STUDIES ON VERATRUM ALKALOIDS. XLI. THE ACTION OF SOME ESTERS OF PROTOVERINE WITH ACETIC ACID ON THE SARTORIUS MUSCLE OF THE FROG

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

The effects of protoverine, protoveratrine and several semisynthetic esters of protoverine on isometric tension development and on bioelectric behavior of isolated sartorius muscles of the frog were studied. The dissected muscles were suspended in oxygenated physiologic salt solution and stimulated directly with supramaximal single shocks or short tetani. Protoveratrine produced a transient veratrinic response and a rapid loss of excitability. Protoverine and protoverine monoacetate did not alter the twitch in concentrations depressing tetanic tension development. Protoverine diacetate (PDA), protoverine acetonide diacetate (PADA), protoverine triacetate (PTA) and protoverine acetonide triacetate (PATA) caused a veratrinic effect of the "brief" type, i.e., an increase in tension with moderate prolongation of the contraction after a single stimulation. Protoverine pentaacetate (PPA), protoverine isopentaacetate (PisoPA) and protoverine hexaacetate (PHA) produced a prolonged veratrinic effect similar to that seen typically with veratridine; i.e., the twitch-like initial contraction was followed by a prolonged aftercontraction. With PDA, PTA, PPA, PisoPA and PHA under optimal conditions, tetanic tension was neither enhanced nor depressed by the alkaloids. The increased tension development following a single stimulation was accompanied by repetitive electric activity. The effects occurred equally in normal muscles, and in the presence of blocking concentrations of d-tubocurarine and in chronically denervated muscles. The basic action of the protoverine ester alkaloids on skeletal muscle of the frog is an alteration of the muscle membrane leading to repetitive firing following a single stimulation. Elevation of the external calcium concentration decreased and eventually abolished the veratrinic effect.