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 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.