SUBCELLULAR ACTIONS AND POTENTIAL ADVERSE CARDIAC EFFECTS OF THE CARDIOTONIC IONOPHORE MONENSIN

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Abstract
Monensin concentrations between 0.5 and 30 .mu.M produced dose-dependent positive inotropy when administered to electrically driven normal rabbit left atria. These doses did not produce contracture. When monensin was combined with very low concentrations of ouabain (10 or 50 nM), irreversible contracture, irregular responses to electrical stimulation, or both, occurred in a significant number of atria treated with both drugs. This was apparently due to intracellular Na+ overload produced by both drugs, with secondary elevations of intracellular Ca2+ concentrations. Monensin (17 nM, 1.7 or 170 .mu.M) did not inhibit canine myocardial Na+,K+-ATPase activity. When administered to mitochondria isolated from normal rabbit hearts, monensin concentrations > 10 nM significantly depressed ADP-stimulated (State 3) respiratory rates and calculated respiratory control ratios. Maximum inhibition of the respiratory control ratio (85% decrease) occurred with monensin concentrations of 1 .mu.M or more. These concentrations also significantly decreased calculated ADP:0 ratios. The data show that monensin concentrations required to increase contractility of isolated myocardium can produce marked inhibitory effects on isolated mitochondria, but apparently, do not do so when the drug is administered to intact, normal cardiac tissue.