PHYSIOLOGICAL ACTION OF LYCOCTONIA. BY ISAAC OTT, M.D., DEMONSTRATOR OP PHYSIOLOGY, UNIVERSITY OF PENNSYLVANIA. LYCOCTONIA and napellina were dis- tinguished as separate alkaloids from aconitia by He procured them from Aconitum lycoctonum. The specimen used by me was made by Tromms- dorf, and was a white crystalline powder. Bromine-water added to it gave a yellow precipitate, Nessler’s reagent precipitated it largely, sulphuric acid gave a colorless solution, as did also phosphoric with heat. In the succeeding experiments each cubic centimetre of our neutral solution contained a centigramme of the alkaloid in shape of acetate. Klebs made some unpublished experiments with it, and inferred that it was much less energetic than aconitia. pupil contracted, disappearance of respira- tory movements, heart beating for a very long time after the absence of every sign of life. Exp. /.—Frog. Weight, sixteen grammes; at 8.46 a.m. received .05 gramme lycoctonia sub- cutaneously; leaps away; respiratory move- ments less frequent. 8.49 a.m., complete relax- ation; pupil contracted, respiratory movement now and then. 9 a.m., death; motor nerves not irritable; heart beat forty-eight per min- ute, and was beating still an hour afterwards. Exp. ll.—Frog. Weight, 29.3 grammes; at 8.42 A.M. received subcutaneously .1 gramme of lycoctonia. 8.45 a.m., respirations less frequent; lying on abdomen; great want of co-ordination ; loss of movement in posterior extremities. 8.50 a.m., pupil contracted; occasional respiratory movement. 9.5 a.m., .1 gramme under the skin in the vicinity of the lymph-sacs. Mechanical irritation causes muscular twitchings. 9.53 a.m., death ; motor nerves irritable only with strongest currents of Dubois’s induction-apparatus with Helm- holtz’s arrangement; thrusting probe down the spine caused no movement; heart beat thirty-two per minute, and continued its move- ments for over an hour. Bucheim and Eisenmenger* made a few experiments on frogs. They saw muscular movements, convulsions, extended extremi- ties, loss of reflex action, with the presence of muscular contractility, contracted pupil, and few respirations. They used doses varying from .0015 to .005 gramme. Schroff-!* saw in two men .05 gramme of the acetate produce at first an increased frequency of pulse. In a rabbit .4 gramme by mouth produced increase of pulse and decrease of respiratory movement, with sub- sequent fall of the former. The pupil was dilated, and the movements wholly undis- turbed ; the animal recovered. The above experiments represent the action of lycoctonia, that it paralyzes the motor nerves or diminishes their irritability. In the majority of cases I found the motor nerves completely non-irritable; but in some frogs, without regard to species, and even in the same species, the motor nerves were not completely paralyzed. A similar action has been observed by Boehm on frogs with aconitia. In another rabbit .4 gramme subcutane- ously caused dilated pupil, very frequent pulse and respiration. With doses of .005 to .06 gramme subcutaneously in frogs, sensibility remained intact, the spinal cord appeared not directly affected, the motor nerves were paralyzed, muscles excitable, The heart was always beating, lycoc- tonia not being a cardiac poison in like aconitia, as the following experiment with the latter shows. * Eckhard’s Beitrage, funfter Band, zweites Heft, f Beitrag zur Kenntniss des Aconit. PHYSIOLOGICAL ACTION OF LVCOCTONIA. 2 Exp. lll.—Frog. Weight, forty-nine grammes ; received subcutaneously at 9 a.m. .025 gramme of aconitia of Menck’s in shape of acetate; leaps away; lower jaw drooping. 9.08 a.m., complete relaxation; slight move- ment on mechanical irritation. Exp. Vll.—Small rabbit received, per ju- gular, ,1 gramme of lycoctonia; at 9.43 A.M. unable to maintain an erect posture; convul- sive movements ; pupil dilating ; convulsive action of muscles about the neck; respiratory movements ceased. 9.15 a.m., death; ventricle in complete diastole, no movement in it; auricle beating now and then. It is evident that lycoctonia is a poison which kills mainly by arrest of respiratory apparatus, as cardiac movements continue after death. 9.57 A.M., death, heart beating. To study the action on the sensory nerves and spinal cord I used the method of Bernard. Exp. IV.—Frog. Weight, fifty grammes. At 9.10 a.m., received .1 gramme of lycoc- tonia, the right iliac artery and vein tied pre- viously. 9.12 a.m., diminished respiration ; want of co-ordination and power ; pupil con- tracted ; mechanical irritatio.n calls out move- ment only in leg in which supply of poison is shut off; respirations now and then. The action on the circulation was studied on rabbits. I made sixteen ex- periments. The animals were narcotized by morphia. In all other respects every- thing was conducted in the same manner as laid down in my paper on gelsemia. The pressure and pulsations are given for periods of .fifteen seconds. Circulation. 9.43 a.m., death ; motor nerves upon which the poison acted non-excitable ; gastrocnemii of either side equally irritable; heart beat thirty per minute, and pulsated over an hour afterwards. Exp. I. Rabbit. Curare ; tracheotomy ; artificial respiration ; jugular and carotid pre- pared. Time. Pulse. Pressure. A.M. 67 102 66 Lycoctonia .1 grm. 8.20.15 43 8.20.30 37 54 8.20.45 3i 46 8.21.30 48 42 8.21.45 47 44 8.59.OO So 82 Lycoctonia .1 grm, 8.59.15 46 82 9.OO.OO 33 60 9.OO.15 32 70 9.06.15 49 60 Exp. V. Frog. Weight,, thirty-nine grammes ; right iliac artery and vein ligated ; received at 9.53 a.m. .1 gramme lycoctonia subcutaneously. 9.55 a.m., loss of co-ordina- tion ; occasional respiratory movements. 10.14 a m., pupil contracted from position; pinching causes movement only in the limbs in which the access of the poison has been prohibited. 10.18 a.m., .1 gramme lycoctonia subcutane- ously. 10.40 a.m., death; sciatic nerve on left side not irritable, but irritation of its cen- tral end called out movements in right pos- terior extremity ; right and left gastrocnemius equally irritable; heart beat twenty-four per minute. Exp. ll.—Rabbit, Curare ; artificial respi- ration ; carotid and jugular prepared ; trache- otomy. These observations show conclusively that the sensory nerves and spinal cord are not affected by this alkaloid. Time. Pulse. Pressure. A.M. 75 IOO Lycoctonia .05 grm IO.05.i5 72 98 IO.05.30 59 84 IO.06.OO 64 84 IO.08.OO 56 9° IO.O9.i5 66 24 IO.37.30 66 24 To study the action oh the muscle I used Marey’s myograph and regu- lator, after the method laid down by Marey. In no case did I find any prolongation of the curve as produced by veratria, or as Weyland states takes place under aconitia. Boehm and Wartmann were unable to con- firm this discovery of Weyland’s. The preceding experiments show that the action of lycoctonia is a reduction of the pulse and pressure. Immediately after the injection the pulse-waves are considerably greater and steeper. In small doses, like aconitia, its action on the heart causes a delirium cordis, that is, periods where the pulse is suddenly greatly slowed whilst the pressure also rises and falls in a man- ner not to be predicted. Unlike the action of aconitia, the blood-pressure in Exp. Vl.—Large rabbit received at 12.32 p.m. .1 gramme of lycoctonia into arterial system ; the animal immediately became quiet and was unable to stand. 12.35 P.M., .1 gramme injected into arterial system. 12.42 p.m., .1 gramme injected into arterial system. Convulsions, with clonic contractions of muscles of neck and jaws; respirations ceased. 12.43 p-M., death ; heart beating. PHYSIOLOGICAL ACTION OF LYCOCTONIA. 3 rabbits never suffers a preliminary rise. This series of results can happen either by a central.or a peripheral excitation of the pneumogastrics. In nicotin and atropin we have an agent that paralyzes the peripheral end of the vagi. Schmiede- berg* has shown that in a heart stopped by muscarin, which greatly excites the cardio-inhibitory ganglia, nicotin is unable to start the heart, whilst atropin does. This led him to infer that nicotin paralyzes the nerves uniting the peripheral end of the vagi to the cardio-inhibitory ganglia, and that atropin paralyzes the ganglia themselves. ratus. The peculiar paroxysmal action of the heart continues after the use of atropin. That the vagi are not paralyzed by small doses the following observations show, Exp. Vl.—Rabbit. Tracheotomy ; curare ; artificial respiration ; carotid and jugular pre- pared ; left vagus prepared. Time. Pulse. Pressure. P.M, 68 126 Lycoctonia .05 grm. 3.50.OO 63 126 3-50-I5 78 120 3.51.0° 63 124 4.06.15 62 96 4.07.OO 62 78 Lycoctonia .05 grm. 4.07.15 5§ 77 4.07.30 55 64 4.08.OO 57 68 4.O9.3O 46 102 4.I2.45 55 108 Lycoctonia .05 grm. 4-I3-I5 61 116 4-I3-30 49 in Vagus irritated for three seconds. Du- bois’s secondary coil at 4. 4.19.55 CO vn ’ 120 Lycoctonia .05 grm. 4.20.10 63 113 4.20.25 61 114 4.2I.OO 51 no Vagus irritated for one second. Du- bois’s coil at 4. 4.24.30 52 130 Lycoctonia .05 grm. 4.24.45 58 120 4.45.I9 60 128 4-45-34 36 110 Vagus irritated four seconds. Dubois’s coil at 4. Exp. 111.—Rabbit. Tracheotomy; curare; artificial respiration ; carotid and jugular pre- pared; vagi cut. Time. Pulse. Pressure. A.M. 78 106 Lycoctonia .1 grm, IO.45.OO 71 90 IO.45.3O 48 36 IO.45.45 49 30 IO.46.3O 63 30 IO.5i.3O 75 70 IO.55.45 60 82 II.17.30 65 72 Exp. IV.—Rabbit. Tracheotomy ; curare ; artificial respiration; atropin ; carotid and jugular prepared ; paralysis of vagi as tested by strong currents. Time. Pulse. Pressure. P.M. 60 I30 6.OO.15 IOO' Lycoctonia .1 grm 57 6.OO.3O 56 68 6.01.00 50 38 6.01.15 48 40 6.IO.3O 59 120 Coagulation. 6.11.15 60 118 6,12.00 61 120 6.12.45 64 118 Exp. VII—Rabbit. Right vagus prepared ; canula in jugular; Middeldorpf’s needle used to observe the action of the heart. Exp. V.—Rabbit. Tracheotomy; curare; vagi paralyzed by nicotin as proved by irri- tating with strong currents. Carotid and jugu- lar prepared; artificial respiration. Time. P.M. 2.15 Dubois’s coil at 11. Stops heart. Ly- coctonia .1 gramme. 2.18 Dubois’s coil at xr. Slows the heart. 2.24 Lycoctonia .4 gramme. 2.26 Artificial respiration. 2-33 Dubois’s coil at 0. slows the heart. 2-43 Dubois’s coil at 0. no power over the heart. Time. A,M. Pulse. Pressure. 9.OO.OO 70 Il8 Lycoctonia .1 grm, 9.OI.OO 62 54 9.OI.I5 62 55 9.OI.3O 67 54 9-2I*53 57 108 Coagulation. Exp. VII. shows that large doses are able to paralyze the vagi, for when the sec- ondary coil was shoved over the primary the pneumogastric had no action on the heart. These observations show conclusively that the sinking of pulse and pressure has not its seat either in a central or peripheral stimulation of the cardio-inhibitory appa- Exp. VIII. Rabbit. Tracheotomy; cu- rare ; artificial respiration ; carotid, jugular, and sciatic nerve prepared ; Ludwig’s screw- electrode fastened into the atlas and occiput; Pohl’s commutator so arranged that the cur- * Ludwig’s Arbeiten, 1870. 4 PHYSIOLOGICAL ACTION OF LYCOCTONIA. rent of electricity can be sent either to the sciatic nerve or the vaso-motor centre by roll- ing the cradle. It is evident that the fall of pressure and of pulse is due to diminished excitability of the heart, and, as the striated muscles are not affected by the poison, it must be due to the nervous mechanism being changed. But how are we to explain the paroxysmal changes of pulse and pressure, the delirium cordis? Heidenhain, on irri- tating directly the vaso-motor centre after previous section of the vagi and artificial respiration, observed the following : when strong currents were used there ensued a want of rhythm similar in appearance to that observed after the use of lycoctonia. He had to deal with a high pressure in the circulatory system. He then sought out the cause of this want of rhythm, whether it was seated in the cardiac nerves or the heart itself. After separation of the cardiac nervous apparatus external to the heart, he found it to be localized in the heart itself. He then thought it must be either in a weakening of the motor ganglia of the heart or increased action of the inhibitory ganglia. The weakening of the motor ganglia seemed to him to fail utterly in accounting for this appearance. His con- clusion was that high pressure irritates the cardio-inhibitory ganglia, and thus causes these paroxysms, but when their excitability sinks the want of rhythm disappears; that this delirium is an expression of the antag- onism of the forces of the cardio-motor and cardio-inhibitory ganglia, and irrita- tion of the vagi for very short periods gave curves precisely similar. Atropin did not prevent this want of cardiac rhythm, which caused Heidenhain to doubt if it paralyzed all the inhibitory ganglia. Boehm and Wartmann, who observed a similar want of rhythm after small doses of aconitia, think that it is probable that an excitation of the cardio-inhibitory apparatus is called into play, or that aconitia antagonizes the para- lytic effect of atropin. Time. Pulse. Pressure. A.M. 57 94 Lycoctonia .05 grm. IO.46.i5 55 76 IO.46.30 53 80 IO.46.45 5i 54 IO.47.3O IO.52.OO to II.O2.05 5i 60 Lycoctonia .15 grm. I I.03.IO 56 90 Vaso-motor centre irritated indirectly for two seconds. Dubois’s coil at 16. I I.O3.25 54 102 11.08.28 44 84 11.16.01 11.34.01 to 12.16.56 5o 62 Depressor nerve irri- tated for eleven seconds. Dubois’s coil at 16. Lycoctonia .2 50 grm. 12.19.17 40 48 12.19.32 45 70 Vaso-motor centre irritated indirectly for nine seconds. Dubois’s coil at 16. 12.24.36 54 94 12.24.51 45 120 Vaso-motor centre directly irritated for six seconds. Dubois’s coil at 5. In Exp. VIII. I have tried to see if the alkaloid paralyzes the vaso-motor centre. Unlike aconitia, it does not, either to direct or indirect irritation. It is quite probable that enormous doses might do so; but that large doses do so is not tenable. This ex- periment also confirms the view that this poison does not act on the sensory nerves or the spinal cord. Exp. IX.—Rabbit. Tracheotomy; curare ; artificial respiration ; carotid and jugular pre- pared ; all cardiac nerves in neck are cut; cord cut between the atlas and occiput; hem- orrhage checked by bovista. Mr. Lewin explains the want of rhythm after aconitia by an action at dissimilar times and unequal in strength upon one or the other intracardiac nervous apparatus, probably produced by an unequal division of the alkaloid in the blood. It is difficult to see how an unequal distribution of this poison in the circulatory system can occur. It cannot be through any change in the cor- onary vessels, as the same paroxysms occur in a frog’s heart, which has been shown by Hyrtl to be devoid of blood-vessels. Certainly in the case of lycoctonia high Time. Pulse. Pressure, P.M. 54 52 2.08.15 Lycoctonia .1 grm, 42 S2 2.08.30 37 34 2.08.45 26 28 2.O9.30 33 19 2.I5-I5 30 22 In the ninth experiment the heart is entirely freed from its afferent and efferent nerves. Here the same change takes place, —that is, fall of pulse and of pressure. PHYSIOLOGICAL ACTION OF LYCOCTONIA. 5 pressure does not irritate the inhibitory- mechanism, and atropin does not prevent the want of rhythm. Either one must as- sume that atropin does not completely paralyze all the inhibitory ganglia, or that lycoctonia antagonizes it. 3* That it paralyzes the motor nerves. 4. That it does not affect the sensory nerves, spinal cord, or the striated muscles. 5. That it reduces the blood-pressure and pulse without any previous rise of the for- mer as produced by aconitia. 6. That the decreased pulse-rate and pressure are due to an action on the intra- cardiac nervous apparatus. 7. That the pneumogastrics are para- lyzed only by large doses. 8. That the delirium cordis produced by small doses is due to a change in the mechanism of the nervous apparatus of the heart. To my mind neither explanation is suf- ficient. The recent experiments of Bow- ditch, Luciani and Kro- necker, seem to be near the discovery of the real cause. The following expresses my conclusions in regard to this poison : 1. Lycoctonia is a weaker toxicant than aconitia. 2. That it kills mainly through the re- spiratory apparatus. Physiological Laboratory of the University of Pennsylvania. Fig. 2.—Pulse-curve of rabbit seven seconds after injection_of .1 gramme of lycoctonia; curare; artificial respiration. Fig. x.—Pulse-curve of rabbit just before injection; artificial respiration; curare. Fig. i. Fig. 2. 6 Fig. 3. Fig. 4. Tigs. 3 and 4.—The delirium cordis of rabbit produced by small doses of lycoctonia. 7