Inhibition of Incorporation of Leucine into Myocardial Proteins of the Rat by Antiarrhythmic Agents

Abstract

Incorporation of tritiated leucine into myocardial proteins was inhibited at low concentration by quinidine, procaine amide, and diphenylhydantoin, but not by lidocaine or propranolol. This inhibition could be demonstrated in vitro and when the animals were treated with these agents. The relationship between this finding and myocardial depression produced by these antiarrhythmic agents is not known but may reside in general depression of cellular metabolism and protein synthesis or in inhibition of synthesis of a specific membrane carrier protein. ADDITIONAL KEY WORDSquinidine procaine amide propranolol diphenylhydantoin protein synthesis lidocaine actomyosin tritium• In an earlier communication, we described the inhibition by emetine hydrochloride of the incorporation of tritiated leucine into myocardial proteins (1). Emetine was studied because of reported cardiac toxicity with myocardial depression and because evidence for inhibition of protein synthesis by the alkaloid in cell cultures, plants, and yeast had previously been presented by Grollman (2). In our work with emetine, we were able to develop an in-vitro assay system for quantifying the incorporation of isotopic leucine into the soluble proteins and actomyosin of rat heart. With this system we have now been able to test the effects of other pharmacologic agents useful in the therapy of cardiac arrhythmias and also reported to depress myocardial function and the conduction system. This investigation was supported by grants from the San Antonio (Texas) Heart Association and the Westchester (New York) Heart Association. Part of this work was done while Dr. Beller was a Clinical Science Fellow of the New York Heart Association.Received July 7, 1969. Accepted for publication August 21, 1969.The agents selected for this study were quinidine sulfate, procaine amide hydrochloride, lidocaine hydrochloride, diphenylhydantoin sodium, and propranolol hydrochloride. Results of this study indicate that of these, quinidine, procaine amide, and diphenylhydantoin inhibit the incorporation of isotopically labeled leucine into cardiac proteins both in vitro and in vivo, whereas lidocaine and propranolol do not. Methods and MaterialsA detailed description of the methods employed in this study has been published (1). Rat hearts were exposed in vitro to each agent by incubating increasing concentrations of each drug in 0.1 ml of deionized water or the appropriate solvent with uniform particles of rat myocardium prepared from Sprague-Dawley rats weighing 100 to 150 g. These particles were suspended in 9.8 ml of minimal essential tissue culture medium (3) prepared without leucine and incubated at 39°C for 15 minutes. Fifty fjic of 3 H-L-leucine in 0.1 ml of 0.025N HC1 (specific activity 5 c/mM) was then added to each flask with the same pipette, and the incubation was continued for 2 hours. The myocardial tissue was then homogenized, and proteins soluble in low ionic strength were extracted in phosphate buffer pH 7.4, containing 0.1M KC1. From the tissue residues, ac...

Protein Synthesis in the Myocardiopathy and Muscular Dystrophy of the Syrian Hamster

“…Immediately after decapitation the heart, diaphragm and biceps femoris were removed and placed in ice-cold 0.1 M KCl, pH 7.4 (Beller, 1968;Beller & Mongillo, 1969) which was gassed with 95% 0, and 5% CO,. Heart muscle slices, hemidiaphragms and biceps femoris muscle strips were found to give the best results of several tissue preparations tested.…”