Mechanism underlying hypokalemia induced by trimethyltin chloride: Inhibition of H+/K+-ATPase in renal intercalated cells

Trimethyltin chloride (TMT), a byproduct of plastic stabilizers, has caused 67 poisoning accidents in the world; more than 98% (1814/1849) of the affected patients since 1998 have been in China. As a long-established toxic chemical. TMT severely affects the limbic system and the cerebellum; however, its relationship with hypokalemia, a condition observed in the majority of the cases in the last decade, remains elusive. To understand the mechanism underlying hypokalemia induced by TMT, Sprague-Dawley (SD) rats were administered TMT to determine the relationship between H+/K+-ATPase activity and the blood and urine K+ concentration and pH, respectively. H+/K+-ATPase protein and mRNA were observed too. In vitro changes to intracellular pH, K+ channels in renal cells were measured. The results showed that TMT increased potassium leakage from the kidney, raised urine pH, and inhibited H+/K+-ATPase activity both in vitro and in vivo. In the tested animals,H+/K+-ATPase activity was positively correlated with the decrease of plasma K+ and blood pH but was negatively correlated with the increase of urine K+ and urine pH (P< 0.01), while TMT did not change the expression of H+/K+-ATPase protein and mRNA. TMT decreased intracellular pH and opened K+ channels in renal intercalated cells. Our findings suggest TMT can directly inhibit the activity of H+/K+-ATPases in renal intercalated cells, reducing urine K+ reabsorption and inducing hypokalemia. (C) 2010 Elsevier Ireland Ltd. All rights reserved.