ENDOCYTOSIS INHIBITION PROTECTS THE ISOLATED GUINEA-PIG HEART AGAINSTOUABAIN TOXICITY

We have tested whether toxicity and uptake of ouabain are linked pheno mena in isolated guinea-pig heart. We perfused toxic dose of either ou abain, dihydroouabain (hydrophilic cardiac steroids), ouabagenin or di gitoxin (hydrophobic steroids) in conditions of endocytosis inhibited. We used two schemes of inhibition of endocytosis First, we cooled the heart at 0-4 degrees C and exposed it 60 min to either 1 X 10(-6) M o uabain or 3 X 10(-7) M digitoxin. Upon rewarming, the heart exposed to ouabain relaxed with a shorter time constant than those exposed to di gitoxin. Second, we perfused four receptor mediated endocytosis (RME) inhibitors at the same rime that the cardiac glycosides. RME inhibitor s significantly delayed the cardiac arrest caused by ouabain and dihyd roouabain but they did not modify the toxicity of 3 X 10(-7) M digitox in or 5 X 10(-6) M ouabagenin. None of RME inhibitors modified the tox icity of 0.5 mM K+ or zero Na+ saline solution. We suggest that the pr otection against ouabain toxicity brought by endocytosis inhibition, i s related to the Na-pump recycling. We infer that besides the sarcolem mal exposed Na-pumps, the intracellular Na-pumps pool may be of import ance for the pharmacological effects of digitalis steroids.