Studies on Myocardial Metabolism. V. the Effects of Lanatoside-C on the Metabolism of the Human Heart

Home , Cardiac glycoside, Lanatoside C, Ouabain

STUDIES ON MYOCARDIAL METABOLISM. V. THE EFFECTS OF LANATOSIDE-C ON THE METABOLISM OF THE HUMAN HEART

J. M. Blain, … , A. Siegel, R. J. Bing

J Clin Invest. 1956;35(3):314-321. https://doi.org/10.1172/JCI103280.

Research Article

Find the latest version: https://jci.me/103280/pdf STUDIES ON MYOCARDIAL METABOLISM. V. THE EFFECTS OF LANATOSIDE-C ON THE METABOLISM OF THE HUMAN HEART 1 By J. M. BLAIN, E. E. EDDLEMAN, A. SIEGEL, AND R. J. BING (From the Departments of Experimental Medicine and Clinical Physiology, The Medical College of Alabama, Birmingham, Alabama, and the Veterans' Administration Hospital, Birmingham, Ala.) (Submitted for publication Septenber 6, 1955; accepted November 16, 1955) Since 1785 when Withering undertook the first this method should aid in elucidating the meta- systemic study of the effects of digitalis, a large bolic pathways within the heart muscle; thus reac- amount of data has been accumulated describing tions determined by more precise in vitro methods its pharmacological effects. Despite intensive could be re-evaluated in the light of data obtained study, the underlying mechanism responsible for on the human heart in vivo. the beneficial results in patients with heart failure The various cardiac glycosides differ in time of remains obscure. Although digitalis in small doses onset and persistence of action. Lanatoside-C, the may affect the heart rate through its vagal effect, preparation used in this study, is a purified deriva- it is agreed that the predominant action of this tive of digitalis lanata which can be given intra- drug is on the heart muscle directly (1). In ad- venously. The onset of action depends on the dition, the cardiac glycosides also influence the dosage used; with average digitalizing doses of 1.2 ionic gradient between the muscle cell and the sur- to 1.6 mgm., the so-called "vagal effect" usually rounding medium (2-8). Its effect on oxygen appears within 15 to 20 minutes, reaching a maxi- consumption and foodstuff utilization of the heart mum in about 40 minutes. Weisberger and Feil has been repeatedly investigated in the heart-lung (14), for example, reported their results in treat- preparation, in tissue slices and in tissue homoge- ing 17 cases of resistant paroxysmal auricular nates (9). The reader is here referred to the re- tachycardia. Sixteen cases reverted to normal view article of Wollenberger (10). However, the sinus rhythm within 40 minutes, with an average abundance of conflicting results suggests that response of 17.6 minutes. Barrow (15), in a cardiac glycosides may exhibit different metabolic series of 26 patients, found the average time for defects dependent on the experimental condition. reversion to be 19 minutes. Nicholson (16) ad- It appears likely that one limiting factor in elu- ministered 1.6 mgm. of Cedilanidg to 22 subjects cidating the mechanism of action of the glycoside with auricular fibrillation whose rates were stabi- has been the lack of means for direct study of the lized at 120 beats per minute. In all patients there metabolic responses of the heart beating in a more was a drop of from 15 to 80 beats within 15 min- physiological environment. By the technique of utes, with an average decrease in heart rate of 24 coronary sinus intubation, a direct study of pa- beats. Stead, Warren, and Brannon (17) ad- tients treated with therapeutic doses of a rapid ministered 1.6 mgm. of lanatoside-C intravenously acting cardiac glycoside is possible. Simultaneous to 22 patients with congestive failure. The first sampling of arterial and coronary venous blood, effect noticed was a fall in venous pressure which together with measurement of the coronary flow, began in 5 to 10 minutes and continued for 30 to permits the determination of the net myocardial 60 minutes. Cardiac output, measured 60 to 70 gain or loss of foodstuffs, gases or other metabolites minutes after the injection, showed an average rise (11-13). While providing no information re- of 1.6 liters per minute. This effect was noted re- garding intermediary reactions, data obtained by gardless of the cardiac rhythm or the initial stroke volume. 1 Work supported by the U. S. Public Health Service Grant No. H-1129 (C3), The Life Insurance Medical The present paper reports on the action of la- Research Fund, the American Heart Association, and natoside-C on the myocardial metabolism of glu- Sandoz Pharmaceuticals. cose, pyruvate, lactate, amino acids, ketones and 314 EFFECTS OF LANATOSIDE-C ON CARDIAC METABOLISM 315 fatty acids. A subsequent report will deal with determined by the manometric method of Van Slyke and the effect of this glycoside on the sodium and po- Neill (24). Blood glucose was measured by the method tassium balance of the human heart. of Hagedorn and Jensen, using Somogyi's method to pre- pare the filtrates (25, 26). Pyruvate was determined according to the method of Friedemann and Haugen (27), PROCEDURE using a tricloracetic acid filtrate, and lactate by the method of Barker and Summerson For the deter- Twelve (28). undigitalized adult patients were selected for mination of fatty acids the method of Man and Gildea was the study (Table I). Seven of these had heart disease used (29). This is essentially a modification of the pro- with evidence of left ventricular hypertrophy but had no cedure of Stoddard and Drury's volumetric analysis (30). symptoms of congestive failure other than decreased ex- Amino acids were estimated according to the method of ercise tolerance. Five of these seven were hypertensive Albanese and Irby (31) and ketones by a modification of (J. B. J., G. G., E. E., W. H., and M. T.), one had rheu- the micromethod of Greenberg and Lester (32). matic heart disease (D. T.) and one had aortic insuffi- From the analysis of the blood samples the myocardial ciency due to syphilis (F. M.). Congestive heart failure extraction (coronary arteriovenous of was present in four difference) oxygen, patients. Heart failure in these indi- carbon dioxide and individual metabolites was determined. viduals resulted from rheumatic valvular disease (L. W.), The myocardial usage of 100 grams of left ventricle was hypertension (W. B.) and from congenital malformation calculated as the product of the myocardial extraction of the heart (E. F.). In the fourth patient the cause of times the coronary flow. The oxygen extraction ratio the failure was unknown (J. R.). One of the subjects in was determined by multiplying the myocardial extraction the series had no evidence of heart disease (J. W.). by the oxygen equivalent of the All patients particular metabolite di- were studied in the post adsorptive state. vided by the myocardial oxygen extraction. This ratio In three of the subjects (W. B., E. F., and J. R.) with represents the of congestive percentage oxygen extracted by the failure preliminary treatment with bed rest, heart which could be accounted for catabo- diuretics and salt restriction was by complete necessary before the lism of foodstuff to carbon dioxide and water. Because studies could be performed. Small doses of merperidine of the temporary storage of metabolites and their con- or pentobarbital were given on the morning of the study version within the metabolic the sum of the indi- to those individuals who seemed pool, unduly apprehensive. vidual oxygen extraction ratios at any one moment need The majority received no premedication. not total 100 per cent. Cardiac catheterization was performed in the usual The percentage myocardial extraction manner (12, 13). If diagnostic represents the procedures were indicated, percentage of the arterial concentration of a metabolite these were completed first. Cardiac output was meas- which is removed from blood ured by the coronary during its pas- method of Fick (18), the mixed venous sam- sage through heart muscle; it is calculated by the formula: ple being obtained from the most distal cardiac chamber A-V entered. Expired air was collected in a Douglas bag or A X 100, where A and V represent the respective Tissot spirometer. Oxygen and carbon dioxide in ex- arterial and coronary venous concentrations of the metab- pired air was determined by the method of Scholander olites. It has previously been shown that extraction (19). of The coronary sinus was intubated according to a substrate by the human heart varies in proportion to previously described methods (20). Simultaneous blood the arterial concentration (11). Since the percentage samples were collected from the coronary sinus and right myocardial extraction takes into consideration the fluc- femoral artery for determinations of oxygen, carbon di- tuations in arterial level, this calculation provides a more oxide, glucose, pyruvate, lactate, fatty acids, amino acids accurate means of comparing changes in uptake of car- and ketones. In most cases duplicate samples were drawn bohydrates, fats and proteins by the myocardium than and the results of the two analyses averaged. Coronary does the arteriovenous difference alone. flow was measured 30 to 40 minutes following the inges- Evidence of effect was obtained tion of the glycoside. Cedilanid® from com- Coronary flow was not determined parisons of electrocardiograms taken before and at in- prior to the injection of lanatoside-C, since this would tervals of five to ten minates have following the injection of unduly prolonged the procedure; also it had been the glycoside. The earliest and most consistent previously found that digitalis in therapeutic doses change does observed was slowing of the ventricular rate, which was not influence the rate of coronary blood flow (21). present in nine the end Lanatoside-C was subjects by of thirty minutes administered intravenously in doses and was most marked in the two patients with auricular of .02 to .03 mgm. per 1il body weight, and coronary blood fibrillation (L. W. and E. F.). In seven subjects with flow was measured using the nitrous oxide desaturation normal sinus method rhythm the average decrease amounted to 10 (22, 23). Thirty to forty minutes later, or as beats per minute. Other soon as definite electrocardiographic changes in- electrocardiographic changes appeared cluded depression of the S-T in three (slowing of heart rate, depression of ST segment patients, segment or pre- flattening of the T-waves in five patients, and the onset mature ventricular contractions), blood samples for of frequent ventricular metabolic determinations were extrasystoles after digitalis ad- again obtained from the ministration in one individual. No femoral artery and coronary sinus. electrocardiographic alterations were present in one and the Oxygen and carbon dioxide contents of patient, tracings blood were of one subject were lost. However, the develoDment of 316 J. M. BLAIN, E. E. EDDLEMAN, A. SIEGEL, AND R. J. BING

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0 c o00N0 o od0.C o. Cd Cd - OD Cd 00 o 00 CdcC~ OD ai = U) o z co U) E o4 * | _- 0 U o 0 00 14c A c U) 4 '0 0 .c: 0~ co (4 YC . J,0 E'X co -I a % C 2 a X~~~C v ~4 4 IX 0% Cd C'; .0IinU0 C0 C:. ao 0 cd (4 z~ C4 318 J. M. BLAIN, E. E. EDDLEMAN, A. SIEGEL, AND R. J. BING nausea and vomiting forty minutes after the administra- creased in two subjects and increased in nine. tion of Cedilanid* (ten minutes after blood samples were For the group as a whole, there was an average taken) probably constitutes adequate evidence of drug effect in this person. fall of 1.9 mgm. per 100 cc. in the arterial level The individual observations before and after CedilanidO of glucose and an average rise of 0.6 mgm. per administration are shown in Table I. Differences ob- 100 cc. in its myocardial extraction. Neither of served after injection of the glycoside were subjected to these changes was statistically significant. Be- statistical analysis, each patient serving as his own con- cause of the lower arterial level, the percentage trol. Changes were considered significant only if there was less than one chance in twenty that the effect could glucose extraction by the heart showed a more con- have been due to chance alone (p < .05). spicuous gain, increasing from 3.7 per cent to 4.5 per cent. Although the p value was > .10, RESULTS slightly above the level accepted as significant in this study, it can be seen in Figure 1 that the No significant changes in the respiratory quo- percentage extraction increased in all subjects tient of the heart could be attributed to the action except the two who initially had the highest per- of Cedilanid®. Of the ten observations available centages of glucose extraction (W. H. and E. F.). before and after treatment, the respiratory quotient Myocardial pyruvate extraction showed small decreased in seven and increased in three (Table fluctuations in both directions, but no consistent I). The myocardial oxygen extraction for the changes occurred which could be ascribed to the group showed a mean increment of 0.37 volumes drug. There was a slight gain from 16.4 per cent per cent, increasing in eight subjects and decreas- to 19.2 per cent in the mean percentage pyruvate ing in two. The difference was not statistically extraction. However, in four individual observa- significant (p > .20). Since digitalis causes no tions this ratio declined. significant alteration in coronary flow, it can be as- Alterations in arterial lactate level and myo- sumed that myocardial oxygen usage likewise re- cardial lactate extraction were similarly inconsis- mained unchanged (21). tent. As in the case of glucose and pyruvate the Observations of the arterial concentration and mean percentage extraction advanced slightly, ris- coronary arteriovenous glucose difference were ing from a control level of 24 per cent to 29 per available in eleven subjects. The arterial glucose cent after the administration of Cedilanid@. concentration decreased in eight and increased in Data of fatty acid metabolism were available in three patients, while the myocardial extraction de- ten subjects. The arterial concentration of fatty acids decreased in seven and increased in three PERCENTAGE MYOCARDIAL GLUCOSE EXTRACTION J=~lX 900 individuals with a mean increase of .031 mEq. per 100 cc. (p > .10). Changes in fatty acid extraction and percentage extraction were more variable and did not approach statistical significance. The average percentage extraction by the heart increased from 1.2 per cent to 1.7 per cent. Despite the small percentage of available fatty acids extracted, their importance as a potential source of energy to the heart muscle is demonstrated by their high oxygen extraction ratios. In several instances the quantity of fatty acids removed from the coronary circulation could account for more than 100 per cent of the simultaneous oxygen extraction if it is assumed that they are completely PATIENT metabolized to carbon dioxide and water. Similar FIG. 1. ILLUSTRATES THE PERCENTAGE MYOCARDIAL GLU- findings have been described in previous publica- cOSE EXTRACTION IN THE ELEVEN PATIENTS STUDIED tions (11, This ratio increased in all but two patients (10 and 13). 11); these had the highest initial percentage of glucose In eight of nine patients on whom data were extraction. available the amino acid extraction by the heart EFFECTS OF LANATOSIDE-C ON CARDIAC METABOLISM 319 declined. In one subject myocardial extraction of diac output and efficiency without causing signifi- amino acids was zero before and after injection of cant changes in oxygen consumption (21). Cedilanid®, and in four others the extraction fell The results of the present study demonstrate to zero. It should be noted, however, that the that digitalis in therapeutic dosage produces only arterial amino acid concentration also declined in minimal changes in the extraction of foodstuffs by six of the patients, so that the decrease in percent- the heart. Since there is some rise in the mean age extraction was not as marked as was the coro- extraction percentage of pyruvate and lactate, the nary arteriovenous difference. The mean per- lower amino acid extraction after digitalis may be centage extraction before and after therapy was 2.5 due to the "protein sparing" effect of carbohy- per cent and 1.1 per cent, respectively. The myo- drates. cardial metabolism of ketones was not altered by The negative effect of Cedilanid@ on carbohy- digitalis. drate metabolism in the intact human heart con- trasts with results of Wollenberger (34). This DISCUSSION investigator found, in studying the action of The mass of conflicting data in the literature Ouabain on the respiration of heart slices in the makes it likely that the difference in metabolic ef- Warburg apparatus, that the glycoside accelerates fects of digitalis on heart muscle may be the re- the oxidation of glucose and lactate. This action sult of various concentrations of drug employed accounts for the simultaneous increase in respira- and the differences in the kind of substrates and tory activity, with the acceleration of glucose oxi- the techniques used in the studies (10, 33, 34). dation exceeding, in proportion, that of the oxygen However, even with identical techniques and con- uptake. The results reported in this paper dem- centrations of drugs the results have been contra- onstrate only a slight elevation in percentage glu- dictory. For example, various observers have cose extraction without any change in myocardial noted that Ouabain increased the oxygen con- oxygen utilization. Since myocardial lactate utili- sumption of cardiac muscle slices respiring in the zation remains unchanged, a digitalis-induced shift Warburg apparatus, while others have reported a from a glycolytic to a largely respiratory metabo- decreased oxygen uptake with the same concentra- lism of carbohydrates as suggested by Wollen- tion of glycosides (10, 33). Using human auricu- berger is unlikely in the human heart under these lar appendages obtained at operation, Burdette conditions. (35) found that the addition of lanatoside-C The finding that the cardiac glycoside produces tripled the rate of respiration. David (36) on the no significant changes in myocardial oxygen con- other hand, found that after an initial increase sumption or in total foodstuff utilization suggests Ouabain caused a diminution in the respiration of that the improvement in work capacity of the fail- the isolated frog's auricle. ing heart induced by these glycosides must be the Studies on the heart-lung preparation have result of their action on energy liberation, or more yielded equally variable results. Evans (37) re- specifically, on the contractile proteins of failing ported that while digitalis increased cardiac out- heart muscle directly. Digitalis can accelerate the put and efficiency, the oxygen consumption of the spiraling of myosin threads (38). Mallov and heart diminished. Peters and Visscher (9) found Robb (39) reported that actomyosin threads pre- that digitalis increases both oxygen consumption pared from beef hearts showed increased spiraling and efficiency of the perfused heart. However, and shortening when digitoxin was added. In a the increase in efficiency on a percentile basis was later report the same authors, using protein sur- four to five times as great as the increase in myo- face films, found that Ouabain increased the work cardial oxygen consumption (9). performance of actomyosin prepared in this man- The bulk of evidence suggests that in the various ner (40). Digitalis also influences the polymeriza- types of experimental "failure" digitalis increases tion of actin (41). Furthermore, digitoxin does the work performance of the heart out of propor- not combine with sarcosomes of heart muscle, in tion to the changes in oxygen consumption, thereby which the enzymes concerned with energy produc- increasing myocardial efficiency. In patients with tion are concentrated (42). Additional evidence congestive failure cardiac glycosides increase car- that cardiac glycosides do not influence energy 320 J. M. BLAIN, E. E. EDDLEXAN, A. SIEGEL, AND R. J. BING production is available from the findings of Wol- 8. Boyer, P. K., and Poindexter, C. A., The influence lenberger (43) that Ouabain or Digoxin in thera- of digitalis on the electrolyte and water balance of heart muscle. Am. Heart J., 1940, 20, 586. peutic dosages causes no change in the concentra- 9. Peters, H. C., and Visscher, M. B., The energy tion of high-energy phosphate carriers and phos- metabolism of the heart in failure and the influ- phocreatine. Similar conclusions can be drawn ence of drugs upon it. Am. Heart J., 1936, 11, 273. from the work of Rothlin, Taeschler, and Cerletti 10. Wollenberger, A., The energy metabolism of the (44). These investigators induced heart failure failing heart and the metabolic action of the cardiac glycosides. Pharmacol. Rev., 1949, 1, in the heart-lung preparation with dinitrophenol, 311. a drug which increased myocardial oxygen con- 11. Bing, R. J., The metabolism of the heart. Harvey sumption. Lanatoside-C restored the initial work Lecture Series (In Press). performance of the heart without further influenc- 12. Bing, R. J., Siegel, A., Vitale, A. G., Balboni, F., ing myocardial oxygen consumption. Sparks, E., Taeschler, M., Klapper, M., and Ed- wards, S., Metabolic studies on the human heart in vivo. I. Studies on carbohydrate metabolism of SUMMARY the human heart. Am. J. Med., 1953, 15, 284. The effects of therapeutic doses of Cedilanid® 13. Bing, R. J., Siegel, A., Ungar, I., and Gilbert, M., Metabolism of the human heart. II. Studies on on the metabolism of glucose, pyruvate, lactate, fat, ketone and amino acid metabolism. Am. J. amino acids, fatty acids and ketone bodies of the Med., 1954, 16, 504. human heart have been investigated. The studies 14. Weisberger, A. S., and Feil, H., Lanatoside C in the were carried out on patients using intubation of treatment of persistent paroxysmal auricular tachy- the coronary sinus. cardia. Am. Heart J., 1947, 34, 871. 15. Barrow, J. G., Treatment of paroxysmal supraven- Only minimal changes in the extraction of tricular tachycardia with Lanatoside C. Ann. Int. metabolites by the heart were observed. The find- Med., 1950, 32, 116. ings suggest that the improvement in work ca- 16. Nicholson, J. A., The intravenous use of lanatoside pacity of the failing heart induced by the glycoside C. New England J. Med., 1943, 229, 619. is the result of its action on energy liberation. 17. Stead, E. A., Jr., Warren, J. V., and Brannon, E. S., Effect of lanatoside C on the circulation of patients REFERENCES with congestive failure. A study using catheterization of the right side of the heart. Arch. Int. Med., 1. Lown, B., and Levine, S., Current concepts in digi- 1948, 81, 282. talis therapy. New England J. Med., 1954, 250, 18. Fick, A., Ueber die Messung des Blutquantums in 771. den Herzventrickeln. Verhandlungen. Sitzungs- 2. Stutz, H., Feigelson, E., Emerson, J., and Bing, R. J., bericht, phys. med. 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