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

Abstract

Serine-specific reagents, anticholinesterase organophosphorus compounds like Vx provoke, in the micromolar range, digitalis-like ventricular arrhythmias of non-cholinergic origin in rodent hearts. The sensitivities of the two rat cardiac Na+,K(+)-ATPase isoforms (alpha 1 and alpha 2) to Vx (0.1-100 microM) were measured in sarcolemma vesicles. At 1 microM Vx, the inhibition of the total activity averaged 18% but never exceeded 75% with 100 microM. When the alpha 2 isoform activity was inhibited by 0.1 microM ouabain, alpha 1 was 35% inhibited by 1 microM Vx, i.e. a 16 +/- 4% inhibition of the total activity. The cardiac alpha 1 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 alpha 1, 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.