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Effects of Epinephrine on Frog Ventricle By RICHARD A. HENXACY, P H . D . pressure drop between the heart container and beaker was used to measure the flow rate. The extracardiac pressures (within heart container) and the lateral isotonic pressures were recorded by means of 2 Statham gages (F and G) and a Hathaway recorder with a paper speed of either 4 or 10 inches per second (fig. 1). In some experiments, valves (J and K) were introduced in both the inflow and outflow channel, which permitted an additional resistance (hypodermic needle) to be inserted on the outflow side. Isoehoric (isovolumetric)2 pressures were often recorded. When the extracardiac pressure (P n ) dropped below the base line (fig. 2), the heart was actively expelling its contents back into the reservoir. Pressures above the base line indicated filling. Since the filling pressure is constant, the rate of change of the transmural pressure is indicative of the relaxation rate, and is calculated from the pressure-time curve from manometer F (fig. 1). Whereas this is usually approximated as the difference between the pressure recorded by an intraventricular manometer and either atmospheric or intrapleural pressure, such an approach did not seem feasible in these experiments. Since the extracardiac pressure in this preparation is constantly changing and it was not possible to use an intracardiae transducer, transmural ventricular pressures, and flow rates were calculated from the information obtained from the manometers and the resistance of the inflow cannula and "U" tube. FR = Po/Wo whore Fli is the flow rate, Po is the pressure outside the heart as related to the surface of the fluid in the beaker, and Wo is the resistance of the "U" tube and attached resistor. W T Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 HE possible methods by which epinephrine may increase cardiac output, though in practice they are not completely independent, can be separated for purposes of discussion as follows: (1) increase in end-diastolic volume; (2) decrease in end-systolic volume; and (3) increase in heart rate. The first 2 factors determine the stroke volume. Assuming a constant heart rate, the end-diastolic volume can be increased by only one of the following factors: (1) an increase in diastolic time by shortening systole; (2) decrease in the average resistance to filling (renitenee) either by decreasing the average resistance of the myocardium during diastole (an increase in distensibility) or by hastening relaxation after contraction, or both; and (3) by increasing the filling pressure. A decrease in the end-systolic volume (assuming constant end-diastolic volume) can be accomplished by an increase in the strength of contraction, an increase in its duration, a decrease in the opposing (aortic) pressure, or by atry combination of these. It is well known that epinephrine increases the strength of contraction and the heart rate. However, little conclusive evidence has been presented about the effects of epinephrine on relaxation and resistance to filling. The present series of experiments were performed in order to determine these effects. Pc = Po X — --- , Pc = pressure drop through ''' o the heart cannula, Wc = the resistance of the inflow cannula. Pv = 1\ - Pc - Ph - Po (Wc/W0) where Pv is the true intraventricular pressure and Ph is the head of pressure in the reservoir. The transmural pressure (Pt) at any instant is Pv - Po = Ph - Po (1 + WC/WJ. The rate of change d P,/dt — K APJAi since Ph is a constant, and Methods The methods wore similar to those used in the preceding- experiment;1 however, some changes were lmidc. Instead of a recording pipette, a "U" tube with a 16 gage needle attached was used to connect the heart chamber to a beaker, and the K = From the Department of Physiology, Ohio State University, Columbus, Ohio. Supported by a grant from the National Institutes of Health, U. S. Public Health Service. Research performed during Dr. Hennaey's tenure of a Post-Doctoral Fellowship of the Central Ohio Heart Association. Received for publication March 28, 19G0. Circulation Research, Volume VIII, .Inly lltoo -1-WC/WO. As the pressure outside the ventricle increases, the drop in pressure across the ventricle decreases. At the time of the greatest extra cardiac pressure the diastolic flow rate is maximum. This is the point of minimum renitenee (R,,,) and it is calculated as previously reported.1 The volume difference between the end of systole and the end of diastole was determined by use of a 831 HENNACY 832 .2 ,B i) 1 c Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 I -A 4 fi B 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2fl 3.0 —-5TS—1 G ^ . 1 1 p • Figure 2 N Figure 1 Apparatus used icith the isobaric and isochoric heart preparation. In certain experiments, a valve J and a return flow tube I with valve K icere used. Otherwise, the heart pumped fluid bach into the reservoir except during isochoric contractions. A = Heart cannula. B and C = Three-way stopcocks. D = U tube. E = Resistor. F — Statham gage (venous) measures extracardiac pressure. G — Statham gage (venous) measures intracardiac pressure. H — Outflow resistor. I = Outflow tube. J = Inflow valve. K — Outflow valve. L = Tube from oxygen tank. ]\[ — Reservoir. N = Heart container. planiineter, since during diastole the area of the P0-timo curve is proportional to the total flow. Another measurement of relaxation is the time required from the beginning of filling until the plateau is reached (fig. 2 A-B, relaxation time) at which time the resistance is at a minimum and inflow rate becomes constant. Results Without Valves or Added Kesistors Effect of Pressure Changes on the Relaxation Rate Normal ventricle. Within a range of small filling pressures (1 to 2 cm.) the rate of relaxation is constant, and therefore independent of the pressure. However, with higher filling pressures gradually applied, the rate of relaxation becomes proportional to the pressure. Previous experiments have established that sudden pressure increases lead to increases in the minimum renitence.1 How- Comparison of isobaric to isochoric (isorolumetric) transmural pressures. Ordinate, pressure in grams/ t:m..1; abscissa, time in seconds. Solid line, normal; dashed line, after 0.2 [x.g. of epinephrine/ml. Upper. Isobaric contractions. Transmural pressures above 0 line are positive, obtained during filling; pressures below the 0 line are negative, obtained during systole. A-B = Diastolic relaxation time. Lower. Isochoric contractions. Transmural pressures are measured relative to the filling pressure at the commencement of contraction. ever, the first effect of a pressure increase is an acceleration in the rate of relaxation, followed by a decrease if high (> 8 cm. H^O) pressures are used. If the pressure is then reduced, the rate of relaxation continues to be slower than that previously observed for the lower pressure, but the relaxation rate returns to normal over a period of 5 to 10 minutes. I-Iypodynarnic ventricle. In a ventricle with a small stroke volume, the relaxation rate is small, and initially proportional to the filling pressure. "With higher pressures, the relaxation rate increases, but still remains relatively small if the ventricle does not respond to increased filling pressure by an increased ejection (hypodynamic heart). This may be related to the low pll and hypoxia which accompany small stroke volumes in this preparation. Effect of Frequency on the Rate of Relaxation If the filling pressure is low or medium (1 to 8 Gm.), the rate of relaxation is slowed by both fast and slow contraction rates, and has Circulation Research, Volume Vlll, July 1900 833 EPINEPHRINE IN DIASTOLE a particular rate at which the most rapid relaxation occurs. Thus, with about 5 cm. of filling pressure, the maximum relaxation rate is observed at about 15 to 20 contractions a minute. In contrast to low pressures, in 1 experiment in which the filling pressure was .15 cm., the slowest relaxation rate occurred when the contraction rate was 30 beats/min. Higher or lower rates of contraction resulted in a great increase in the relaxation rate. Effects of Epinephrine on the Relaxation Sate and Diastolic Relaxation Time Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 Low pressures (1 to 2 cm.) and a contraction rate of 12 beats/min. At low pressures, the normal relaxation is sometimes greatly slowed, even without epinephrine. In hearts with a fairly rapid relaxation at low pressures, epinephrine greatly lengthens the diastolic relaxation time and greatly reduces the maximum relaxation rate (fig. 3). However, if sufficient time is given for complete filling by adjusting the contraction rate, the volume intake during diastole will usually be slightly increased, in spite of the slowing of relaxation. This indicates probably a decrease in the end systolic volume as a result of the inotropic effect of epinephrine. At 5 cm. filling head, contraction rate 12 to 30 beats/min. In 9 out of 13 cases, the maximum rate of relaxation was slower with epinephrine. In 2 instances, the maximum rate remained the same. In only 2 experiments did the rate increase. In one of these experiments, the stroke volume was small. In the other, the beginning of the relaxation was considerably slower. In all but 2 cases, the relaxation time (time from the beginning of filling to the plateau) increased. At pressures from 8 to 15 cm. and contraction rate from 12 to 30 beats/min. With the filling pressure at 8 cm., 3 out of 4 experiments showed an increase in the maximum rate of relaxation, while 1 experiment showed no change. "With new preparations, 2 out of 4 at 10 to 15 cm. of filling pressure showed no change, while the other 2 showed a decrease in maximum rate of relaxation. However, in all experiments the diastolic reCirculation Research. Volume VIII, July 1060 r* ^ — • T.-.-C 1 2 3 4 ! Figure 3 Effect of epinephrine and pressure changes after epinephrine on the relaxation rate. Solid line, normal (5 cm. JJ^O pressure); dashed line, 0.2 jxg. epinephrine/ml. added; dotted line, pressure raised to 9 cm. JJ^O. Ordinate, renitenee in Gm. sec. cmr" laxation time was increased after using epinephrine. At continuous filling pressures of 10 cm. or greater, the heart appeared distended and gradually contracted less effectively, which was irreversible upon reducing the pressure. It is presumed that these hearts were damaged by the high pressure. Effects of 'Epinephrine on the Minimum Renitenee In table 1 are the values of the minimum renitenee (P/Flow) of the heart at 20 to 22 C, before and after the addition of 0.2 ^g of epinephrine per ml. ("Winthrop Laboratories). The last 2 columns in the table show that there is no consistent change in this value due to epinephrine, though the dosage consistently increased S3-stolic pressure. In hearts that are hypodynamic either naturally or from the effects of sodium pentobarbital, epinephrine does lower the Em toward the normal value.1 Effect of Valves and Added Outflow Resistance on the Relaxation Rate With the insertion of valves, it is possible to have a low filling pressure, and yet insert resistance into the outflow channel. The addition of a resistor (no. 18 needle attached to reservoir return tube) to the system only slightly affected the rate of relaxation of the normal heart. In some cases, the relaxation rate continuously decreased, because of probably a reduction of stroke volume and the effects of hypoxia. With epinephrine and valves but no resistor the rate of relaxation was greatly slowed, as in the case of those 834 HENNACY Table 1 Effect of Epinephrine on Rm and the Maximum Rate of Relaxation'"' Experiment no. Heart rate Cont./min. 1 2 20 4 5 12 12 20 12 6 24 7 8 IS 3 Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 9 10 :n 12 13 12 12 12 12 20 20 Stroke volume After Norm. .2/iEp. .71 .40 .81 .74 .27 .24 .90 .75 .41 .77 .71 1.00 .69 .26 .28 .75 .41 .82 Maximum relaxation rate K - j — Cm./sec. After .2 ii Ep. Norm. 10.7 28.5 20.S 29.6 13.3 10.7 14.5 9.1 13.8 16.0 8.0 5.9 20.S 44.9 12.8 20.S 20.S 2.6 6.2 2.1.6 64.0 14.0 .SI .SO 7.6 .85 .92 .50 1.00 3.1.2 27.0 22.0 .60 .50 Relaxation time (sec.) Min.— (dm. sec.cm.-°) Flow After .2 n Ep. Norm. .6 .3 .4 1.0 .4 0 3.1 0 3.1 .5 .1 1.1 .4 4.6 2.2 2.7 12.0 3.S 1.6 2.9 9.9 3.3 8.3 5.9 Norm. 1.4 .5 .2 .5 .45 .13 .3 .25 1.00 .7 .7 .1 .25 .30 .4 3.3 3.1 9.4 1.00 2.0 l.S 2.0 .60 6.0 After .2 IL Ep. l.S 1.6 1.0 6.0 "Filling pressure 5 em.; no valves. experiments without valves. "With the addition of the resistor, however, the rate of relaxation usually approached the normal rate (before administering epinephrine and inserting resistance), and in some cases was more rapid. Effect of Epinephrine on Isochoric and lsobaric Contractions Epinephrine increases the maximum rate of relaxation in isochoric contractions. However, contraction time (period of positive tension greater than the filling head) appears to remain constant, although Segall and Anrep reported a lengthening of contraction time with epinephrine.8 In comparing isobaric to isochoric contractions, it can be seen (fig. 2) that the maximum rate of volume change (isobaric) occurs before the maximum tension (isochoric), and after administering epinephrine, this difference becomes even more pronounced so that the isobaric volume change is completed considerably earlier than the corresponding contraction time of the isochoric heart. Discussion Several investigators4"0 have stated that epinephrine has a direct effect on cardiac muscle during diastole. Luudin7 and F. Moore (personal communication) have shown that the resistive properties to stretch, and thus, stiffness and viscosity, are not changed in frog ventricular tissue by the addition of adrenaline or epinephrine, respectively. The present experiments on the intact frog ventricle substantiate these conclusions. In comparing the maximum rate of relaxation of the isochoric contraction in the normal and epinephrine-treated heart, it is obvious that the rate of relaxation is increased to a greater extent than the pressure is increased after epinephrine. Therefore, it seems probable that, epinephrine increases the relaxation rate independently of its inotropic effect in increasing pressure. Epinephrine may influence the relaxation in the isochoric contraction by prolonging the contraction time of some elements in a similar fashion to that observed by Goffart and Ritchie with skeletal muscle.s However, none of the elements must be prolonged beyond the maximum time of the elements of the normal heart, or else the total positive tension time would be prolonged. If certain elements were prolonged, while others are unchanged, subsequent relaxation would apparently be rapid as more elements would relax together. Circulation Research. Vohtmc VIII, July J!)GO 835 EPINEPHRINE IN DIASTOLE Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 The slowing of relaxation during diastole with epinephrine iu isobaric contractions may seem at first to be contradictory to the above conclusions. Lundin,7 however, has shown that a cardiac fiber in the contracted state can lose its tension when released, but when subsequently stretched, develops a greater tension at a given length than the isometric tension at that length. Thus, a heart contracting with much force can reach a sufficiently small volume so that most of the tension disappears, and filling can then commence before the diastolic state is fully established. Onflow would then lead to a re-establishment of some tension, due to the stretching of fibers. Also, since epinephrine increases the amount of tension per unit stretch of contracted fibers, this would further increase the resistance to filling so long as there is any residual tension from the preceding systole. By these means, filling would be slowed and controlled by the relaxation rate. In fact, pressure changes have little effect on the initial relaxation rate after epinephrine, (fig. 3) or at very low pressures. At a large volume, however, the linear stretch of a heart during filling may be too slow to produce tension if relaxation is also occurring. For a given flow rate, the rate of linear stretch would be inversely proportional to the square of the heart's radius (assuming the heart to be spherical). Epinephrine, by accelerating the relaxation rate of contractile units, would then accelerate the relaxation rate during filling. A resistance in the outflow channel would serve to increase the end systolic volume, and thus, enhance relaxation. Increasing the filling pressure, in the preparation without valves, however, would act in 2 opposite directions, since not only will the outflow resistance increase, but also the inflow rate. This is probably the reason for the conflicting results using high filling pressures without valves. The contraction time is decreased with increasing contraction rates." This would be expected to accelerate the relaxation rate. By this means, a heart with a small end-systolic volume may fill rapidly, even with epinephCirculation Research, Volume VJIT, Jvly 19fiO vine. At low contraction rates, however, tiie treppe effect will produce weak contractions which would have 2 effects on increasing the relaxation rate: (1) increasing the size of the heart at the beginning of filling, and (2) prolonging the ejection time so that filling only occurs after the residual tension from the preceding systole is over. There are, therefore, both high and low rates of contraction that will produce rapid relaxation at least with some filling pressures. Summary Thirty-six isolated frog ventricles were attached to an inflow cannula with stopcocks that could permit direct systolic ejection back into the reservoir, return flow back to the reservoir by another route through a valve, or isochoric contractions. The heart, enclosed in a container with a " U " tube outlet, produced pressure changes (extra-cardiac) which could be used in determining the in-flow rate and transmural pressures. The rate of change of the transmural pressure was calculated for the frog ventricle during early diastole. This value was taken as a measurement of the rate of relaxation. The effects of epinephrine (.02 /xg./ml.) Avere studied. At low filling pressures without valves (and therefore with outflow pressure equal to inflow pressure), epinephrine slows the rate of relaxation, although other inotropie effects, such as an increase in stroke volumes, are present. If, however, the heart contracts against a high outflow pressure or resistance the rate of relaxation is increased by epinephrine. The slowing of relaxation in the former case is a result of filling commencing before relaxation is complete. In the isochoric heart, epinephrine does not change the time of positive tension, but does accelerate the relaxation after contraction. Summario in Interlingua Treiita-sex isolate ventriculos do rana ossovii attaeliate a un cannula de influxo con obturatores que pcrmittcra lo directo retro-ejection systolic a in le reservoir, lo refluxo al reservoir per un altcre circuito via un valvula, o contractiones isochoric. Le corde, includite in un receptaculo con un eflluxo a tubo in " U , " produceva altcrationcs do prcssion (extra-cardiac) que poteva esser usate in determinar le intensi- 836 HENNACY Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 tate del influxo e le pressiones traiisiuural. Le magnitude del alteration in le pression traiisiuural essev.a calculate pro le ventriculo del rana durante le eodiastole. Iste valor esseva acceptate eomo mesura del magnitude del relaxation. Lc effeeto de epinephrina (0,02 /ig/ml) esseva studiate. A basse pressiones de rcplenaniento sin valvulas (e assi sin pression de cffluxo equal al pression de influxo), epineplirina relenta le progrosso del relaxation, ben que altere effectos iuotropic—conio per exemplo un augmento del voluinines per pulso—es presente. Tnmen, si lc conic so eontralie contra un alte pression o resistentia de eflluxo, le relaxation es promovite per epineplirina. Le relentaniento del relaxation in le prime de istc cases cs le resultato del facto que le replenamento coinencia ante que le relaxation es complete. In lo corde isochoric, epineplirina non altera le temporo de tension positive sod accelera le relaxation post, contraction. References 1. HENNACY, E. A., AND OGDEN, E.: Factors affect- ing the filling of the f.rog's ventricle after isotonic contraction. Circulation Research 8: 825, 3960. 2. CLARK, A. J., ET AL.: Metabolism of the Frog's Heart. London, Oliver & Boyd, 1938. 3. SEGALL, H. N., AND ANREP, G. V.: Isometric con- traction of the frog's ventricle. Heart 12: 61, 1926. 4. WIGGERS, C. J.: Cardiodynamic action of drugs. J. Pharmacol. & Exper. Therap. 30: 217, 1927. 5. OFDYKE, B. I"1.: Effect of changes in initial tension, initial volume, and epinephrine on the ventricular relaxation process. Am. J. Physiol. 169: 403, 1952. 0. BUCKLEY, N. M., SIDKY, M., AND OGDEN, E.: Fac- tors altering the filling of the isolated left ventricle of the dog heart. Circulation Kesearch 4: 148, 1956. 7. LTJNDIN, G.: Mechanical properties of cardiac muscle. Acta physiol. scandinav., Suppl. 20, 7: 1, 1944. 8. GOKPART, M., AND EITCHIK, .1. M.: Effect of adrenaline on the contraction of mammalian skeletal muscle. J. Physiol. 116: 357, 1952. 9. CLARK, A. J.: Effect of alterations of temperature upon the functions of the isolated heart. J. Physiol. 54: 275, 392L Circulation Research, Volume VIII, July I960 Effects of Epinephrine on Frog Ventricle RICHARD A. HENNACY Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 Circ Res. 1960;8:831-836 doi: 10.1161/01.RES.8.4.831 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1960 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/8/4/831 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. 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