmol/L. Artesunate 10(-4) mol/L added to the perfusion solution did not change Cl Jlb.


CONCLUSIONS
These findings suggest that artesunate decreases glomerular filtration rate and increases renal blood flow and urinary excretion of Na, Cl, and K. These effects were due, at least in part, to the inhibition of Cl transport across cortical and medullary TALH, and were mediated by local production of nitric oxide, since it is associated with an increase in NO(2)/NO(3) urinary excretion and it is blocked by L-NAME in vitro.
Campos
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SB
Laboratório de Pesquisa Básica, LIM-12, Disciplina de Nefrologia, Faculdade de Medicina USP, São Paulo, Brazil.
Rouch
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LH
Seguro
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AC
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins; D000077332:Artesunate; D002712:Chlorides / Q000378:metabolism; D004573:Electrolytes / Q000652:urine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000502:physiology*; D007677:Kidney Function Tests; D008138:Loop of Henle / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D012717:Sesquiterpenes / Q000494:pharmacology*
D000962:Antimalarials; D037621:Artemisinins; D002712:Chlorides; D004573:Electrolytes; D004791:Enzyme Inhibitors; D012717:Sesquiterpenes; D009569:Nitric Oxide; D000077332:Artesunate; D019331:NG-Nitroarginine Methyl Ester