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Subcellular actions and potential adverse cardiac effects of the cardiotonic ionophore monensin
Abstract:
Monensin concentrations between 0.5 and 30 microM produced dose-dependent positive inotropy when administered to normal, electrically driven 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 Ca++ concentrations. Monensin (17 nM, 1.7 or 170 microM) did not inhibit canine myocardial Na+mK+-adenosine triphosphatase activity. When administered to mitochondria isolated from normal rabbit hearts, monensin concentrations greater than 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 microM 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.
Insights
Monensin enhances heart muscle contraction at therapeutic doses but can cause severe issues when combined with other drugs, impacting cardiac function and mitochondria.
Area of Science:
- Cardiology
- Biochemistry
- Pharmacology
Background:
- Monensin is an ionophore with known effects on cellular ion transport.
- Its impact on cardiac function and mitochondrial respiration requires detailed investigation.
Purpose of the Study:
- To investigate the effects of monensin on cardiac contractility and cellular ion balance.
- To assess the impact of monensin on mitochondrial function and its interaction with other cardiac drugs.
Main Methods:
- Electrically driven rabbit left atria were used to study monensin's inotropic effects.
- Canine myocardial Na+mK+-adenosine triphosphatase activity was measured.
- Isolated rabbit heart mitochondria were used to assess monensin's effects on respiration.
Main Results:
- Monensin (0.5–30 microM) produced dose-dependent positive inotropy in rabbit atria without contracture.
- Combining monensin with low-dose ouabain led to contracture or irregular responses, suggesting intracellular Na+ and Ca++ overload.
- Monensin ( >10 nM) inhibited ADP-stimulated mitochondrial respiration and respiratory control ratios, with significant effects at 1 microM.
Conclusions:
- Monensin increases cardiac contractility at concentrations that do not cause toxicity in intact atrial tissue.
- Monensin's interaction with ouabain highlights potential risks of combined drug use due to ion overload.
- Monensin significantly impairs mitochondrial respiration, suggesting a potential mechanism for cardiac dysfunction at higher concentrations.