Interactions between Changes in the Intensity and Duration of the Active State in the Characterization of Inotropic Stimuli on Heart Muscle By Robert A. Buccino, M.D., Edmund H. Sonnenblick, M.D., James F. Spann, Jr., M.D., William F. Friedman, M.D., and Eugene Braunwald, M.D. ABSTRACT The responses of isolated cat papillary muscles and left atrial strips to a variety of procedures were classified systematically according to the induced changes in peak tension (T), mean rate of tension development (AT/At), and time to peak tension (TTP). Increasing temperature from 25° to 37°C aug- mented AT/At but reduced TTP reciprocally so that T remained constant. Increased frequency of contraction, thyroid hormone, and increased tempera- ture markedly augmented AT/At but shortened TTP, with relatively little altera- tion in T. Norepinephrine, tyramine, paired electrical stimulation, strophan- thidin, and calcium increased T by augmenting AT/At proportionately more than they reduced TTP. Acetylcholine and serotonin augmented T by raising AT/At with relatively little effect on TTP. Strontium increased T by causing both a prolongation of TTP and an augmentation of AT/At. Depression of T in muscles from failing hearts occurred primarily by a reduction of AT/At, and the negative inotropic effects of hypoxia or pentobarbital resulted from re- ductions in both AT/At and TTP. In muscles from hypothyroid cats, depression of AT/At was partially compensated for by prolongation of TTP. Since AT/At is related to the intensity of the active state and TTP to its duration, such analysis of these variables should provide a framework for the characteriza- tion and quantitative comparison of various types of inotropic stimuli. ADDITIONAL KEY WORDS time to peak tension rate of tension development frequency of contraction thyroid norepinephrine strophanthidin strontium hypoxia pentobarbital congestive heart failure cats • Changes in the contractile state of heart muscle have, in general, been classified simply according to whether they produce an increase or a decrease in the tension developed by the myocardium. However, from a considera- tion of the contour of the isometric contrac- tion it is evident that the tension generated depends on two factors: the rate of tension development and the length of time during From the Cardiology Branch, National Heart In- stitute, Bethesda, Maryland 20014. Dr. Sonnenblick's present address is Peter Bent Brigham Hospital, Harvard Medical School, Boston, Massachusetts. Accepted for publication October 17, 1967. which tension is generated (1, 2). In terms of the muscle model proposed by A. V. Hill (3), tension is generated by a contractile element arranged in series with an elastic element. The rate of tension generation de- pends on the stiffness of the elastic element and the rate of shortening of the contractile element. The latter, in turn, is determined by its active state, which reflects the rate of chemical processes at contractile sites, and may, at any instant in time and at any muscle length, be characterized by the measurement of the tension and the velocity of shortening (4-6). At a given muscle length, the rate of tension development is dependent on the Circulation Research, Vol. XXI, December 1967 857 by guest on May 26, 2018 http://circres.ahajournals.org/ Downloaded from
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Interactions between Changes in theIntensity and Duration of the Active Statein the Characterization of Inotropic Stimulion Heart Muscle
By Robert A. Buccino, M.D., Edmund H. Sonnenblick, M.D.,
James F. Spann, Jr., M.D., William F. Friedman, M.D.,
and Eugene Braunwald, M.D.
ABSTRACTThe responses of isolated cat papillary muscles and left atrial strips to a
variety of procedures were classified systematically according to the inducedchanges in peak tension (T), mean rate of tension development (AT/At), andtime to peak tension (TTP). Increasing temperature from 25° to 37°C aug-mented AT/At but reduced TTP reciprocally so that T remained constant.Increased frequency of contraction, thyroid hormone, and increased tempera-ture markedly augmented AT/At but shortened TTP, with relatively little altera-tion in T. Norepinephrine, tyramine, paired electrical stimulation, strophan-thidin, and calcium increased T by augmenting AT/At proportionately morethan they reduced TTP. Acetylcholine and serotonin augmented T by raisingAT/At with relatively little effect on TTP. Strontium increased T by causingboth a prolongation of TTP and an augmentation of AT/At. Depression of Tin muscles from failing hearts occurred primarily by a reduction of AT/At, andthe negative inotropic effects of hypoxia or pentobarbital resulted from re-ductions in both AT/At and TTP. In muscles from hypothyroid cats, depressionof AT/At was partially compensated for by prolongation of TTP. SinceAT/At is related to the intensity of the active state and TTP to its duration,such analysis of these variables should provide a framework for the characteriza-tion and quantitative comparison of various types of inotropic stimuli.
ADDITIONAL KEY WORDS time to peak tensionrate of tension development frequency of contraction thyroidnorepinephrine strophanthidin strontium hypoxiapentobarbital congestive heart failure cats
• Changes in the contractile state of heartmuscle have, in general, been classified simplyaccording to whether they produce an increaseor a decrease in the tension developed bythe myocardium. However, from a considera-tion of the contour of the isometric contrac-tion it is evident that the tension generateddepends on two factors: the rate of tensiondevelopment and the length of time during
From the Cardiology Branch, National Heart In-stitute, Bethesda, Maryland 20014.
Dr. Sonnenblick's present address is Peter BentBrigham Hospital, Harvard Medical School, Boston,Massachusetts.
Accepted for publication October 17, 1967.
which tension is generated (1, 2). In termsof the muscle model proposed by A. V. Hill(3), tension is generated by a contractileelement arranged in series with an elasticelement. The rate of tension generation de-pends on the stiffness of the elastic elementand the rate of shortening of the contractileelement. The latter, in turn, is determined byits active state, which reflects the rate ofchemical processes at contractile sites, andmay, at any instant in time and at any musclelength, be characterized by the measurementof the tension and the velocity of shortening(4-6). At a given muscle length, the rate oftension development is dependent on the
position of the force-velocity relation, sincethe elastic element is a constant passive spring(7). The tension generated by heart muscle,then, is dependent on the position of theforce-velocity relation and the time duringwhich the contractile element is generatingtension, i.e., the duration of the active state(6,8).
Thus the rate of tension development re-flects the intensity of the active state, i.e., theposition of the force-velocity curve of thecontractile element, and the time required toreach peak tension is directly proportionalto the duration of the active state (8) . Thesetwo easily measured mechanical characteris-tics of an isometric contraction offer a prac-tical way of assessing the intrinsic contractileproperties of heart muscle, which is morecomplete than that afforded by measuringpeak tension alone. The present investigationrepresents a systematic analysis of the changesthat occur in three interrelated variables,peak tension, rate of tension development,and time to peak tension, when a number ofphysiologic and pharmacologic stimuli knownto alter the contractile state of heart muscleare applied.
Definition of Terms
Peak Tension (T) in g/mm2 is the maximumactive tension which is actively developed bythe muscle following stimulation.
AT/At in g/mm2/sec is the mean rate of develop-ment of active tension.
TTP in msec is the time from the onset of tensiondevelopment to the peak of tension develop-ment.
Contractile state is characterized by the inverserelation between force and velocity of short-ening. When force is zero (muscle is un-loaded) the velocity is maximum (Vmax), anda given Vmax is unique for a given contractilestate.
Inotropic stimuli are chemical and physical fac-tors that alter the contractile state of themuscle.
Active state is a mechanical measure, in termsof force and velocity of shortening, of thechemical processes that take place in the con-tractile machinery of the activated muscle.The intensity of the active state is an indicationof the degree to which the muscle is activated,expressed in terms of force or speed of con-
traction; the duration indicates how long theactive state persists.
Methods
Isometric tension and responses to variousphysiologic and pharmacologic stimuli wereanalyzed in right ventricular papillary musclesfrom cats; 90 were normal adults, 11 hyperthy-roid, 13 hypothyroid, 9 with experimentally pro-duced right ventricular hypertrophy, and 10with experimentally produced right ventricularhypertrophy and congestive heart failure. Thecats were rendered hyperthyroid by daily intra-peritoneal injection of 1 mg/kg thyroxine for8 to 17 days and hypothyroid by a single intra-peritoneal injection of 1 me/kg m I 3 monthsbefore study. Serum protein-bound iodine av-eraged 4.3 ±0.2 (SEM) in the normal cats,1.2 ±0.2 in the hypothyroid cats, and morethan 25 fig per 100 ml in the hyperthyroid cats.In addition, changes in hemodynamic measure-ments and in the contractile state of isolatedcardiac muscle from these cats were documentedas described in detail previously (9).
Experimental right ventricular hypertrophywith or without associated congestive heart fail-ure was produced by constriction of the pulmo-nary artery (10). In addition, five experimentswere performed in left atria removed from nor-mal hearts, and their responses to various ino-tropic stimuli were compared to those of rightventricular papillary muscles removed from thesame hearts.
All cats were anesthetized with sodium pento-barbital (25 mg/kg) intraperitoneally, and rightventricular papillary muscles and left atria wereremoved rapidly and suspended in a bath con-taining oxygenated Krebs solution, as describedin detail previously (11). Papillary muscles andatria were held at one end by a spring-loadedclip forming the end of a rigid pin attached di-rectly to a Statham force transducer (GI-4-250).In papillary muscles peak isometric tension (T),measured at the apex of the length-active tensioncurve and corrected for cross-sectional area,was expressed in grams per square millimeter;time to peak tension (TTP) was measured fromthe onset of tension development at a paperspeed of 100 mm/sec and expressed in milli-seconds. Since atrial fibers are not parallel, cor-rection for cross-sectional area is impossible, andatrial tension was expressed in absolute termsonly.
Papillary muscles and atria were stimulatedwith square-wave, direct-current impulses of 9msec and a voltage 10% to 25% greater thanthreshold delivered through field electrodes placedparallel to the muscle's long axis. Temperature
The relations between the calculated mean rate of tension development (AT/bt) and themeasured maximum rate of tension development. Each point represents the analysis of a singlecontraction from different normal and abnormal muscles and after various procedures. Normalmuscles at temperatures of 21°, 25°, 30°, and 37°C (»); normal muscles treated with pentobar-bital (*•), strontium (*), and norepinephrine (a); and muscles from animals with hyperthy-roidism (o), hypothyroidism (o), and right ventricular hypertrophy (u).
was maintained at 30°C, frequency of contrac-tion at 12/min, and calcium concentration at2.5 mM, except when the effects of changes inthese variables were studied specifically. Theeffects of the following changes were measured:varying the temperature of the bath between21° and 37°; altering frequency between 12 and48 contractions/min; sustained post&xtrasystolicpotentiation (using the shortest interval betweenthe driving stimulus and effective premature stim-ulus); hypoxia (nitrogen replaced oxygen in thesolution bathing the muscles); increasing calciumconcentration from 2.5 to 6.5 mM and additionof tyramine hydrochloride, ICHM; norepineph-rine, 10-°M; acetylcholine chloride, 1 ( H M ; sero-tonin creatinine sulfate, 2 X ICMM; tZZ-propranolol,K H M ; quinidine, l(h5M; strontium lactate, 8.8 X
; pentobarbital, 5 X I O ^ M ; and strophanthi-din, 10-GM. The muscles were in the bath for 45min before drugs were added. The maximumeffect of each agent was measured at a time whenthe response appeared stable. In almost all in-stances one muscle was used for studying the ef-fects of only a single drug or a single procedure.
From measurements of T and TTP, the mean
Circulation Research, Vol. XXI, December 1967
rate of tension development (AT/At) was cal-culated. This value was 64% of the maximumrate of tension development (maximum slopeof the tension curve) and directly proportionalto it. Mean rate was used in place of the maxi-mum rate of tension development in order toderive isotension lines according to the formula:T = AT/AtxTTP (Fig. 1). Responses were ex-pressed in absolute terms and, in order to usea common coordinate system for comparison ofdifferent experiments, in percentages of controlvalues. In measuring the response to pharma-cologic agents, change in temperature, increasingfrequency of contraction, paired electrical stim-ulation, and hypoxia, it was possible to use amuscle as its own control. In describing theeffects of alterations in thyroid activity, rightventricular hypertrophy and congestive heart fail-ure, data from different muscles were groupedand compared with those from a group of normalmuscles studied under similar condtions. Thedata were analyzed statistically by Fisher's £-testand by the paired t-test when applicable (12).Absolute values are presented in the tables; rel-ative changes, which allow a comparison of the
effects of different stimuli, are plotted as percent-age changes from control in the figures.
ResultsInotropic Stimuli Associated with Increases in T and ATMt
In Table 1 and Figure 2, the stimuli thatincrease T and AT/At are classified into fourgeneral categories according to the associatedeffects on TTP.
Large Reductions in TTP (Exceeding 25%of Control).—Increasing the frequency of con-traction resulted in a relatively large reduc-tion in TTP. Since AT/At rose relatively more
• Tyramine
\ Norepinephrine
v • Sfrophan,12—48/min \ Colcium
• \ •\ •Serotonin
\
• Hyper thyroid
%TTP
» Hypoxio
• Penlobarbital
Hypothyroid
~-~~ 40%.>'0/v
*CHF
J--80
FIGURE 2
Effects of various inotropic stimuli on peak tension,mean rate of tension development (&T/&t), and timeto peak tension (TTP). Reciprocal changes in &T/&tand TTP calculated to yield constant tension arerepresented by the isotension curve. Increments intension would appear as points to the right and decre-ments to the left of this curve. Broken curves repre-sent isotension curves, showing a 40% change aboveor below control. For each stimulus studied, the per-centage change in the AT/At is plotted against theconcurrent change in the TTP. Each point representsthe mean value for the group of muscles studied.PES = paired electrical stimulation; strophan. =strophanthidin; Ach = acetylcholine; dl propranol. =dl-propranolol; Quin = quinidine; RVH — right ven-tricular hypertrophy; CHF = congestive heart failure.
Circulation Research, Vol. XXI, December 1967
than TTP fell, T was augmented. TTP wasalso markedly lower in muscles from hyper-thyroid cats than in those from euthyroidcats.
Modest Reductions in TTP (Less than 25%of Control).—The addition of norepinephrine,tyramine, strophanthidin, and calcium, as wellas the institution of paired electrical stimula-tion, produced marked increases in AT/At,accompanied by reductions in TTP, which,though statistically significant, were smallerthan those when frequency was increased orhyperthyroidism induced (Table 1, Fig. 2).
Minimal Changes in TTP.—Both acetylcho-line and serotonin also increased T and AT/At. However, the accompanying changes inTTP were minimal.
Prolongation of TTP.-The addition ofstrontium was the only procedure that sub-stantially prolonged TTP.
Inotropic Stimuli Associated with Reductions in T and AT/At
In Table 2 and Figure 2, stimuli that re-duced these variables are classified accord-ing to their relative effects on TTP.
The addition of pentobarbital or the in-duction of hypoxia was associated with sig-nificant reductions in TTP. The addition ofdZ-propranolol and quinidine and the pro-duction of right ventricular hypertrophy andcongestive heart failure produced small, sta-tistically insignificant changes in TTP. Themuscles of hypothyroid cats showed modestprolongations of TTP.
Temperature
The effects of changing temperature be-tween 21° and 37° on papillary muscles from10 normal, euthyroid cats are shown in Table3 and Figure 3. Increasing temperature from25° to 37° resulted in a marked increase inAT/At and a reciprocal decrease in TTP, withno significant change in T (Table 3). Thechanges in the AT/At and TTP over thisrange are such that the isotension curve isfollowed nearly exactly, as shown in Figure3. When temperature was reduced from 25°to 21°, TTP increased by an average of 32%of the control value; this was not accompa-nied by further depression in AT/At and
therefore a substantial (average, 32%) in-crease in T ensued (Table 3). This is shownby the divergence of the temperature line tothe right and above the isotension line inFigure 3.
Combined Influence of Alterations in ThyroidActivity and Temperature
The directional effects of thyroid state onAT/At and TTP already described for musclesstudied at 30° also applied at 21°, 25°, and37° (Table 4 and Fig. 3). Qualitatively, theresponses of muscles from both hyperthyroidand hypothyroid cats resembled those ob-served in euthyroid cats, in that an increasein temperature augmented AT/At and re-duced TTP. At each specific temperaturestudied the effect of the thyroid state couldbe demonstrated; muscles from hyperthyroidanimals exhibited higher values of AT/At andshorter durations of TTP, while muscles fromhypothyroid animals had lower values ofAT/At and longer durations of TTP. Thehighest absolute values of AT/At and shortest
%TTP
ISO-TENSION
-80-1-
O co IS *to
HYPOTHYROID
FIGURE 3
The influences of alterations in temperature andthyroid activity on the percentage changes in &T/Mand TTP are plotted as in Figure 2.
durations of TTP in ventricular muscle en-countered in this study were observed inmuscles obtained from hyperthyroid catsstudied at 37°. Conversely, the lowest valuesof AT/At and the longest durations of TTPwere observed in muscles from hypothyroidanimals studied at 21°. The interaction be-tween the effects of changes in the thyroidstate and the effects of changing temperatureis also evident from the finding that TTP wasessentially equal in muscles from hyperthy-roid cats studied at 25°, muscles from euthy-roid cats at 30°, and muscles from hypothy-
roid cats at 33° (by extrapolation from Figure3).
Comparison of the Effects of Norepinephrine and Calcium
When the effects of norepinephrine or cal-cium were studied in separate groups of mus-cles, it was observed that these two inotropicagents exerted similar effects, increasing Tand AT/At but reducing TTP only modestly.In two groups of muscles the reductions inTTP produced by these two agents did notdiffer significantly (Table IB). However, amore precise comparison between the effects
TABLE 3
Influence of Temperature on Peak Tension, Rate of Tension Development, and Time to PeakTension in 10 Normal Cat Papillary Muscles
Tension(g/mm2)
Rate of tensiondevelopment(g/mm-/sec)
Time to peaktension(msec)
21°25°30°37°
6.2 + 0.54.7 ± 0.4*4.4 + 0.5t4.7 + 0.4f
8.3 ± 0.98.1 + 0.9t
11.9 + 1.2*21.9+1.9*
772 ± 44585 ± 20*374 ± 15*212 ± 10*
All observations were made at 12 contractions/min and values represent the mean + SEM.*P < 0.01 and fP > 0.05 by paired t-test compared to the same measurement at the next
lower temperature.
TABLE 4
Combined Influence of Alterations in Thyroid Activity and Temperature
A. Hyperthyroid21°25°30°37°
B. Euthyroid21°25°30°37°
C. Hypothyroid21°25°30°37°
No. ofmuscles tested
8
10
5
Tension(g/mm-1)
7.2 + 1.16.0 ± 1.0*5.6 + 0.9*4.9 ± 0.7f
6.2 ± 0.54.7 + 0.4*4.4 ± 0.5*4.7 + 0.4*
2.2 ± 0.62.2 + 0.6*2.9 + 0.9f3.1 + 1.0*
Rate of tensiondevelopment(g/mm2/sec)
14.1 + 1.915.8 ± 2.2*23.7 + 3.2*40.9 ± 4.8*
8.3 ± 0.98.1+0.9*
11.9+1.2*21.9 + 1.9*
2.2 + 0.23.5+1.If6.2 + 1.5*
11.4 + 3.0*
Time to peaktension(msec)
515 + 35384 + 32*241 + 21*122 + 10*
772 + 44585 + 20*374 + 15*212 + 10*
983 + 50640 + 18*455 + 25*265 + 18*
All observations were made at 12 contractions/min and values represent the mean + SEM.*P < 0.01, fP < 0.05, * P > 0.05 by paired t-test compared to the same measurement at the
of these two agents was provided by the se-quential administration of calcium (2.5 to6.5 mM) and norepinephrine ( K H M ) to thesame papillary muscle, the sequence beingalternated in different experiments. The in-creases produced in T were similar, froman average of 4.9 ± 0.7 to 7.5 ± 0.4 for calciumand from 4.8 ±0.8 to 7.4 ±0.8 g/mm2 fornorepinephrine. Norepinephrine produced agreater increase in AT/At, averaging 88%, ascompared to calcium, which averaged 67%,and the decrease in TTP was greater fornorepinephrine than for calcium, averaging20% and 8% respectively (P<0.05).
Comparison between Atrial and Ventricular Myocardium
A comparison between papillary musclesand isolated left atria studied at 30° and 12contractions /min showed that the TTP wasthree to four times longer in the papillarymuscles, and that to develop any given levelof tension, AT/At was therefore correspond-ingly lower in papillary muscles (Table 5).Further differences between the two tissueswere noted by comparing the responses offive additional papillary muscles with thoseof left atria obtained from the same cats(Table 5). Increases in frequency, paired
electrical stimulation, calcium, and norepineph-rine shortened TTP in these papillary musclesby averages of 149, 65, 28, and 73 msec,respectively. However, these same proce-dures in left atria, while also producing sub-stantial increases in T and AT/At, resulted inonly trivial changes in TTP, averaging — 5,+1, +2, and —5 msec, respectively.
Discussion
Both increasing the temperature and aug-menting the thyroid state of the animal in-creased AT/At, while shortening TTP of theisolated cat papillary muscle. Both of thesestimuli, which augment the velocity of short-ening of the contractile elements (6, 9, 13)and therefore elevate the intensity of theactive state, produce relatively minor changesin T because of the concomitant decrease inthe duration of the active state. These findingsare consistent with the observations of Brew-ster and associates (14) on the intact heartsof hyperthyroid, euthyroid, and hypothyroiddogs. Furthermore, the similarity betweenthe effects of temperature and thyroid onheart muscle, and the additive effects of bothof these influences, are compatible with the
TABLE 5Comparison of Responses between Atrial and Ventricular Myocardium
Frequency12/min to 48/min
Papillary musclesLeft atria
PESPapillary musclesLeft atria
CalciumPapillary musclesLeft atria
NorepinephrinePapillary musclesLeft atria
Ten:sion(PM-g/mm2; LA-g)Control
5.1 ± 0.53.0 ± 0.6
3.9 ± 0.73.4 ± 0.4
4.9 ± 0.73.1 ±0.5
4.8 ± 0.83.0 ± 0.5
Experiment
7.4 ± 0.5*3.9 ± 0.6*
9.2 ± 1.4*5.6 ± l.Of
7.5 ± 0.4*5.2 ± 0.9*
7.4 ± 0.8*4.6 ± 0.3*
Rate of tension development(PM-g/mnV7sec; LA-g/sec)Control
11.2 ±0.930.8 ± 7.5
10.2 ± 3.133.7 ± 6.3
13.1 ±2.131.9 ± 6.2
13.4 ± 1.328.0 ± 5.4
Experiment
31.5 ±42.5 ±
28.2 ±54.0 ±
21.9 ±51.0 ±
25.2 ±46.2 ±
5.0*8.6*
4.6*11.0*
1.6*10.6*
3.8*5.4*
Time to peak tension(msec)
Control
395 ± 24102 ± 10
393 ± 40103 ± 10
375 ± 25102 ± 10
373 ± 31107 ± 8
Experiment
246 ± 26*97 ± 9*
328 ± 25t104 ± 12+
347 ± 25*104 ± 10t
300 ± 28*102 ± 9*
Observations at 30° and 12 contractions/min in 5 normal cat papillary muscles and left atria from the samehearts. Values represent the mean ± SEM.
*P < 0.01, t ? < 0.05, fP > 0.05 for paired values before and after the institution of increased frequency ofcontraction, paired electrical stimulation (PES), increased calcium concentration, and exogenous norepinephrine.PM = papillary muscles; LA = left atria.
hypothesis that they operate through similaror perhaps even identical mechanisms.
The effects of increasing frequency of con-traction resemble those of hyperthyroidismand increased temperature in that a markedreduction in TTP occurs. However, only alimited range of frequency was explored, 12to 48 contractions/min, to avoid hypoxia andto assure stability of high energy phosphatestores and the contractile properties of themuscles. Over the range of frequencies stud-ied, an increase always produced a relativelygreater augmentation of AT/At than reductionof TTP, so that T was increased. Increasesin frequency in the intact heart have alsobeen shown to augment the velocity of fibershortening and to reduce the duration ofcontraction (15-18). However, tension doesnot change consistently and the changeswhich do occur depend on the specific con-ditions of the experiment, such as the actualfrequencies involved, the species studied, andwhether atrial or ventricular myocardium isexamined (19). The effects of increasing fre-quency on TTP are of considerable impor-tance, since they determine the extent towhich the increase in AT/At is offset by asimultaneous reduction in TTP; thus theeffects of frequency on TTP in part determinethe effects of frequency on T.
The findings with strontium differed fromall of the other positive stimuli which elevatedT and AT/At, since this substance produceda substantial augmentation in the durationof the active state in addition to augmentingits intensity. The additive effect of this com-bination of actions resulted in a particularlystriking elevation of T. Indeed, the averagepeak tension developed by the musclestreated with strontium (12.3 g/mm2) ex-ceeded that observed following any of theother positive inotropic stimuli, which raisedT to averages ranging from 6.2 to 11.0 g/mm2.It has been suggested that strontium maysubstitute for calcium in the activation pro-cess of muscle (13, 20), and although thisaction resembles calcium in increasing T andAT/At, the difference in the effects of stron-tium and calcium on TTP suggests that the
Circulation Research, Vol. XXI, December 1967
action of strontium is more complex (Table1)-
It has been known for some time that hypo-thermia increases tension development, bothin the isolated myocardium and in the intactheart (6, 21). The findings of the presentinvestigation are in accord with those ofother investigators (22) who indicated thatthe augmentation of T during hypothermiaresults from a prolongation of the durationof contraction which more than compensatesfor any simultaneous depression of AT/At.The effects of temperature illustrate the prob-lems inherent in classifying inotropic stimuli.As temperature was reduced from 25° to21°, T rose significantly, and such an eleva-tion would, in general, be considered torepresent a positive inotropic effect. How-ever, this reduction in temperature produceda striking reduction of the AT/At, an effectwhich has been interpreted to represent anegative inotropic influence. This apparentdiscrepancy can be explained by a considera-tion of the effects of temperature reductionon the force-velocity curve. It has been ob-served, both in isolated myocardium (6) andin the intact left ventricle (21), that hypo-thermia may reduce the velocity of short-ening of the unloaded muscle (Vmas) whileincreasing the peak tension development.Thus, it does not appear satisfactory to class-ify hypothermia as a simple positive or nega-tive inotropic influence, but rather it seemsmore meaningful to characterize separatelyits effects on the intensity of the active state,on its duration, and on the interaction ofthese two independent variables.
It is interesting to note the differences be-tween ventricular myocardium and skeletalmuscle on the one hand, and atrial myo-cardium on the other. The changes in twitchtension developed by skeletal muscle result,almost without exception, from variations inTTP, with little or no alteration in AT/At(23-26); in contrast, in atrial myocardium Tis altered primarily by changes in AT/At,while TTP remains almost constant (Table5). In ventricular myocardium changes in T
usually result from a combination of variationsin AT/At and TTP.
A major unresolved problem is the elucida-tion of the underlying factors which controlAT/At and TTP. On first approximation,changes in the intensity of the active statecan result from alterations in excitation-con-traction coupling and/or in the chemical in-teractions of the contractile proteins them-selves. Thus, it has been suggested that anincrease in external calcium concentration,an increase in frequency of contraction (27),or paired electrical stimulation all increaseAT/At by making greater quantities of calciumavailable for activation of the contractile sys-tem, while elevation of temperature mightincrease AT/At by increasing the velocity ofthe chemical reactions involving the contrac-tile proteins themselves. In this connectionit is interesting to note that muscles fromanimals with experimentally induced conges-tive heart failure have recently been shown toexhibit reductions in AT/At that are propor-tional to the lowering of myofibrillar ATPaseactivity (28) and that the velocity of shorten-ing in skeletal muscle is correlated grossly withits myosin ATPase activity (29). On theother hand, the duration of the active statemay be dependent on the speed with whichthe relaxing system can remove an activatingsubstance, such as calcium. This too is anactive, energy-dependent, enzymatic process(30) and therefore should be affected bychanges in temperature.
AcknowledgmentsThe authors are indebted to Dr. W. W. Parmley for
data on dZ-propranolol and quinidine and to MissNancy Dittemore for technical assistance.
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