STUDIES ON VERATRUM ALKALOIDS XXVI. COMPARISON OF THE CARDIAC ACTION OF VARIOUS TERTIARY AMINE ESTER ALKALOIDS

¹ Department of Pharmacology, Harvard Medical School, Boston, Massachusetts

When administered by continuous infusion into the dog heart-lung preparation, the veracevine, zygadenine, germine and protoverine ester alkaloids studied produced effects qualitatively similar to those reported for the cardiac glycosides. A therapeutic action on cardiac contractility was first noted; this was followed by the onset of cardiac irregularities terminating in ventricular fibrillation. The character of the irregularities produced varied with the number and nature of the acids as well as with the nature of the alkamine. Sinus tachycardia was the characteristic irregularity with cevadine while veratridine and the other closely related zygadenine esters produced electrical alternation and 2:1 heart block. The germine and protoverine esters, on the other hand, evoked ventricular premature contractions with bigeminal rhythm and ventricular tachycardia. Germidine, a diester of germine, possesses characteristics of both groups in that it produced first an electrical alternation followed by bigeminal rhythm. The negative chronotropic effect of these alkaloids, if present, is of the order of less than ten per cent. This makes it improbable that the marked bradycardia seen following their administration in the intact animal has any appreciable direct cardiac component. A significant relationship between lethal dose and rate of infusion, established for the cardiac glycosides, was observed only for veratridine and veratroylzygadenine. A significant inverse relationship between lethal dose and average heart rate, not apparent with the cardiac glycosides, was established for veratridine and vanilloylzygadenine. With the exception of cevadine, for which the minimal lethal dose was about 200 micromol./kgm., the minimal lethal doses were in the range of 1 to 30 micromol./kgm. This is of the same order reported for the cardiac glycosides. Highest molar potency was found in the tri- and tetraesters. The therapeutic ranges for some of the veratrum alkaloids studied were three to four times greater than those reported for various cardiac glycosides. However, the variability from experiment to experiment with the same alkaloid, as well as the variability between different alkaloids, was much greater than with the cardiac glycosides.