An organophosphorus compound, Vx, selectively inhibits the rat cardiac Na+,K+-ATPase α1 isoform Biochemical basis of the cardiotoxicity of Vx

AbstractSerine-specific reagents, anticholinesterase organophosphorus compounds like Vx provoke, in the micromolar range, digitalis-like ventricular arrythmias of non-cholinergic origin in rodent hearts. The sensitivities of the two rat cardiac Na+,K+-ATPase isoforms (α1 and α2) to Vx (0.1–100 μM) were measured in sarcolemma vesicles. At 1 μM Vx, the inhibition of the total activity averaged 18% but never exceeded 75% with 100 μM. When the α2 isoform activity was inhibited by 0.1 μM ouabain, α1 was 35% inhibited by 1 μM Vx, i.e. a 16±4% inhibition of the total acitivity. The cardiac α1 being related to the digitalis-induced toxicity, its selective inhibition by a micromolar dose of Vx fully accounts for the cardiotoxicity of Vx. Inasmuch as Vx had no effect on the rat kidney α1, differentially inactivated the cardiac isozymes and specifically reacted with serine residues, the putative binding-site(s) of the organophosphorus compound on the Na+,K+-ATPase molecules has been considered