Energy considerations

Energy

Considerations

JOHN C. KOVACH, M.D., Vancouver,

From the Cardio-Pulmonary Laboratory of the City of New York, and tbe Trjboro Hospital, New York, New York.

change in the actin of muscIe from a IongitudinaI cyIindric to a globuIar molecuIar form shortens it. This, together with heat production, is the energy reIease of muscuIar contraction. The appearance of active or free acetyIchoIine at the muscIe end-pIate causes this transformation in configuration by releasing adenosinetriphosphate (ATP) which forms an actomyosin ATP compIex from actomyosin. ATP contains instantly avaiIabIe high energy phosphate bonds (vide +a). The Krebs tricarboxyIic acid cycIe reIeases the bound energy of sunIight stored in fats, proteins and CHO to yieId 18 net high energy phosphate bonds (one is used to prime the cycIe). These are stored as “quanta” of high energy ATP. The process is termed coupIed phosphoryIation, and takes place in the grana of the ceI1. Three ATP bonds are formed for every atom of O2 utiIized. When O2 is added to a moIecuIe, an atom of H, is dispIaced and there is Ioss of an eIectron. This eIectron loss is energy Iiberation-the crux of the whoIe matter. Reduction is remova of an 02, addition of H, and addition of an eIectron. If one starts with a carbohydrate gIycogen, energy storage in the form of high energy phosphate bonds is brought about by the foIIowing transformations:

T

HE

glycogen

phosphorylases _____ .____~___~

_____ glycose-I-phosphate

mutases _ _ _ _ gIucose-6-phosphate isomerases

phosphofructokinases

_ _ _ fructose-6-phosphate _ _ _ fructose-x ,6-diphosphate

B. C., Canada

aIdolases and isomerases 3-phosphoglyccraIdehyde phospho-dehydrogenases _________________----transphosphoryIases ______________...-----

3-diphosphoglyceric acid 2 ATP formed 3-phosphoglyceric acid

mutases

transphosphoryIases transphosphorylases

condensing

2-phosphopyruvic acid 2 ATP formed pyruvic acid 3 ATP formed acety1 coenzyme A (this can come from fat or protein)

enzymes oxaloacetic citric acid

dchydrogenases ____________________-dehydrogenases

acid

&citric acid 3 ATP formed alpha-ketogIutaric acid 1 ATP ,jormed

dehydrogenases

succinic acid 2 A TP formed f umarases fumaric acid

f umarases

fumarases ______________________

malic acid 3 ATP ,formed osaloacetic

acid

The CO2 produced is expired, converted to urea or bicarbonates; 02 is utilized and energy produced and stored as described heretofore. Again the roIe of 02 in ATP formation can be visuaIized in photosynthesis. In the presence of the energy of sunIight through the action of dehydrogenase coenzyme I: Hz0 + DPN,,--

+ DPNred-

+ ->$ 02

Kovach In the absence of Iight: DPN,,d- + -44 0, + -3 ADP- + -3 POr-+ 3 ATP + DPN.H,O

oxidation reduction and energy reIease, be succintIy summarized as foIIows: In the tissues: KHbOz---+ KHb - - 02 KHb - - HzC03 ---+ KHCO,

The other method by which radiant bound energy is utiIized by the ceII is fermentation. MuscIe cells use both methods. Here gIucose is converted to Iactic acid without 02; in the yeast ceI1, gIucose becomes ethy1 aIcoho1, which is just a revamped Iactic acid moIecuIe. Fermentation, however, is wastefu1 and is approximateIy 350th as efficient as oxidation in the liberation of energy. NevertheIess, since the energy of the disease neopIasia comes from fermentation and not oxidation, it behooves the clinician to famiIiarize himseIf with this phenomenon. When ceIIs revert to this primitive method of metaboIism irreversibIy, true neopIasia has deveIoped. It is aIso of interest to observe that this process of fermentation goes on in the cytopIasm and not in the nucIeus. Oxidation of course occurs in the mitochondria. A brief summary of the roIe of vitamins in the oxidation reduction mechanism of the Krebs cycIe foIIows: Tbiamine is important in oxidation reduction by acting on aIpha-keto acids (pyruvic) through decarboxyIase. Thiamine forms pyrophosphate (cocarboxyIase), the coenzyme or prosthetic group of decarboxyIase. Ribojlavin is the prosthetic group of the Aavoprotein enzymes used in oxidative processes. Its consumption varies with the amount of protein metaboIism. Niacin is contained in coenzyme I and II used in H, transport and in CHO metabolism. Tryptophan can be a niacin precursor and aIso varies with protein metaboIism. Pantothenic acid is the prosthetic group of acetyIation and is important in adrenocortica1 function. Pyridoxine is used in amino acid decarboxyIation and deamination, and is important in anaboIism. Folic acid and Blz are important in hematopoiesis and B12 in transmethyIation as weI1. Ascorbic acid is important in detoxification and interceIIuIar coIIoid formation. It is a requirement of venuIar-vascuIar fragiIity, tissue repair and adrenocorticoids. The Iiver converts vitamins into enzymes. The roIe of potassium (K) in the transport of O2 and COZ, and hence its indirect influence in

In the Iungs: HHb - - 02 ----a HHbOz HHbOz - - KHCOs ---+

KHbO,

may

- - HI lb

- - CO2 --Hz0

In the tissues (CL shift): H.&O3 - - NaCI ---+ NaHC03 - - HCI HCI - - KHb ---+ KC1 - - HHb In the Iungs (CL shift in reverse): KC1 - - HHbOz--+ KHbOz - - HCI HCI - - NaHC03 ---+ NaCI - - CO, - - Hz0 “Potassium hypoxidosis” is the term used by the author to describe the train of events seen cIinicaIIy in hypokaIemia, as is we11 exempIified in postoperative potassium Ioss with a reIativeIy sudden onset of signs and symptoms when the critica level of interference in tissue metaboIism is reached due to impairment of 02 transport and utiIization, and concomitant interference with CO2 eIimination. The intraceIIuIar potassium exists in a two-compartment phase, i.e., a Iow phase of approximateIy 5 mEq./L. and a high phase of approximateIy 50 mEq./L. The biphasic phenomenon is much Iess apparent for sodium. It is suggestive that low potassium perhaps affects the specific conducting tissue of the heart through its importance in the oxidation reduction mechanism of the specific ceIIs. The Iessened effectiveness of digitaIis in hypokaIemia may be on a simiIar basis. From the extraceIIuIar fluid, a lake of intermingIed fibriIs, “free and bound water,” eIectroIytes and proteins, 0, passes through the junctiona zone commonIy caIIed the ceI1 membrane to the interior of the ceI1. The bIood brings the O2 to this extraceIIuIar ffuid compartment from the aIveoIar capiIIary. The 02 diffused across the 0.1 micr6n thick aIveoIar membrane from the aIveoIar gases. Here its 14 per cent concentration was approximateIy at a partia1 pressure of 105 mm. of mercury. The CO2 concentration in the aIveoIus is approximateIy 5 per cent at a partia1 pressure of 40 mm. of mercury. Its course through the body foIIows that of the O2 in a reverse direction. As a matter of fact, CO2 eIimination is every bit as important as 02 utiIization; but since 32

Energy

Considerations substances which utilize the 02, as in hypogIycemia, (3) deficiency of respiratory enzymes such as occurs in beri-beri, (4) enzyme toxins such as cyanides. Consciousness is Iost in eight seconds if no O2 is supplied to the brain, and this becomes irreversible in three to three and a half minutes. The norma venous PO2 is 95 mm. of mercury. When this is reduced to 19 mm., which results in 13 mm. at the points in the brain farthest from the capiIIary wall, irreversible brain damage occurs. The normal brain 0, requirement is 2.8 mI./Ioo gm./min. If this is reduced to 18 per cent, survival is impossible. In the newborn a11 these surviva1 times are Iengthened because they vary- with the surface area of the sum total of the dendrites which is much less in the newborn. The discussion has referred to brain tissue at a body temperature of 37’C. When the body temperature is Iowered, the 0 2 and CO, requirements decrease in an esponentia1 manner until 30’~. is reached, after which they a11 increase again folIowing the same mathematica1 function. Hibernation, on the other hand, is based upon endocrine changes and is an entireIy different phenomenon. Shivering increases the 02 demands due to the energy requirements of the work invoIved, and is of course prevented by Iight ether anaIgesia in cardiac surgery. (This is the third phase of the first pIane of anesthesia.) “The heart is the first to Iive and the Iast to die; the brain is the Iast to live and the first to die.” AIkaIoids and anesthetics inhibit the dehydrogenases while suIfides, cyanides, carbon monoxides, etc., inhibit the oxidases, froth of which are part and parce1 of the Krebs cycle. When one remembers that these agents act on the specific conducting tissue of the heart, it is obvious how lethal “sedatives” such as 0.2 gm. sodium amytaI@ may be in a preoperative mitral. In such an instance a single fiber may be a11 that is functioning and yet may show as a norma conduction system. Today, when cardiac arrest is so much to the forefront, one shouId carry some theoretic knowledge as to its possibIe basic mechanism beyond the much discussed factors of CO, aIterations, O2 reduction and vagal stimulation. Models of pure muscIe fibriIs (free from connective tissue, Iymph, etc.) go into a state of rigor when compIeteIy free of ATP. This is anaIogous

it does not coIor the blood and so the patient (unIess it be to make the patient paIer), its significance is often missed. Carbon dioxide is transported simuItaneousIy from the ceII to the aIveoIus by the same mechanism as that utilized by O2 transport. CO2 is approximateIy twenty-five times more diffusabIe than 02, and so the aIveoIocapiIIary membrane allows its diffusion Iong after disease has impaired O2 diffusion. The association S-shaped curve of 02 becomes a Iinear function when pIotted for COZ. As the PC02 increases, the CO, content increases proportionately, and vice versa, whereas the 02 content does not increase nor decrease significantly over a Iong range toward the right of the classic curve. The cardiac intraceIIuIar potassium content varies greatly with the plasma CO?, decreasing as it increases. This is probabIy accompanied to “free” Ca+, with a change of “bound” and intracellular dehydration due to an outward water shift. This increased intraceIIuIar free Ca+ may be very significant in cardiac arrest where anoxia is usuaIIy bIamed but where hypercapnia may be more significant. To the clinician, be he surgeon or internist, the foregoing discussion has practical significance. The role of vitamins in the cellular oxidation reduction mechanism is obvious. Perhaps it is not so apparent that ten times the normal requirements are needed in disease with its cataboIism followed with anabolism and increase in O2 utiIization from a normal of 200 to 1,000 ml. per minute. Today the surgeon, internist and anesthetist are a11 finding it necessary to take cognizance of the mode of effect of various agents upon energy release. Hibernation, hypothermia and hypoxia, to mention intenseIy practica1 exampies, owe their importance to the aIteration produced in the reIease of high energy bonds. The O2 uptake of the organism which varies directIy with the rate of oxidation in the body can be foIIowed by rapid optica (photocoIorimetric) anaIysis of the pyruvic acid content and is governed by the energy utiIized. The genera1 causes of hypoxic hypoxidosis are: (I) hypoxemia such as occurs at high aItitudes, (2) ischemia due to vasoconstriction, (3) anemia. Oxidation in the brain is interfered with through the foIIowing means: (I) diminished suppIy (poor ventiIation under anesthesia, faiIing cardiac output, anemia, hemorrhage, vasoconstriction, etc.), (2) decreased suppIy of 33

Kovach but it immediateIy rises again. This is termed the quick-reIease phenomenon (this does not occur in eIastic shortening). Some phase of this is constantIy occurring in the muscIes of bIood vesseIs and in the myocardium. It can be shown that contracted models (of muscIe fibrils) exposed to a pIasticizer pyrophosphate to prevent rigidity, reIax as soon as ATP is removed. Here no reaction is occurring to suppIy energy during relaxation. The clinica counterpart is obvious; the myocardium does not buiId up energy, rest or recuperate during diastoIe. Actomyosin receives its energy during contraction, not during reIaxation (diastoIe). Aerobic ceIIs generate high energy ATP from ADP and orthophosphate by the addition of eIectrons which are derived from the oxidation of food moieties via the respiratory carriers. This is termed oxidative phosphoryIation or a coupled synthesis of ATP. Carbohydrates and fatty and amino acids are broken down into acety1 CoA fragments which in turn are oxidized by the fina common pathway of the Krebs cycIe yieIding high energy phosphate bonds incorporated in ATP, the universa1 storer and provider of the energy of life. In the nervous system, for exampIe, the energy required to free bound inactive acetyIcholine in the resting nerve is aIso derived from these high energy bonds. The acetyIchoIine now acts upon a receptor protein and aIters the ionic permeabiIity of the nerve membrane in such a way that sodium and potassium wiI1 shift, and by this shift generate an ionic concentration gradient which is in reaIity an eIectromotive force and constitutes an action current. I have started with the very obvious premise that Iife is associated with energy. The present concept that energy is not a reaIity is compIeteIy ignored, and the caIcuIus of statistica probabiIities through mathematica1 functions is the best means of deaIing with the oIder “mass energy transformations.” It has been shown how this force is provided by high energy phosphate bonds through the intermediary of the Krebs cycIe.

to the extreme hardness and fast fibriIIar movement feIt by the hand in a heart in ventricuIar fibriIIation before arrest. Immersion of the mode1 in ATP (if inhibitors are used to prevent contraction) now shows the “pIasticizing effect” causing the fIbriIs to become pIastic due to the binding of ATP to actomyosin. Pyrophosphate is also a pIasticizer and prevents the rigidity caused by ATP remova1. Perhaps these two phenomena have direct clinica appIication. In the exergonic (energy-yieIding) process ATP is being split, and contraction continues onIy whiIe this is occurring. This represents the conversion of energy to work. The energy required for other endergonic processes, such as ciIiary movement, fibrobIast and epitheIia1 contraction of mitosis, chemica1 biosynthesis of compIex moIecuIes and osmotic work as exempIifIed in secretory activity such as tubular potassium reabsorption or zymogen reIease, is provided and stored in the same way, nameIy, by ATP. ReIaxation sets in when this ATP breakdown is inhibited. What inhibits this process? Excess ATP, ionic concentrations of supraoptima1 vaIues and the M.B. (Marsh-BendaII) factor are the cIinicaIIy important inhibitors. SaIyrgan@ inhibits spIitting. The M.B. factor is a norma Iiving muscIe protein which constitutes the physioIogic regulator of this mechanism. The M-B.-inhibited splitting of ATP can be restored by caffeine, caIcium chIoride and cysteine. The cIinica1 importance of this is apparent if one reaIizes that cardiac arrest is fIbriIIar reIaxation proIonged. If a fibri1 is now aIIowed to contract, the energy is utiIized in the production of tension (isometric ventricuIar contraction). This varies directIy with the temperature. The constants of the function depend on the specific actomyosin (different muscIes vary differentIy with temperature but a11 vary directIy). The same Iaws hoId for contraction. If fibriIs in isometric contraction (under tension aIone) are now aIlowed to shorten IO per cent of their initia1 length, the tension drops to zero (is aboIished)

34