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Dopamine-lnduced Alterations In Left Ventricular Performance By William L. Block, M.D., and Ellis L. Rolett, M.D. Downloaded from http://circres.ahajournals.org/ by guest on June 14, 2017 ABSTRACT Left ventricular responses to dopamine infusion of 1 to 5, 8, and 10 /Ltg/kg per min for 30 minutes were studied in 14 anesthetized intact dogs. Cardiac output (dye dilution) and stroke volume increased progressively while the end diastolic volume (thermodilution) remained constant, signifying more complete ventricular ejection and resulting in a progressive decline in end systolic volume. Heart rate remained unchanged as did aortic mean pressure, but in the presence of a greatly increased systemic blood flow, the calculated peripheral vascular resistance declined progressively. A linear dose-dependent increase in both systolic ejection rate and circumferential shortening rate suggested directionally similar changes in myocardial fiber shortening. Isovolumic contraction was characterized by a marked increase in the peak velocity of left ventricular pressure rise and presumably in the velocity of force generation without change in the maximum pre-ejection force. These results indicate that dopamine increased myocardial contractility. At these infusion doses dopamine differs from norepinephrine and isoproterenol in causing little change in systemic blood pressure or heart rate in the intact dog. The steady heart rate, stable blood pressure, and constant end diastolic volume suggest that the inotropic response to dopamine administration was due to a direct myocardial action which was otherwise unmodified by the preload or afterload of ventricular contraction. ADDITIONAL KEY WORDS catecholamines inotropy myocardial contractility pressure derivative cardiac catheterization • Dopamine (3, 4-dihydroxyphenylethylamine), the immediate biological precursor of norepinephrine, has pronounced cardiovascular effects which have not been fully defined. Experimentally produced effects on peripheral vasomotor activity have included (1) renal and mesenteric vasodilation in the dog and (2) predominant vasoconstriction in the extremities of the dog and man.1"4 Augmented renal blood flow and sodium excretion have been described in both species.5' ° Direct cardiac effects of dopamine have varied, presumably because of differences in From the Department of Medicine, University of North Carolina and North Carolina Memorial Hospital, Chapel Hill, North Carolina. Supported by Grant HE-08580 from the U. S. Public Health Service and Grant 5 T l HE-5486 from the National Heart Institute. A portion of this material lias previously appeared in abstract form in Clinical Research, April, 1965. Accepted for publication January 17, 1966. Circulation Resojcb. VoL XIX, July 1966 beta-adrenergic stimulation thermodilution anesthetized dogs dosage and experimental procedure. Using an open-chest canine preparation and single injections of dopamine (10 to 40 /ig/kg), Eble showed small and inconsistent changes in cardiac output.2 Holmes and Fowler, however, demonstrated significant increases in cardiac output and right ventricular contractile force (strain gauge arch) in a canine heart-lung preparation following single doses of 100 to 500 fig.7 McDonald and Goldberg, studying the intact dog, reported elevated systolic and decreased diastolic systemic pressures without change in heart rate following dopamine injections of 2 to 16 fig/ kg.4 Larger doses produced more pronounced pressor responses. Dopamine infusions in the human subject (5.9 to 11.6 //.g/kg/min) increased cardiac output with essentially no change in heart rate.8 Systemic pressure elevations were largely systolic, although diastolic pressure was also slightly raised. 71 72 Downloaded from http://circres.ahajournals.org/ by guest on June 14, 2017 Most administered catecholamines produce either a substantial pressor response or a prominent tachycardia with or without an associated fall in systemic pressure. These effects are believed to be mediated through alpha and beta adrenergic receptors respectively.9 Catecholamine-induced increases in myocardial contractility may be modified by such changes in blood pressure or heart rate.10'X1 Because small doses of dopamine do not produce major changes in heart rate and systemic blood pressure, the following study was undertaken to define more thoroughly the effects of dopamine on left ventricular performance in the intact anesthetized dog. Methods Fourteen mongrel dogs weighing 16 to 31 kg were anesthetized with 40 to 70 ml of chloralose (1.6%) and urethane (16%) 15 minutes after intramuscular administration of 3.0 mg/kg of morphine sulfate. Additional 5 to 10 ml supplements of the chloralose and urethane solution were administered during the study in order to maintain a relatively steady state of anesthesia as judged by absence of comeal reflexes. Respiration was maintained by a Harvard pump and cuffed endotracheal tube. The femoral veins were cannulated with polyethylene tubing for intravenous administration of drugs. Retrograde catheterization of the left ventricle and central aorta was performed through one femoral and one carotid artery leaving the other carotid artery intact. The pressure signals were obtained through 50-cm 7F woven dacron catheters connected to Statham P23Db transducers by means of 80-cm lengths of polyethylene 280 tubing. The catheters were filled with heparinized isotonic saline; the polyethylene tubing and transducers were filled with mineral oil. The amplitude-frequency response of each catheter system was linear (±5%) to 25 to 30 cycles/ sec as determined by periodic testing with a sine wave pressure generator. Peak velocity of left ventricular pressure rise (dp/dt) was obtained by electronic differentiation of the left ventricular pressure signal using a Philbrick P2 differential operational amplifier and external circuit linear to 28 cycles/sec. Calibration was accomplished by differentiating a sine wave from a waveform generator.12 Cardiac output (CO) was determined in duplicate by indicator dilution (left ventricular injection of indocyanine BLACK, ROLETT green*) and ventricular volumes by thermodilution (10 dogs).18 Mean aortic pressure (AOm) was obtained by electronic integration of the aortic pressure signal, and the left ventricular end diastolic pressure (LVed) was evaluated from high gain tracings of left ventricular pressure. Lead n of the electrocardiogram was constantly monitored. All signals were recorded on a Sanborn 550M photographic recorder either directly or after initial recording on a model 700 TMC magnetic tape recorder. One to two hours after the induction of anesthesia, control observations were obtained. Dopamine,** diluted with isotonic saline, was then infused intravenously at rates of 1, 2, 3, 4, 5, 8, or 10 /ng/kg/min for 30 minutes utilizing a peristaltic roller pump (Holter, model RDO34). Ah1 hemodynamic measurements were repeated during the last fve minutes of each infusion period. Once initiated, the rate of dopamine infusion was increased from one level to the next without interruption. Each dog was studied at one to five of the selected levels of dopamine infusion. During dopamine stimulation (4 yug/kg/min) one dog was given, intravenously, 10 mg (0.4 mg/kg) of propranolol.t a known beta adrenergic blocking agent, and hemodynamic measurements were repeated within fifteen minutes. CALCULATIONS For each period of observation mean values for heart rate (HR), stroke volume (SV), systolic ejection period (SEP, seconds/beat), and systolic ejection rate (SER, SV/SEP) were calculated. Peripheral vascular resistance (PR, dynes'sec* cm-5) was estimated by: P R = ( A O m / C O ) x 79.92. Mean left ventricular end diastolic volume (EDV) was computed from the thermodilution curves by: EDV = SV where t n + 1 and tn represent deflections of the thermodilution curves from base line on sequential strokes. A mean t n + 1 /t n value was obtained from 20 to 45 determinations during each period of observation. Mean left ventricular end systolic volume (ESV) was calculated by: ESV = EDV — SV. The ejection fraction (EF, SV/EDV) was obtained from the thermodilution curves as 1 — ( t n + 1 / t n ) . The left ventricle was assumed to be spherical in shape, and its mean circumferential shortening rate (CSR, cm/sec) was calculated *Cardio-Green; Hynson, Westcott and Dunning, Inc. "3-hydroxytyramine • HC1, California Corporation for Biochemical Research. tlnderal, Ayerst Laboratories. Gradation Reseucfa, VoL XIX, July 1966 73 DOPAMINE AND VENTRICULAR PERFORMANCE from the equation: CSR= 2TT{T1 — r 2 )/SEP, where i1 and r2 are the respective left ventricular end diastolic and end systolic radii. ANALYSIS OF DATA Downloaded from http://circres.ahajournals.org/ by guest on June 14, 2017 Experimental observations at any dose level of dopamine were compared with the appropriate control observations. Because of the nonhomogenous animal population the signed rank method was used to determine statistically significant (P<0.05) changes from control observations.14 Regression equations relating mean differences between control and experimental observations to dopamine infusion rates were calculated by the method of least squares. Correlation coefficients for dose-response relationships and standard errors of individual mean observations were calculated from standard formulae of statistical analysis. dogs, closely approximate basal values reported for the unanesthetized dog.17 All dogs had either regular sinus rhythm (10 dogs) or sinus arrhythmia (4 dogs). DOPAMINE INFUSIONS Cardiac Output and H«art Rat* The directional changes in the mean cardiac output and heart rate values are illustrated in figure 1. All dogs except one responded to dopamine administration with increases of systemic blood flow which were significant at infusion rates of 5, 8, and 10 /Ltg/kg/min. Furthermore, five of eight and six of seven dogs had elevated cardiac outputs at 3 and 4 /xg/kg/min respectively. The Results CONTROL OBSERVATIONS r-0.233 y-O.I86X+O.I77 p>0.60 "5—I •- 10 Mean values for control observations of all dogs are listed in table 1. Minor discrep- 5 6 <^ 0 < S -I0J TABLE 1 1.6 Mean (±SE) Values of Control Observations Cardiac output (L/min) Heart rate (beats/min) Stroke volume (ml) Ejection fraction LV end diastolic volume (ml) LV end systolic volume (ml) Systolic ejection period (sec/beat) Systolic ejection period (ml/sec) Circumferential shortening rate (cm/sec) LV dp/dt (mm Hg/sec) Aortic systolic pressure (mm Hg) Aortic diastolic pressure (mm Hg) Aortic mean pressure (mm Hg) LV diastolic pressure (mm Hg) Peripheral resistance (dynes • sec • cm- 8 ) 2.59 ± 0.34 74 ± 6 34±3 0.35 ± 0.02 96 ± 6 63±4 1.2 I 0.205 ± 0.004 0.975 yO.l55X-0.053 (XO.OOOI o 0.8 168 ± 1 4 1 12.0 3549 165 100 131 7.9 ± 0.8 ±340 ±6 ±4 ±5 ± 0.4 4826 ± 550 ancies among these figures are accounted for by the four dogs which did not have ventricular volume determinations. The values for stroke volume and end diastolic volume are approximately 503? greater than those values initially reported for chloralose-anesthetized dogs but are essentially the same as more recent values obtained from dogs of comparable size.15'16 The heart rates, although lower than those found usually in anesthetized Grcularion Reieirch, Vol. XIX, July 1966 1.4 O6 S °4 0.2 MM 1 2 3 4 3 8 DOPAMINE, ;ig/kg/mln 10 FIGURE 1 Mean changes, dopamine over control values, in cardiac output and heart rate at different levels of dopamine stimulation. Each point represents the average of observations made in six to nine dogs. The calculated least squares regression equations ate drawn, and r is the coefficient of correlation between the observed mean values and corresponding dopamine infusion rates. Although no significant change (P > 0.6) in heart rate was observed, the cardiac output shows a highly significant (P < 0.0001) doserelated rise. 74 BLACK, ROLETT TABLE 2 Effects of Dopamine on Cardiovascular Pressures and Peripheral Resistance; Mean (±SE) Changes from Control Values Dopunine, /ig/kg/min —> l Aortic systolic pressure, mm Hg < 2 3 4 j 8 10 ±2.5 <1 ±3.9 1.4 ±4.5 <1 ±3.3 -5.4 ±3.4 17 ±17.3 28.5 ±12.9 Aortic diastolic pressure, nun Hg 4.4 ±3.0 <1 ±2.0 0 ±3.1 -2.7 ±1.8 -6.3 ±2.7 -2.8 ±6.1 4.8 ±9.0 Aortic mean pressure, mm Hg -3.6 ±1.7 —3.0 ±3.3 -1.0 ±2.2 -3.6 ±3.9 -6.0 ±3.6 3.0 ±6.0 15 ±9.0 LV end diastolic pressure, nun Hg <1 <1 <1 <1 <1 <1 <1 Peripheral resistance, dynes • sec • cm-* -204 ±362 -355 ±445 -359 ±129 -962 ±430 -871 ±226 -924 ±343 -1281 ±240 Downloaded from http://circres.ahajournals.org/ by guest on June 14, 2017 *LV: left ventricular. tdp/dt = peak velocity of LV pressure rise. one dog that never responded with an increased blood flow received a maximum dopamine dose of only 3 /Ag/kg/min. Mean increments in cardiac output, despite being statistically significant only at higher infusion rates, were nearly linear over the entire dose range. Heart rate for most dogs remained relatively constant, and there was no significant difference from control values at any level of dopamine infusion. Stroke and Left Ventricular Volumei The increase in cardiac output without change in heart rate represented a significant elevation of stroke volume at 4, 5, 8, and 10 /^g/kg/min. In addition, stroke volume was increased in seven of eight dogs at 3 fig/'kg/ min. The progressive rise in stroke volume was a function of more complete ventricular emptying from a constant end diastolic volume (fig. 2). The dopamine-induced increments in stroke volume and ventricular emptying resulted in a concomitant decline in end systolic .volume. The change in stroke volume as a function of the rise in ventricular ejection fraction can be examined further in figure 3. In 36 of 39 paired stroke volume and ejection fraction determinations obtained during dopamine infusion, both variables increased simultaneously over their respective control observations. In only one instance was the ejection fraction elevated from control without a simultaneous rise in stroke volume. Velocity Function! of Ventricular Performance Figure 4 illustrates the induced changes in three velocity functions of left ventricular performance. The systolic ejection rate (fig. 4A) and circumferential shortening rate (fig. 4B) rose to maximum differences of 153 ml/sec and 11.5 cm/sec respectively. These values represent an increase of almost 200% of control. Both variables were elevated significantly from control observations by doses of 4 to 10 /xg/kg/min. The systolic ejection period, important in the calculation of systolic ejection rate and circumferential shortening rate, was shortened maximally from control by a mean difference of 0.03 sec at 10 /Ag/kg/min. This was not statistically significant. The dp/dt (fig. 4C) proved to be an easily monitored indicator of alterations in left ventricular performance. During dopamine infusion at levels which changed cardiac performance significantly, an observable rise in the monitored dp/dt signal occurred within five minutes after initiating a given infusion dose. In 45 paired SV and dp/dt determinations the SV was increased. In 43 of these, dp/dt increased simultaneously above control values, regardless of changes of heart rate, aortic pressure or end diastolic volume. Mean dp/dt values were elevated significantCircuktion Rejeirdi, VoL XXX, July 1966 DOPAMINE AND VENTRICULAR PERFORMANCE 75 20 16 12 8 E 3° > z < -4 -8 2 -12 3 r» 0.953 y-l.49X-2.54 P *aooi -16 -20 4 3 DOPAMINE, Downloaded from http://circres.ahajournals.org/ by guest on June 14, 2017 FIGURE 2 Mean changes in stroke volume and left ventricular volumes secondary to dopamine administration. The stroke volume figures are based on values from aU dogs and on the ventricular volume figures from 10 of 14. The mean difference from control for end diastolic volume varied no more than ±3 ml; however, the mean stroke volume change at 10 iig/kg/mhi represented 156% of control observations. 30 28 26 24 r = 0.776 (wOOOOOl 22 20 18 -4-2 <"•* 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 A IN EFxOO FIGURE 3 Individual changes in stroke volume (ml) plotted vs. ejection fraction (%) for all animals. The relatively high correlation coefficient (r) confirms conclusion that changes in stroke volume were primarily a function of changes in ejection fraction rather than in end diastolic volume. ly from control at a lower dose level, 3 /tg/kg/min, than any other variable measured. Pressures and Peripheral .Resistance Mean changes in pressure values and calGrcnlauoo Reseircb, Vol. XIX. July 1966 culated peripheral resistances are tabulated in table 2. Only one of the -fourteen dogs demonstrated a pressor response, and this accounts for the elevated aortic systolic pressure at 8 /Ag/kg/min. Five of six dogs, however, had elevated aortic systolic pressures at 10 /ig/kg/min; and of these five, three had a simultaneous rise in aortic diastolic pressure. Aortic diastolic pressure tended to fall at 4, 5, and 8 /ig/kg/min but was significantly lowered from control at 5 /ig/kg/min only. No significant change in mean aortic pressure or left ventricular end diastolic pressure was found at any level of dopamine infusion. Calculated peripheral resistance declined progressively. Because the mean aortic pressure was never significantly different from control, the changes in peripheral resistance were inversely proportional to increases in systemic blood flow. Beta Adrenerglc Receptor Blockade In the one dog given propranolol during dopamine stimulation, the effect of dopamine was abolished almost instantaneously as judged by a prompt fall in the monitored dp/dt signal. Measurements obtained within fifteen minutes after propranolol administra- 76 BLACK, ROLETT tion revealed a return to control values (table 3). dopamine-induced changes in left ventricular performance have not been characterized previously.18 The presently described cardiac stimulatory properties and previously noted peripheral vascular effects of dopamine suggest that it may be a useful agent in the clinical management of congestive heart failure and nonhemorrhagic shock.1-6> 18 At- Ditcuision In the present study, dopamine has proved to be a potent stimulant of the canine myocardium. Although clinical benefit has been demonstrated in congestive heart failure, 175 3600 13 ISO 3900 14 B r = 0.974 y=l5.9X-l3.7 p<O.OOOI T r>0.985 yl.23X-l .17 p<0.000l 12 II 1 1 3300 4 ; 3000 /i S 10 2700 ]/ 1/ S 9 IOO I UJ /1 7 z < < a 4 3 25 2 8 10 i i X a. 2400 2100 1800 z 1500 V 1J UJ \ z 5 I if / 1 / 1 / c UJ SO / T 1 1 to o -4-1 in E E _• ^ / « e• UJ I <n +j 1200 EAI Downloaded from http://circres.ahajournals.org/ by guest on June 14, 2017 / i 125 0 1 2 3 4 3 r = 0.997 y=383X-546 p<0.000l A • /! "ft 2 900 600 300 / l 0 0 12 3 4 5 8 10 0 12 3 4 5 8 10 DOPAMINE, pg/ kg/ min FIGURE 4 Mean (±SE) differences from control in A: systolic ejection rate; B: circumferential shortening rate; and C: dp/dt induced by dopamine. Although individual bars showing standard error exhibit overlap, each of the three variables increase almost linearly with increasing dopamine infusion rates over the range of 1 to 10 itg/kg/min. This dose-dependent relationship Is characterized by a highly significant r value for each variable instance, although the individual mean values were not significantly elevated at infusion rates below 3 to 4 ng/kg/min. TABLE 3 Effects of Beta Adrenergic Blockade on Action of Dopamine Stroke vofrime Ejection fraction ml Hurt rate beati/min Control 25 67 0.31 Dopamine, 4 jig/kg/min 41 71 Propranolol, 0.4 mgAg 28 56 dp/dt* nun Hg/iec Syitolk Circumferential ejoction ihortening rate rate cm/iec ml/sec 3154 125 9.9 0.49 5182 210 17.5 0.35 2659 120 9.9 *dp/dt = peak velocity of LV pressure rise. Circulation Research. Vol. XDC July 1966 DOPAMINE AND VENTRICULAR PERFORMANCE Downloaded from http://circres.ahajournals.org/ by guest on June 14, 2017 tempts to elucidate the adrenergic mechanisms by which dopamine produces its effects have been complicated by a wide variation in administered dopamine doses.4'7i 19 The doses employed in the present study are those which have been shown previously to increase stroke volume without a major change in heart rate or mean systemic blood pressure in the dog and which cover the range of dopamine infusion rates employed in clinical studies.6'8 The pressor response associated with larger doses of dopamine could itself be a prominent factor in modifying left ventricular performance, and such doses were therefore avoided.20'21 In addition to direct catecholamine stimulation, regulation of myocardial performance can be achieved by changes in end diastolic ventricular volume (Frank-Starling principle), heart rate (frequency-dependent modification of contractility), and resistance to systolic ejection (afterload*) ,22 In the present study none of these mechanisms can be implicated because end diastolic volume and pressure (preload), heart rate, and aortic systolic pressure were relatively uniform over the dose range examined. The rise in stroke volume represents an increased fraction of ventricular volume emptied rather than an enlargement of end diastolic volume. In these respects dopamine differs from two of the most commonly used catecholamines: norepinephrine and isoproterenol. The myocardial stimulatory properties of norepinephrine in the intact subject are countered by a potent alpha adrenergic action which causes a pronounced pressor response, thereby inducing a reflex bradycardia and afterloading the ventricle. As a consequence the end diastolic volume tends to increase, and any augmentation of stroke volume may be a reflection of this increase rather than of a change in the ejection fraction.10 Isoproterenol, often considered the prototype of beta adrenergic catecholamines, induces a tachy•Variabons in afterload, under the present experimental conditions, are detectable primarily by changes in aortic pressure during systole. Circulation RoMrch, VoL XIX, July 1966 77 cardia, reduces end diastolic volume, and lowers the resistance to ventricular ejection through active peripheral vasodilation. Although isoproterenol causes more complete ventricular emptying, stroke volume increments are small and variable because of the decreased end diastolic volume.10' n The calculated ejection variables (stroke volume, systolic ejection rate, and circumferential shortening distance and rate) are functions of ventricular end diastolic volume and myocardial fiber shortening distance and rate. Since dopamine produced no significant change in the end diastolic volume, the increases in these four variables of systolic ejection reflect enhanced myocardial fiber shortening distance and rate and can be explained by a direct myocardial action. The peak velocity of left ventricular pressure rise occurs during isovolumic contraction and may be altered by variations in heart rate, aortic blood pressure, and ventricular end diastolic pressure.28'24 Changes "in dp/ dt observed in the present study, however, cannot be explained by alteration of any of these variables. If the surface area of the left ventricle is considered to be relatively constant during isovolumic contraction, then the peak velocity of left ventricular pressure rise is proportional to the peak velocity of left ventricular force generation. Although instantaneous force-velocity relationships and maximal left ventricular force generation could not be evaluated with this experimental model, the peak isovolumic contraction force (Fp) could be estimated from Fp = AOdp • Aed, where AOdp is the aortic diastolic pressure and Aed is the end diastolic area of the left ventricular chamber. Because the end diastolic volume was never significantly altered, the calculated end diastolic area can be assumed to have been essentially constant. The aortic diastolic pressure was ' feither slightly decreased or unchanged, suggesting a relatively constant Fp despite dopamine administration. Nevertheless, the peak velocity of force generation (as judged from dp/dt) during the same period was greatly enhanced. This finding is essentially similar BLACK, ROLETT 78 Downloaded from http://circres.ahajournals.org/ by guest on June 14, 2017 to those catecholamine-induced alterations in isolated papillary muscle and isometric ventricle preparations in which the velocity of pressure rise divided by the integrated systolic isometric tension proved useful as an index of myocardial contractility.25 Thus, the dopamine-induced alterations in dp/dt appear to represent a catecholamine-mediated increase in myocardial contractility which was otherwise unmodified by changes in heart rate, end diastolic volume, or aortic blood pressure over the dose range employed. The biochemical and pharmacological mechanisms responsible for the observed effects of dopamine have yet to be elucidated, but fall potentially into three classes: direct myocardial beta adrenergic stimulation, release of norepinephrine from adrenergic nerve endings, or in vivo hydroxylation to norepinephrine. As illustrated by one animal of the present study, a drug (propranolol) which blocks beta adrenergic receptors completely abolished dopamine-induced alterations in cardiac performance. Furthermore, recent evidence from this laboratory has demonstrated a complete lack of inotropic response to dopamine infusions of 5, 8, and 10 /u.g/kg/min following propranolol-induced beta adrenergic blockade.26 When these and previous studies are considered together there seems to be little question that these myocardial responses to dopamine were mediated through beta adrenergic receptors.4 Very little is known about the relationship between dopamine and norepinephrine release, and an earlier investigation is difficult to interpret because extremely large doses were used.18 The rapid onset of dopamine-induced changes might be interpreted as evidence against the in vivo conversion of dopamine to norepinephrine. Levitt et al., however, have recently presented data indicating that hydroxylation of dopamine can proceed very rapidly.27 Utilizing their data, one can estimate a local norepinephrine production of 2 /u.g/min for a 100-g left ventricle under our experimental conditions. The possibility that norepinephrine is formed or released does not, however, fully explain the lack of chronotropy in the absence of important changes in systemic pressure, the failure to elevate plasma nonesterified fatty acids,28 and the peripheral hemodynamic effects found with dopamine.2"4 Studying rabbit atria, Lee and Yoo have obtained additional evidence that dopamine has a direct myocardial stimulatory effect that is independent of norepinephrine release.29 Acknowledgment The authors acknowledge gratefully the technical assistance of Mr. H. Dieter Ambos. References 1. MCNAY, J. L., MCDONALD, R. H., JR., AND GOLDBERG, L. I.: Direct renal vasodilatation produced by dopamine in the dog. Circulation Res. 16: 510, 1965. 2. EBLE, J. N.: A proposed mechanism for the depressor effect of dopamine in the anesthetized dog. J. Pharmacol. Exptl. Therap. 145: 64, 1964.^ 3. ALL WOOD, M. J., AND GINSBURC, J.: Peripheral vascular and other effects of dopamine infusions in man. Clin. Sci. 27: 271, 1964. 4. MCDONALD, R. H., JR., AND GOLDBERG, L. I.: Analysis of the cardiovascular effects of dopamine in the dog. J. Pharmacol. Exptl. Therap. 140: 60, 1963. 5. MCNAY, J. L., MCDONALD, R. H., JR., AND GOLDBERC, L. I.: Natriuretic effect of dopamine infusion in the dog. Federation Proc. 22: 662, 1963. 6. MCDONALD, R. H., JR., GOLDBERG, L. I., MCNAY, J. L., AND TUTTLE, E. P., JR.: Effects of dopamine in man: augmentation of sodium excretion, glomerular filtration rate, and renal plasma flow. J. Clin. Invest. 43: 1116, 1964. 7. HOLMES, J. C , AND FOWLER, N. O.: Direct cardiac effects of dopamine. Circulation Res. 10: 68, 1962. 8. HORWTTZ, D., Fox, S. M., Ill, AND GOLDBERG, L. I.: Effects of dopamine in man. Circulation Res. 10: 237, 1962. 9. AHLQUIST, R. P.: A study of the adrenotropic receptors. Am. J. Physiol. 153: 586, 1948. 10. GORLIN, R., ROLETT, E . L . , YuRCHAK, P. M . , AND ELLIOTT, W. C.: Left ventricular volume in man measured by thermodilution. J. Clin. Invest. 43: 1203, 1964. 11. KRASNOW, N., ROLETT, E. L., YUBCHAK, P. M., HOOD, W. B., JR., AND GORLIN, R.: Isoproter- enol and cardiovascular performance. Am. J. Med. 37: 514, 1964. 12. NEAL, J. J., JR., HALPERN, W., AND REEVES, T. J.: Velocity and acceleration of pressure change Circulation Research, Vol. XIX, Jnly 1966 79 DOPAMINE AND VENTRICULAR PERFORMANCE in heart and arteries. J. Appl. Physiol. 15: 747, 1960. 13. ROLETT, E. L., SHERMAN, H., AND GORLIN, R.: Measurement of ventricular volume by thermodilution: an appraisal of technical errors. J. Appl. Physiol. 19: 1164, 1964. 14. Downloaded from http://circres.ahajournals.org/ by guest on June 14, 2017 17. ESSLER, W. O., AND FOLK, G. E.: 19. HARRISON, W. H., LEVITT, M., AND UDENFRTEND, S.: Norepinephrine synthesis and release in vivo mediated by 3, 4-dihydroxyphenylethylamine. J. Pharmacol. Exptl. Therap. 142: 157, 1963. 20. 24. IMPERIAL, E. S., LEVY, M. N., AND ZTESKE, H., JR.: Outflow resistance as an independent determinant of cardiac performance. Circulation Res. 9: 1148, 1961. 21. SONNENBLICT, E. H., AND DOWNING, Orculntioo Re*an±. Vol XJX, July 1966 S. E.: WALLACE, A. G., SKINNER, N. S., JR., AND MITCHELL, J. H.: Hemodynamic determinants of the maximal rate of rise of left ventricular pressure. Am. J. Physiol. 205: 30, 1963. 25. SlECEL, J. H . , AND SoNNENBLJCK, E . H . : IsO- metric time-tension relationships as an index of myocardial contractility. Circulation Res. 12: 597, 1963. 26. BLACK, W. L., AND ROLETT, E. L.: Cardio- vascular alpha adrenergic properties of dopamine. Circulation 32: 11-51, 1965. GOLDBERG, L. I., MCDONALD, R. H., JR., AND ZIMMERMAN, A. M.: Sodium diuresis produced by dopamine in patients with congestive heart failure. New Engl. J. Med. 269: 1060, 1963. GLEASON, W. L., AND BRAUNWALD, E.: Studies on the first derivative of the ventricular pressure pulse in man. J. Clin. Invest. 41: 80, 1962. Determina- tions of physiological rhythms of unrestrained animals by radio telemetry. Nature 190: 90, 1961. 18. 23. WONG, M., ESCOBAR, E. E., MARTINEZ, G., AND RAPAPORT, E.: Effect of coronary artery embolization on ventricular volumes. Circulation Res. 16: 518, 1965. MOMMAERTS, W. F. H. M., AND LANCER, G. A.: Fundamental concepts of cardiac dynamics and energetics. Ann. Rev. Med. 14: 261, 1963. RAPAPORT, E., WDEGAND, B. D., AND BRISTOW, J. D.: Estimation of left ventricular residual volume in the dog by a thermodilution method. Circulation Res. 11: 803, 1962. 16. 22. DDCON, W. J., AND MASSEY, F. J., JR.: Introduc- tion to Statistical Analysis. New York, McGraw-Hill Book Company Inc., 1957, p. 286. 15. Afterload as a primary determinant of ventricular performance. Am. J. Physiol. 204: 604, 1963. 27. LEVITT, M., SPECTOR, S., SJOEBDSMA, A., AND UDENFRIEND, S.: Elucidation of the rate limiting step in norepinephrine biosynthesis in the perfused guinea-pig heart. J. Pharmacol. Exptl. TheFap. 148: 1, 1965. 28. MUELLER, P. S., AND HORWITZ, D.: Plasma free fatty acid and blood glucose responses to analogues of norepinephrine in man. J. Lipid. Res. 3: 251, 1962. 29. LEE, W. C , AND YOO, C. S.: Mechanisms of cardiac activities of sympathomimetic amines on isolated auricles of rabbits. Arch. Intern. Pharmacodyn. 151: 93, 1964. Dopamine-Induced Alterations in Left Ventricular Performance WILLIAM L. BLACK and ELLIS L. ROLETT Downloaded from http://circres.ahajournals.org/ by guest on June 14, 2017 Circ Res. 1966;19:71-79 doi: 10.1161/01.RES.19.1.71 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1996 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/19/1/71 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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