The Science Committee OF THE British Medical Association

1913 BMJ (Clinical Research Edition)  
STROPHANTHIN has a very markedly specific action upon cardiac tissue, and this is shown by the drug, when injected into an intact frog, stopping thle heart in systole, before any other organs are affected. Tlle same specific action can be demonstrated upon the isolated tissues of the frog, the heart being kiilled by concentrations that are too low to produce any effect upon other tissues.2 This selective action might be due to strophanthin entering into cllemical combination with some
more » ... with some constituent of heart muscle. The isolated hearts of frogs an(d mammals, therefore, were perfused to see if tlhe heart tissue iretained the drug; but in no case was there any certain evidence of the drug being either retained or destroyed by tlje heart; in particular it was shown that the frog's heart retained less than 0.0008 mg. of strophanthin.5 Straub had previously obtained a very simuilar result."2 No strophanthin ever could be recovered from the isolated hearts of frogs or mamumals after perfusion, but small quantities were demonstrated in the snake's lheart after perfusion witlh high concentrations of strophanthin, *but in all cases the concentration of strophanthin in the heart was much lower than that in the -perfusion fluid.5 There is therefore no evidence of any specific absorption of strophanthin by cardiac tissue; moreover, the quantity of stroplhantliin retained in tlhe heart is so small that it appears probable, as Straub suggests, that strophanthin exerts its action upon the surface of the heart cells. Tolerance to Strolphanth in. Certain animals show a well-marked tolerance to stroplhanthin, and the isolated organs of these animals were investigated to determine the cause of this tolerance. Com'parative experiments made with atropine confirmed the conclusions of earlier workers, that tolerance to this drug was due to the power of the liver to absorb and destroy it,3 an4 the same cause has been shown to account for the tolerance of certain animals to nicotine (Dixon) and morpliine (Faust). Tlie rat and the grass snake were found to slhow a natural tolerance to stroplhanthin, but the organs of these animals had no power either to absorb or to destroy the drug.5 Hatcher9 also showed that the intact rat, wlhen given strophanthin, excreted the bulk of it unaltered. Gunn8 found that the isolated heart *of the rat showed a well-marked tolerance to strophanthin, and the writer found the same with the isolated heart of the grass snalie.6 The tolerance to strophanthin appears therefore to be of the nature of a tissue immunity, for the tissues upOln whichl the drug acts are, in tolerant animals, less susceptible to the action of the drug. This variety of tolerance is rare, for in most cases tolerance is due to dlefensive mechanisms, wllich prevent tlle drug from reacbing the tissues upon which it acts, and in such cases these tissues upon whicll the drug acts are equally susceptible in tolerant and non-tolerant animals. The action of stroplhanthini, thprefore, is extremely specific, for it acts only on cardiac tissue, and the intensity of its action upon this tissue varies greatly in different animals. It has also been sliown that little, if any, of the druLg enters the heart cells, and that therefore it probably acts upon the surface of the cells. The Relation between the Action of Strop hant hin and the Action of Certain Ion7s Uvlon the Heart. The action of stroplianthlin was found to show a reseniblance to the action of alkalis upon the heart. C -The snake's heart was more tolerant than the frog's heart to strophanthin, and also to the action of acids and alkalis,6 but both hearts were affected equally by other systole-producing agencies (barium and saponin). Moreover, the action of strophanthin upon the frog's heart was found to resemble that of alkali in many respects. Therefore the effect of alterations in the ionic content of Ringer's fluid upon the frog's lheart was investigated in order to compare these with tlle effect produced by strophanthin. Action of Ions upon t7ie Frog's Heart. The following summary is based upon the work of Mines," and on certain unpublished results obtained by the writer. The heart's activities can be considered muost conveniently under the two aspects-the conduction of excitation and the contractile process; and both of these processes are nearly at an optimum in a fresh heart perfused witlh normal Ringer. Botlh the rate of conduction and the rate and force of contraction are reduced by the following changes-namely, an increase in the acidity, or in the potassium or tlle sodium content of Ringer, or, by a decrease in the calciunm content; and tllese may be termed depressant changes. The reverse chanigesnamely, increase in the alkalinity, or a decrease in the potassium or sodium content, or an increase in tlle calcium content of Ringer-may be termed stimulant changes; they produce, however, little beneficial effect either upon the rate of conduction or the force of contraction in the fresh heart. Wheni a heart was exhausted by prolonged perfusion with Ringer (hypodynamic heart), then stimulant changes produced a well-marked increase in the force of contraction, but did not improve the rate of conduction, although this was greatly below the normal in the hypodynamic heart. The depressant clhanges impaired both the rate of conduction and the -force of contraction more markedly in the hypodynamic than in the fresh heart. The difference in the action of ions upon conduction and contraction is of interest, and Mines has shown that a lack of calcium diminishes the force of contraction of the heart much more rapidly than the rate of conduction of the electrical wave of excitation; he concludes that the two processes may vary independently, and that the function of calcium is much -more intimately associated with the contractile process than with the process of conduction. The cause of the hypodynamic state next was investigated, and it was found that the heart during perfusion lost a lipoid-like substance, and that the addition of lipoids, or soaps of the higher fatty acids, produced a very marked beneficial effect upon both the rate of conduction and the force of contraction in the hypodynamic heart. From tllese facts it was concluded that the hypodynamic state was due to a loss of lipoids, and that the activity of the heart was dependent upon the presence of calcium and lipoid, probably in the form of an insoluble compound, at thle surface of the heart cells. Action of Strophanthin. The action of strophanthin upon the heart is represented by Figs. 1 and 2 (p. 898). The action can be divided into two stages-a first or tLerapeutic stage, in which the force of contraction of the auricle, and to a less extent that of the ventricle, are increased, and a second or toxic stage, in wlhiclh tlle force of contraction is diminished, the rate of conduction is impaired, and tlhe diastolic relaxation is imperfect. Tlle action of strophanthin upon the hypodynamnie heart is shown in Fig. 3 , and it will be seen that tlle increase in the force of the ventricular contraction is much greater than iin the fresh lheart; this -difference suggests a possible parallel to the difference in the action of cardiac glucosides upon the healthy heart and tlle diseased heart in mamnlals. The Action of Strolp7ianthin wvhen? the Ionic Content of Ringer is Altered. The effect of various alterations in the ionic content of Ringer upon the action of strophanthin upon the frog's heart was investigated, and it was foundthat the systolic effect was opposed by the presence of acid, or by the [27541 I
doi:10.1136/bmj.2.2754.897 fatcat:p3nb5o5b6vfzffykqzbttekmjm