Endocytosis inhibition protects the isolated guinea pig heart against ouabain toxicity

Abstract

We have tested whether toxicity and uptake of ouabain are linked phenomena in isolated guinea-pig heart. We perfused toxic dose of either ouabain, dihydroouabain (hydrophilic cardiac steroids), ouabagenin or digitoxin (hydrophobic steroids) in conditions of endocytosis inhibited. We used two schemes of inhibition of endocytosis. First, we cooled the heart at 0–4 ° C and exposed it 60 min to either 1 × 10 −6 M ouabain or 3 × 10 −7 M digitoxin. Upon rewarming, the heart exposed to ouabain relaxed with a shorter time constant than those exposed to digitoxin. Second, we perfused four receptor mediated endocytosis (RME) inhibitors at the same time that the cardiac glycosides. RME inhibitors significantly delayed the cardiac arrest caused by ouabain and dihydroouabain but they did not modify the toxicity of 3 × 10 −7 M digitoxin or 5 × 10 −6 M ouabagenin. None of RME inhibitors modified the toxicity of 0.5 mM K + or zero Na saline solution. We suggest that the protection against ouabain toxicity brought by endocytosis inhibition, is related to the Na-pump recycling. We infer that besides the sarcolemmal exposed Na-pumps, the intracellular Na-pumps pool may be of importance for the pharmacological effects of digitalis steroids.