The origin of the heart's “internal stimulus”

Department

of Reviews Critical

THE

ORlGIN

and Abstracts -.-.

Review

OF THE HEART’S

“INTERNAL

STIMlJLUS

C. H. MCDO~TALD, M.D., ASD A. C. &DONALD? LITTLE

“*

3I.D.

ROCK, ARK.

T

HE heart of either a cold or a warm blooded animal is able to maintain strong, rhythmical beats for a lon g time after all nervous, vascular, and supportive connections between the heart and the rest of the animal’s body have been severed provided the heart is perfusetl with a liquid containing certain inorganic salts in proper proportion. To explain this automaticity of the heart many theories have been advanced. Those based upon a more modern conception of physics and has been directed toward chemistry date from about 1870. Attention the various factors supposedly capable of calling out the heart beatthe so-called “inner stimulus”-in a somewhat cyclic manner : toward first the organic constituents, then the inorganic, next the possible physicochemical arrangements of both organic and inorganic, again toward the organic, and at the present time there is a renewed interest in the inorganic constituents with respect to their possible role in releasing the heart beat. Langerdorf”” advanced a theory that the inner stimulus controlling the automaticity of the heart arises from cleavage processes within the heart, probably in the ganglion cells-“Der Lebensproduckt der Zelle is ihr Erreger.” This stimulus originates in the catabolism of the cells, Thus, and anabolic processes are assumed to diminish its production. adopting a view earlier expressed by Gaskell, the inhibitory nerves produce their effects by increasing the anabolic processes. Assuming a constant production of this stimulating substance, he explained the rhythmicity on Rosenthal’s hypothesis of a steady stimulus opposed by a steady resistance. Langendorf placed the burden of calling out the heart’s rhythmic beats upon the organic constituents of the heart and assigned to the inorganic cations, sodium, potassium, and calcium, the minor role of placing the cardiac musculature in proper condition for the action of the inner stimulus. *FKI~ the DeDartment School of Medicine.

of Physiology

and

119

Pharmacology,

17nirersity

of

.%rkansas

Englemann,‘!’ basing his views mainly upon a study of the automaticity of the venous end of the heart, believed t.hat a stimulating substance responsible for the inner stimulus is formed fs a result, of the resting metabolism of the heart. The i~CcUlllul~tiOll of this llliltt?rii31 during the pause suffices eventually to briii, (7 011 a systolic contract,ion. The diastolic pause in its duration is the reciprocal of the rate of clevelopment of the st,imulat,iiig substance. To f~spla in the rhythmicilJ it is suggested that each syst,olie cont,raetion causes a diminution or neutralization of the stimulating snbstancc. These views of both Langendorf and Engle~~~aiin are entirely tlicorctical inasmuch as nothing of the nature of direct proof is given for existence of such a stimulating substance in the heart. RingeP noted that if an excised heart is perfused with an aqueous solution of the salts of sodium, calcium, ant1 potassium in the coricentration in which t,hese salts arc found in the animal’s blood, a rhythmical, functional beat may be obtained for a long time. He believed that no artificial 1)crfusion fluicl could so function unless it contained the salts of these cat,ious a~ltl from this reasoned that an interaction of t,liese iiiorpanic salts is a necessary condition for the heart beat. He emphasized an antagonistjic act’ion of calcium and potassium upon t,he tone of the cardiac muscnlat~lre and suggested that calcium elicits the contraction of the heart’s tissues while potassium brings about their relaxation. Loeb”3 observed lhat the presence of cert,ain ions influences the imbibition of mater by soaps and that variations of the kind and concentration of these ions within the soap can cause water to proceecl into or out of the soap. He further notetl that changing the kind and concentrat,ion of these same ions in the fluid bathing an excised skeletal muscle can vary the activities of t,liis muscle. These observations led him t,o postulate a mechauism by which ionic activit,y serves to release the spontaneous, rhyt,hmic contractions which can be called forth in He expressed the convicskeletal muscle under cert,ain conditions. tion that the same mechanism can be extended to cardiac musculature. According to Loeb’s theory, the various ions cxcrt their influence by entering the cell and unitiug with certain cellular constituents. Acting as the principa,l agent, in initiating automaticity, the sodium ion enters the cell and displaces a small portion of the calcium ion from its intracellular coml~ounde and by this displacement escil-es the mus~cle to contract. If this displacement proceeds too far, the sodium ion “poisons” the tissue. In this theory of the origin of tllc heart’s automaticit,y Lingla concurred. Howell?” advauced a, theory in which an antagonism between sodium and calcium present in balanced ratio a& as the exciting agent for spontaneous beats rather than the activity of sodium alone as Loeb

C’KITICAL

REVTEW

121

believed. Howell denied the “poisoning” action of sodium upon cardiac tissue except so far as any single known substance is likewise poisonous in being unable to support rhythmic beats when used alone. \Varburg*s has recently shown, however, a so-called toxic action of sodium chloride upon certain cells in that their oxidations are greatly increased when sodium chloride is the only salt cont,ained in the fluid surrounding them ; furthermore, this increased oxidation is neutralized by the addition of calcium salts or of sodium cyanide t,o the fluid in contact wit,11 the cells. Loeb, Lingle, and Howell agree in assigning no direct action in the production of t,he inner stimulus to potassium. It should be borne in mind that rhythmicity at this time was defined wholly in terms of mechanical contractions. Zmaarclelllaker,j” however, placed the responsibilit,y of initiating the While holding sodium, heart’s spontaneous rhythm upon potassium. calcium, and potassium as essential to the maintenance of a rhythmic beat, he asserted t,hat, the radiations emanating from the potassium act tlirectly upon the heart ‘H musculature st,imulating it t,o its rhythmic His modified view of the behavior of potassium mill be contractions. notetl in connection with the heart hormone t,heory. IIe held tllilt potassium can be replaced in it,s effect by any other radioactive substance. He divided the radioactive substances into two groups clependent upon the nature of their emanations, soft alpha or hard beta rays: and asserted that the two groups arc antagonistic to each other in their effects upon the heart. This specific ri,le assigned to potassium in calling out the heart beat has been criticized by Clark” and by Libbrecht.,“] while Zeehuisen4” has shown that, failure of the heart’s rhythmicity is not direct,ly connectctl with t,hc rernoyal of potassium from the heart’s tissues. Mines”” advancetl an interesting and rathtar conlprehensi~e physicochemical theory t,o account for the origin of the heart beat. He assumes that the contractile mechanism responds to a transitory increase of hydrogen ions at interfaces within the cardiac muscle structure. Such a change in h)-tlrogen ion concent,ration will be tlrpendent upoll the maintenance of a certain degree of lwrme;~bility of the cell surfaces or cell membranes. Maintenance of this 1)roper tlcgree of permeability is a function both of the chemical coml)osition of the cell membrane and of the electrical potential csistiu g across t,he membrane itself. IIe has classed the calcium ion as a combining ion, capable of entering into chemical union with the iiic~mhranc itself alid exerting an influence upon its permeability. Tllr sotlium and potassium ions he has classed as nomadic ions because of their supposed abilit,y to penetrate the cell membrane and by such migrations exert an influence upon the electrical charge of different parts of the cell. The hydragen and hydroxyl ions he classes as polarizing ions which affect the

surfa.ce pot,ential of hhe cell through adsorpt.ion. Hogben”’ has also furnished experimental evidence in confirmation of this view. C’lark!’ has atlvocatt~d a somewhat similar theory in which lipoids become essential constituents of the cell surfa(:tBs. The function of calcium is t.0 vary the eolloitlal st.ate of this Iipc)itl-coatainill~ cell surface. The permeabilit,y of t,he cell to electrolytes is made dependent on, or influenced by. t#he prescnee of calcium ant1 lipoitls at t,hc cell surface. C20wes1’ has constructetl a mocl~l ill whirh both ~ontluctivity and permeabilit,y c~f a. rrir~i~bra~ic~ soaked in an emulsion of oil and bahIlCed soap solution vary with changes in tltc> calcium t,o sodium and potassium ratio due to the degree of ext,c~rnxlization of the lipoid phase of the cell membranes. Osterhout*” matlc a like observat.ion witch livinp plant t,issutls. Rona and Pctow4’ explain the mut,uat antagonism of calcium ant1 pot.a.ssiuni upon the basis of opposetl inflnenccs in the rxternalizatioil of the lipoicl phase ul’ ~(111niniibranes. and (‘art,rr’ have elaborated a I~h~sicocl~e~nical theory in which the l~ydrogcn ion concent,ration in different paAs of the cell esplains the origk of t,he heart. heat. The c;\rtli;tc rh~t.hnl, according to these illvest,igators, is c111clt,o the rhythmic building up and discharging of a potential tlift’rrence across a semiprrmeablc memhraue. The rate of discharge ant1 tlic magnitutle of this potential cliffrrence are tlrprndent fnntlanlcntall~11p0n the difY~i*rnec: in Iiydrogen ion conc’entration mit,hin the eartli:rc tissues ant1 t-he flllitl bat,hing them. Thr level of the potential ditirrel1c.t4J wllich tllis tliscliarge t.akes place is determined by the permeability of t,lle int,erI)ost?tt mrmbrane which is in turn tlepcndent upon the concentration of the sodium, calcium, and potassiLim salts on either side of t.lle mwlll~ra11(*. Alentioil must he made of >I belief t.hat carbon tlioxide acts rls t.lrr internal stimulus it,self. This view was first atlvanced b>- Martin:‘” and has been elaborated by Xansfeltl alltl Szent-Gyiirgyi.“; I&ieS2 explains t,he heart’s automaticity on t,lle basis of alternation between stat.es of act,ivity and passivity perhaI~s of the nature of oxidation-reduction react,ions. He has coustructcd inorganic models capable of exhibitming such phenomena as ahrona,xia, electrotonus, polar stimuIat,ion, inhibition, au(l rt$ractory I)t~t*iotl in close agreement with living systems. Z~vaardenla,ker51 altered his original theorp in which potassium by its radioactivity stimulates t.?re heart tissue directly to one in which a hormone manufactured by t.lic skrlct.al muscle is changed by the radioactivity of potassium to a substauct> (automat,in) which is capable t,o the cardiac tissue. Haberlandt23 has of inipaPting automaticity which a hormone is formed constantly proposed a similar theory in b)- tI\c conducdinp tissues of t.he heart and is responsible for the cardiac contractions. Be explains alt,ernate contraction and relaxation as Amlrus

ilt

C’KI’J’I(‘AL

I”3

REVIEW

a function of the refractuqlwriotl of the heart cells. Demo0r”’ has According to his advanced a. somewhat difFrrent hwnoral theory. giving :rutd)inatic ccmtractious but view, the myocardiunl is capable of the contractions are ilTeg?lli~~. ~:nder the influence of a substance elaborated particularly by the ll(~di~l tissue the myocartlinm RSSII~W regularity. IIis theory is chiefly llp011 the ObSe~ViltiOTl t,ll;lt tlltl right awicle of tile rabbit excised aid dropped into a. Ringer-Locke solut,ion soon ass\~mes regular rhythm ; the left, auricle. however, If now the solution 4ves onlv aperiodic.. jerky in this s0lntioll. c in which the right anriclc Ilkis been adirca for while is poured over t,he left auricle. ilSSIlJl1~S ~~lr~~tl~rniciil 1WHth. Ll’C IINVP been able to confirm this observation in about 70 per cent of t,rials. (Preliminary publication. Proc. Koc. Eqer. Hiol. & 31ed. 30: 786, bilSt?tl

i

ht’iltS

il.

tl?

Ig,?$.)

nemoor

has

Iilttt’r’

postulated

other

heart

hol.lliones

\vhiCh

bring

about augmentation and inhihit,ion of the heart. The “spevitieity” of these subst.ances has been questioned since extracts of other tissnrs have been shawn to have similar eRects upon the heart tissuc1. A\sh~r and Beyeler!:’ Granit and van I~onsdorff,22 Katz and I~icbensohn.” R ipIer and Singer,41 Riglcr and Tiemann,4’ Ol~l~euhein~er,“! Grant, Frey. ant1 Merle,*” Tl10rpe,~~ Cannon and Griffith,: and Chang ant1 (!l~en’ f>i\ve clemonstrated t,hat such snbstanc~ have a widr tlistriblltion iI1 the tissues. With the development of instrwurnts citl)able of measuring the electrical variations that wmr in connection with the JJJCChalliCi~~ movements in contra&q musculatiwe there has been made available a. new criterion for the presence or ;\bsenee of contractions in R heart. It was long supposed that the electrical ~IheJJolJlf?JJil were couccrncd perhaps snlely with the interual stimulus ant1 tlefinitrly prece(led any distortion of the musclr substancca. Il;intllown,‘i Eiuthown and IIiigeiilldt~z,‘~ Arbriter,? and tic pTong1114have wtluanccd the idea that elrctrical ant1 mechanical phcnomcna are indissoluble; while Gasse~~alli ISill,” R’ijlant.*” Iileinl~nccht,‘” Fnlton.‘” Jolles,‘6 Bishop and Gilsen.” Max,a7 and Baetjer and JloDonalc14 haye l,rescntcd evidence tllat the two may be separated. Without much s]~ecldiltioll up0n the actwl origin of the electric;rl variation shown by the beating heart. C’raib” has callet into question the usual method of explainin g this variation upon the basis of a state of negativity which is developed bp actin g tissue as compared to that of resting tissue. He offers mathematical a.nd experimental proof that the electrical phenomena of the heart partake of the nature of what he terms “electrical cloublet,s” and defines an electrical &)ublet as two closely adjacent poles situated within a conclwding metlium and maintained at. equal and opposite potentials. dt any rate, since the electrical phenomena in connection with the heart’s contraction may be used as a means of measuring the heart’s

t activity, the functional importance of the inorganic ions in the production of the internal stimulus has become a subject for reinvestigaCon. Briefly stated, it appears tha.t according to the present view sodium is perhaps most intimately concerned with actual release of the internal stimulus, calcium with the strength of contraction, and potassium wit,h the counteracting of an irritating antagonism bet,ween sodium and calcium. Reference may be made to Clark,l’ Arbeiter,2 Ten Cate,4” Hogben,’ McDonald,34 Zeehuisen,4” Colle,l” Bouckaert and Belehraclek.” Zwaarclen~al~er,51 MBX,“~ and Baetjer and McDonalcl.4 REFERENCES” 1. An&us, E. C., and Carter, E. Process in Perfused Heart,

P.: Devclopmcnt and Propagation Heart 11: 97, 1924; also Science,

of Excitatory Nov. 9, p. 376,

1923. Phenomena Mechanical and Electrical in the Frog Heart W. C. A.: After Removal of the Calcium. Arch. n&l. de nhvsiol. 5: 185. 1921. Asher, I;., and Beyeler, K.: B&hem. Ztschr. 178: 351, 1926. ’ Baetjer, A. RI., and McDonaId, C. H.: The Relation of the Sodium Potassium, and Calcium Ions to the Heart Rhythmicity, Am. J. Physiol. 99: 666, 1932. Action Potential Accompanying the ConBishop, Cr. H., and Gilsen, A, H., Jr.: tractile Process in Skeletal Muscle, J. Physiol. 82: 478, 1927. Bouckaert, J. P., and Belehradek, J.: Concentration des ions et contraction musculaire, Arch. internat. de uhvsiol. 29: 71, 1937. Cannon, W. B., and Griffith, F. R.: A A Hormone Produced by Sympathetic Action on Smooth Muscle, .4m. .T. Physiol. 96: 392, 1933. Chxng, H. C., and Chen, Y. P.: Chinese .T. Physiol. 5: 363, 1931. Clark, A. J.: The Action of Ions and T&o& Upon the Frog’s Heart, J. Phvsiol. 47: 66, 1913. Idem:” The Mode’of Action of Pot,assium Upon Isolated Organs, J. Pharmacol. &i Exper. Therapeut. 18: 432, 1921. Clowes, CT. H. A.: The Action of ElectroIytes in the Formation and Inversion of an Oil-Wa.ter Svstem. Kolloid-Ztsehr. 15: 723. 1914. Craib, W. H.: A Study’ of the Electrica FieId Surrounding Active Heart Muscle, Heart 14: 71, 1927. Colle, .T. : Ions and the Frog Heart, Arch. internat. de physiol. 29: 71, 1927. de Jongh, C. L.: Der Zeitverhaltnisse xwischen electromeehanokardiogram, Pfliiger’s Arch. 213: 216, 1926. Demoor, M. .T.: Humoral Regulation of Heart Action of Active Substance From Region of Node in Right Auricle, Compt. rend. Sot. de biol. 91: 90, 1924; Bull. Acxd. ray. de m&l. de Belgioue, Dec. 15, 1928; The Humoral Regulators in the Heart, Ext. de la Presse MEd. 60. du .Tuillet, 1929. I&m. and Rplnnt, RI. P.: Arch. internat. de physiol. 23: 121, 1924; ihid. 26: 113 ; ibid. 27: 1, 1926 : Regulation hv Body Fluids of Work of Heart Ventricle -Active Substance of Subendocardial Tissue, Compt. rend. Sot. de hiol. 95: 019, 1926: Mrch. of Action of Ruhrndocardial Tissue in Ventricles, ihid. 95: 221, 1926. Einthocen. W.: The Relation of Mechanical and Electrical Phenomena of Musrlc. Contraction With Special Reference to Cardiac Muscle, The Harvey Lectures, p. 111, 1924. Idem, and Hiigenholtz, F. W. N.: The Electrocardiogram Traced in the Case Where There Is No Yisihle Contractions of the Heart, Arch. neerl. de physiol. 5: 174, 1921. Englemann, Th. TV. : Pfliiger’s Arch. 65: 109, 1897. Fulton, J. F.: The Influence of Tension Upon the Electrical Response of Muscle to Repetitive Stimuli, Proc. Royal Sot. B 97, 1925.

2. Arbeitcr,

3. 4. 5. 6. 7. 8. 9. 10. 31. 13. 13. 14. 15.

16.

17.

18.

19. 20.

may

*A

cium

bibliography

be had Ions

more

in McDonald.

to the

Heart

than

twice

C. H.:

Rhgthmicity.

as extensive

The

Welch

Relation

Medical

of

of

the

tho

Library,

literature

Sodium,

Johns

concerninn

Potassium, Hopkins

this

field

and CalUniversity.

CRITICAL t’l. 22. 23. 24. 25.

26. 27. 28. L'y.

REVIEW

125

Gasser. 11. A.. and Hill. A. V’.: The Dvnamics of Xusculnr Contraction, Proc. Royal Roe. ‘B 96: 398; 1924. nrch. f. Physiol. 5: 24Y, 1!126. Granit, R., and van Bonsdorf?, K. : Skandinav. Haberlandt, L.: Ueber ein Ilormon dcr Hcrzbewcgung, Pfliiger’s Arch. 226: 203, 1928. Studies on the Comparative Physiology of Contractile Tissue, Hogben, L. T.: Quart. J. Exper. Physiol. 15: 263, 19?5. Howell, W. H.: -4n Analysis of the Influence of the Sodium, Potassium, and Calcium Salts of the Blood on the Automatic Contraction of Heart Muscle, Am. J. Physiol. 6: ISI, 1901; Vagus Inhibition of the Heart in Its Relation to the Inoreanie Salts of the Blood, Am. .J. Phvsiol. 15: 280, 1YOfi. Jollrs, W. H.:“ Ondere. Physiol. Lab. Utrecht 5: l”S, lY?i. . Recherches sur les hormones cardiaques, Katz, G. J., and Lcibcnsohn, E. C.: Comlrt. rend. Rot. de biol. 99: liY.5, lD78; Pfliiger’s Arch. 221: X3, 19%. Kleinknecht, F.: Ztsrhr. f. Biol. 81: 5, 1Yz-l. Kraut, II., Frey, E. Ii., aud Werle, E.: Dcr Nnchwcis eines Krcislaufhormons in dcr Pankreasdriisr, Ztsrhr. f. Physiol. Chum. 189: Yi, 10.31); Ucbcr dir Innktirirrung drs Kallckreins; iibrr diescs Krrislaufhormou, ibid. 192: 1, 1930.

Lanecndorf. 0.: Studicn iibcr Rhvthmik und Automat& des Froschherzen. Arch. f:’ Anat. ‘II. Physiol. 1: 737, l&l; Ergcbn. d. Physiol. 2: 263, lYO2; ‘Ucher die aueebliche Unfahiakcit des Inckfarbrcncn Blutcs den Uerzmuskcl zu ernahrbn, Pfliigrr ‘R A.&h. 93: 23fi, lYO:l. 31. Libbrccht, TV.: ContrilJution a i’btnde du rfile biologiclue du potassium sur Ic coeur, Arch. internat. de phpsiol. 15: 446, ICEi. 32. Lillic, K.: Analogies Betwcrn Phvsiologiral Xhpthms and Rhythmical Rcnctions in Inorganic Systems, Science J. 15: 5Y3, 1928. 33. Loch, J.: Frstsrhr. f. Fick, Braunschweig, p. YY, IYDD; On Ion-Proteid Compounds and Thrir Ri?lr in the Mcch. of Lifr Phenomena, Am. J. Phyaiol. 3: 327, lY90: Pfliiger ‘s Arch. 88: 6X> NO1 ; Studies on the Physiological Effects of the Valemy and Possibly the Elcctricnl Charges of Ions, Am. J. Physiol. 30.

6: 34. 35. 36.

37. 38. 30.

90: 3n.

41. 42. 43.

44.

45.

411,

1902.

McDonald, A. D.: Action of iZdrcn:rlinc on the Perfused Fish Heart, Quart. J. Esper. Physiol. 15: 6Y, IY2.5. Mansftld, CT., and Szent-Gyiirgpi, A. V.: Untrrsuchungen iiber die Ursachc des Ucrzschlages, Pfliigcr’s Arch. 184: 336, lY?O. Martin. E. CT.: On the Relation of the Inorganic Salts of Blood to the Automatic Activities of a Strip of Ventricular Muscle. Am. J. Phvsiol. 2: 82. lYO4: A Study of the Absorption and Consumption of Oxvgcn in Ilcart Tissue, ibid. 15: XI:. IYOfl: A Studv of the Relations of the Inornnnic Salts of the Blood to t.hc Contraction of Heart Muscle and Skeletal Muscle, ibid. 16: 191, 1906. Max, L. W.: Timr Relations of Eleetricnl and Mechnnieal Rrsponscs of Hrart Muscle. Am. J. Physiol. 98: 318, lY31. Mines, C,. R.: Elrctrnl~tt=s on tht Hr.1rt, J. Ph,vsiol. 43: 467, lP12; On Functional Analysis by the Action of Electrolytes, ibid. 46: 188, 1913. Opnenheimcr. E. T.: Studies on the So-called Heart Ilormone, Am. J. Phgsiol. 6.56,

1929.

Ostrrhout, TV. J. V.: The Prnctmtion of Ralnncrd Solutions and the Theory of Antagonism, Am. J. Rotnnr 9: 172, IYl6. Ripler. R., and Singer, R.: Urber das Herzhormon, Pfliiper ‘s Arch. 220: 56. 7 928. Idem, and Tiemann. F.: Tiehrr drn JTereautornatiestoff, ibid. 222: 450, lY!?Y. Rijlant, M. P.: Actual Methods of Studying the Automaticity and the Conduction in the Heart. Bull. et Ann. de la Sot. Roy. de Rcicnces M?d. et Nat. de Bruxelles No. 102, 1Y29. Ringer. G. : Concerning the Influence of Each of the Constituents of Blood on the Contraction of the Ventricle. J. Physiol. 3: 380. 1883: ibid. 4: 876, 188.7; On the Mutual Antncronism Rctmeen T,imc and Potash Salts in Toxic Doses. ihid. 5: 247, 18%; Rcgording the Tnflnence of Organic Constituents of Blood on Contractilitv of the Heart, ibid. 6: 3fil. 188.5. Ron%. P., and Prtom. H.: Beitraq EUT Frnge der Ionenvrrtcilnng im Rlutserum. Biochem. Ztschr. 137: 356, 1923.

126

THE

ihid. 218: kardingrnm

AMERICAN

364, 1958: Arch. m&l. des Antom:Ltinll~rzens,

HJiXR’l’

J017RKi.41,

de lbhvsiol. 12: .XL’, 19L’S ; 1)c.r Pfliig&‘s Awh. 221: I.i.5, l!lL’!).

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