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Calorigenic Effect of Norepinephrine Correlated with Plasma Free Fatty Acid Turnover and Oxidation

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Calorigenic Effect of Norepinephrine Correlated with Plasma Free Fatty Acid Turnover and Oxidation Calorigenic Effect of Norepinephrine Correlated with Plasma Free Fatty Acid Turnover and Oxidation Daniel Steinberg, … , Elsworth R. Buskirk, Ronald H. Thompson J Clin Invest. 1964;43(2):167-176. https://doi.org/10.1172/JCI104901. Research Article Find the latest version: https://jci.me/104901/pdf Journal of Clinical Investigation Vol. 43, No. 2, 1964 Calorigenic Effect of Norepinephrine Correlated with Plasma Free Fatty Acid Turnover and Oxidation * DANIEL STEINBERG, PAUL J. NESTEL,t ELSWORTH R. BUSKIRK,4 AND RONALD H. THOMPSON (From the Laboratory of Metabolism, National Heart Institute, and the Metabolic Disease Branch, National Institute of Arthritis and Metabolic Diseases, Bethesda, Md.) The increase in oxygen consumption caused by consumption in man and that this is accompanied administration of epinephrine has been extensively by an increase in turnover of plasma FFA and an studied in animals and in man. Many physiologi- increase in rate of conversion of labeled plasma cal and biochemical correlations have been made FFA to respiratory C1402. All of these effects of and many different hypotheses have been ad- norepinephrine are abolished or radically re- vanced to explain this so-called calorigenic effect, duced when the patient has first been given an in- but there is still no clearly established consensus travenous dose of pronethalol [2-isopropylamino- regarding the mechanism or mechanisms involved 1-(2-naphthyl)ethanol hydrochloride], a drug that (1, 2). inhibits catecholamine stimulation of adrenergic In recent years it has become clear that one of ,8-receptors (8, 9) and that prevents the FFA the most striking metabolic effects of the cate- mobilization induced by catecholamines (10).1 A cholamines is their ability to stimulate mobiliza- preliminary report of these findings has been made tion of depot fat in the form of free fatty acids (11). (FFA) (3). Studies by Fritz, Davis, Holtrop, Methods and Dundee (4) and by Eaton and Steinberg (5) The subjects studied were young, adult, normal, con- have shown, moreover, that the rate of oxidation trol volunteers on regular ward diets, with their total of labeled FFA by isolated skeletal muscle prepa- caloric intake adjusted to maintain constant body weight. rations in vitro is a function of the concentration Metabolic studies were all done after a 12- to 16-hour fast, and subjects remained at rest in bed on the morn- of FFA in the medium. Similar effects of FFA ings of studies. Indwelling plastic catheters were placed concentration on FFA oxidation have been dem- in an antecubital vein of each arm after the skin had been onstrated in rat liver slices (6) and in perfused anesthetized with Xylocaine (2-diethylamino-2',6'-aceto- rat liver (7). We have previously suggested, xylidide). A slow drip of 0.85% NaCl was maintained therefore, that the calorigenic action of catechol- to keep the catheters open. The subj ects were then taken to the metabolic chamber in a wheel chair. The amines might be due, at least in part, to their ef- construction and operation of the metabolic chamber fect in mobilizing FFA (5). have been fully described by Buskirk, Thompson, Moore, The present clinical studies were undertaken to and Whedon (12). At least 30 minutes was allowed to explore this possibility further. Because the meta- establish stable control values for rate of oxygen con- bolic effects of epinephrine are somewhat more sumption. Blood samples were drawn from one arm through a 3-way stopcock and delivered into a chilled complex than those of norepinephrine, in that tube containing heparin. Infusions of drugs, or labeled the former actively mobilizes glucose as well as palmitate, or both, were given into the opposite arm FFA, the present studies were done primarily with Bowman finger pumps. with norepinephrine. It is shown that infusion Plasma FFA were determined by Dole's method (13) of norepinephrine increases the rate of oxygen using isobctane (2,2,4-trimethylpentane) in place of hep- 1 Since these studies were completed, the Research De- * Submitted for publication August 12, 1963; accepted partment of Imperial Chemical Industries, Ltd., Maccles- October 3, 1963. field, England, manufacturers of pronethalol (Alderlin), tPresent address: Department of Medicine, Royal has found that mice on chronic high dosage show a sig- Melbourne Hospital, Melbourne, Australia. nificant incidence of locally malignant lymphosarcomata t Present address: Laboratory of Applied Physiology, of the thymus gland. Further use of the drug in clini- Pennsylvania State University, State College, University cal investigation should probably await thorough eva'u- Park, Pa. ation of these preliminary findings. 167 168 STEINBERG, NESTEL, BUSKIRK, AND THOMPSON TABLE I Effects of infused norepinephrine on FFA levels, FFA turnover, and oxygen consumption in normal control subjects Norepinephrine Plasma Plasma Percentage 02 Percentage Subject, administration FFA FFA change in con- change in sex, age, Dosage Blood Pulse concen- turn- FFA sump- 02 con- wt rate Time* pressure rate tration over turnover tion sumption ,ug/min min mm Hg pEq/ml pEq/min % ml/min % Control values 100/70 60 0.69 326 225 C.H. (I), 6 12 118/85 47 0.85 459 + 41 245 + 9 M, 21, 6 22 1.14 533 + 64 255 +13 66.6 kg 12 15 130/90 45 1.29 544 + 66 245 + 9 12 26 1.38 540 + 66 265 +18 Control values 95/65 70 0.36 215 C.H. (II), Placebo M, 21, infusionj 10 90/65 55 0.33 210 - 2 66.6 kg Control values 0.46 211 12 10 130/90 47 0.93 235 +11 Control values 100/60 55 0.46 205 B.L., 10.5 15 110/80 48 1.16 221 + 8 M, 23, Control valuest 105/60 47 0.54 205 66.1 kg 10.5 16 120/80 47 1.42 229 +12 Control values 110/65 58 0.48 226 192 B.L., 6 10 115/80 48 0.69 280 + 24 202 + 5 M, 23, 6 27 1.65 677 +200 210 + 9 66.1 kg 12 22 124/84 46 1.61 573 +154 231 +20 20 18 150/90 50 1.81 250 +30 L.C., M, 25, Control values 100/76 60 0.90 333 235 72.6 kg 18 16 140/110 60 1.57 506 + 52 286 +22 S.P., Control values 90/60 50 0.39 155 F, 17, 7.2 13 100/70 48 1.21 165 + 6 60.3 kg 14.4 14 1.69 181 +17 14.4 25 120/80 60 1.82 180 +16 * Times indicate the cumulative number of minutes from the start of administration at each dosage rate. Except where indicated by inter- vening control values, dosage rates were changed without interrupting the infusion. t Saline infused by Bowman pump with identical routine of blood pressure readings and blood samplings that accompanied norepinephrine infusions. Infusion identified to patient as "norepinephrine." t Obtained 53 minutes after discontinuing first norepinephrine infusion. tane. Blood glucose was measured enzymatically by the tracting by Dole's method, re-extracting the F-FA from glucose oxidase method described by Keston (14). the isooctane layer into alcoholic KOH, acidifying the Reagents (Glucostat) were obtained commercially.2 latter, and finally re-extracting the FFA into isooctane. Plasma lactate levels were determined enzymatically (15). The isooctane was dried in a counting vial under a Plasma FFA turnover was determined by using a con- stream of N2, the residue was redissolved in toluene stant intravenous infusion of palmitate-1-C'4. The basis containing 0.5% 2,5-diphenyloxazole, and radioactivity for this method has been fully discussed by Armstrong was assayed in a Packard Tri-Carb liquid scintillation and associates (16). The infusion solution was prepared spectrometer. In several experiments the lipids in the by adding a tracer amount of sodium palmitate-1-C'4 to final isodctane extract were fractionated on silicic acid a solution of human serum albumin (5 to 7.5%o). The columns (17). No significant amounts of radioactivity solutions were prepared for clinical use and were tested were recovered with the phospholipid fraction. for sterility and absence of pyrogens.3 The labeled pal- For measurement of C1402 production, a measured mitate was diluted in 100 to 150 ml of 0.85%o NaCl and fraction of the gas stream from the metabolic chamber infused at a rate of 1 to 1.5 ml per minute. Within 15 was diverted and collected in 4- to 5-minute periods in to 20 minutes the total FFA radioactivity per milliliter Douglas bags. The gas from these bags was slowly of plasma had reached a plateau value that did not then pulled through a gas-flow meter and delivered through vary more than + 10% during the control period. a sintered glass diffuser into a column of NaOH. A Plasma FFA radioactivity was measured by first ex- Ba(OH)2 trap connected in series showed that collection 2 of CO, was complete. Three-ml samples of the NaOH Worthington Biochemical Corp., Freehold, N. J. were added to 1 g of fluorescence-grade anthracene,5 and 3 Performed by Mr. William H. Briner, Radiopharma- ceutical Service, National Institutes of Health, Bethesda, 4 Packard Instrument Co., La Grange, Ill. Md. 5 Distillation Products, Inc., Rochester, N. Y. CALORIGENIC EFFECT OF NOREPINEPHRINE AND FFA TURNOVER 169 radioactivity was assayed in the liquid scintillation spec- by intravenous infusion of norepinephrine are trometer ( 18). summarized in Tables I and II. In Table the Pronethalol (Alderlin) was generously donated.0 lI Norepinephrine (Levophed) was diluted in 0.85%o NaCl responses to a second norepinephrine infusion, to a final concentration of 6.6 ,ug per ml (expressed as given immediately after administration of pro- the base).
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