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

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