Cisplatinum-induced lesion of proximal tubule acidification in the rat.
Rats were given a 4- to 6-mg/kg body weight intraperitoneal injection of the antitumor drug, Cisplatin, 5-7 days prior to experiments to study tubule acidification by clearance and stationary microperfusion techniques. Cisplatin reduced the glomerular filtration rate markedly and caused a moderate degree of metabolic acidosis, but urine acidification (pH) was well maintained. Proximal tubule stationary pH and bicarbonate concentrations, as measured by pH microelectrodes, were significantly increased. The defect of proximal H+ secretion is reflected by increased acidification half-times (from 4.44 to 10.2 s) and reduced bicarbonate reabsorption to 37% of control values. H-ion back flux, measured during tubule and capillary perfusions with Ringer's bicarbonate- and CO2-free phosphate solutions, was reduced to 68% of control values. The apparent H-ion permeability was lowered from 0.79 to 0.54 cm/s. These results indicate that proximal acidification is reduced by impairment of H+ transport and not by increased transepithelial H+ shunting. Blunted acidification is compatible with a reduction in the number of Na/H exchangers in the proximal brush border and/or a decrease in the apical sodium gradient, the driving force for proximal H-ion secretion. Cortical distal tubule acidification, measured by double-barreled ion-exchange resin/PD microelectrodes, was not significantly affected by Cisplatin. This accounts for the observation that, in spite of the impaired proximal acidification, urine pH is kept within the normal range.
Lacchini
M L
ML
Department of Physiology, Instituto de Ciencias Biomedicas, University Sao Paulo, Brasil.
Lopes
A G
AG
Malnic
G
G
Giebisch
G
G
D000136:Acid-Base Equilibrium / Q000187:drug effects; D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007274:Injections, Intraperitoneal; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D008297:Male; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D014556:Urine / Q000737:chemistry
D002945:Cisplatin