Effect of Decreased 02 Supply to Tissue

Transcription

1 Effect of Decresed 2 Supply to Tissue on the Lctte:Pyruvte Rtio in Blood WILLuAM A. NEILL, PETER E. JENSEN, GERALD B. RIcH, nd JoHN D. WEmSCKL From the Deprtment of Medicine, University of Oregon Medicl School, Portlnd, Oregon 9721 A B S T R A C T Experiments were performed with trined conscious dogs with permnently implnted intrvsculr ctheters. With the dogs in bsl resting stte, the concentrtions of lctte (L) nd pyruvte (P) in rteril blood fluctuted widely from dy to dy, wheres their concentrtion rtio (L/P) remined reltively constnt. By contrst, decrese in tissue 2 supply induced by severe chronic nemi incresed the rteril blood L/P, specificlly, with only rndom ccompnying chnges in the lctte or pyruvte concentrtions themselves. When systemic 2 consumption ws incresed cutely by musculr exercise, crdic output incresed, nd the chnges in blood L/P were smll nd not consistent between different dogs. But when 2 supply to the tissues ws simultneously limited by nemi, L/P incresed during exercise, nd the mgnitude of the increse ws proportionl to the severity of the nemi. These results suggest tht chnges in blood L/P during exercise re relted specificlly to tissue 2 supply. INTRODUCTION Although 2 trnsport vi blood cn be redily mesured in living body, there is no eqully stisfctory method to determine chnges in the vilbility of 2 for metbolism within the body tissue. Since the rtio between lctte nd pyruvte concentrtions (L/P) is linked to the oxidtion-reduction blnce of the respirtory enzyme system, it might be possible to detect decresed 2 vilbility for metbolism or tissue hypoxi by n increse in blood L/P. Severl investigtors hve shown tht when 2 supply is decresed cutely by ischemi, hypoxemi, or nemi, the blood L/P promptly increses Peter E. Jensen, Gerld B. Rich, nd John D. Werschkul were Student Fellows supported by the Oregon Hert Assocition. Received for publiction 28 April The Journl of Clinicl Investigtion Volume (1-5). Since the supply of 2 to the tissue vi the blood clerly ws decresed in these experiments, here tissue hypoxi stnds s resonble explntion for the incresed blood L/P. Other uthors, however, hve emphsized the complicted nture of the reltionship between blood L/P nd the oxidtion-reduction blnce of the tissue respirtory enzyme system, nd they hve questioned whether n increse in blood L/P cn, s rule, be regrded s evidence of tissue hypoxi (6, 7). Moreover, in some conditions where tissue hypoxi might be expected, especilly chronic tissue hypoxi, chnges reported in blood L/P hve been inconsistent (8-13). Our objective is to determine whether the reltionship between tissue hypoxi nd incresed blood L/P extends beyond the limited experimentl conditions in which it lredy hs been demonstrted. Initilly, we investigted the effect of fctors other thn tissue hypoxi by determining the extent of vribility in blood L/P when these fctors were llowed to vry spontneously from one dy to the next. Subsequently, we determined the chnges in blood L/P during two different conditions in which tissue hypoxi could be expected: () severe chronic nemi, nd (b) restricted 2 supply vi the blood while tissue 2 consumption ws cutely incresed by musculr exercise. To secure informtion under physiologic conditions tht should be brodly pplicble, we crried out these experiments in trined dogs without nesthesi. METHODS Preprtion of nimls 12 mle dogs, ech weighing kg, were trined to lie still for n hour or more without restrint. Four of them were trined lso to run on tredmill. Subsequently, they were nesthetized with pentobrbitl, nd silstic ctheters (.4 inch I.D., Dow Corning Corp., Midlnd, Mich.) were positioned in the pulmonry rtery nd the thorcic ort vi neck vessels. The proximl ends of the ctheters

2 emerged t the bck, where they were secured to the skin. Plstic stub needles with rubber stoppers glued into their lrge ends were fixed to the proximl ends of the ctheters. We smpled blood by puncturing the rubber stopper. The use of this rrngement without disturbing the dogr hs been described (14). TABLE I LIP of Red Cell nd Components of Whole Bli Lctte mmole/liter Pyruvte TABLE I I Hemodynmic Dt in Chronic Anemi Experiments Control Anemi Hert rte per minute 71 (66-82) 111 (1-124) P <.1 Experimentl protocol Chronic nemi. In dog Nos. 1-8, initil control obs;erv- Crdic output, 136 ( ) 231 (23-265) tions were repeted on from 6 to 25 dys during 2-E8 wk. ml/kg per min P <.1 Seven of these dogs were mde nemic during 3 hr p period by repeted removl of 3-ml increments of blood thtrough Stroke volume, 1.94 ( ) 2.8 ( ) the ortic ctheter, with reinfusion of the seprted pllsm ml/kg per bet NS t ech step. The hemoglobin concentrtion ws reduced to 7.1 g in dog No. 1 nd to levels rnging from 2.7 to 4.8 1g/1 Mixed venous blood 2, 7 (67-73) 38 (35-4) ml in dog Nos Subsequently, the hemoglobin ws kept % sturtion P <.1 t constnt depressed level for 5 wk by bleeding 8-12 ml/dy. Observtions were mde t lest twice weekly dur- Systemic2consumption, 5.6 ( ) 6. ( ) ing the 5 nemi wk. Dog No. 8 ws studied for compr- of 5 ml/kg per min. NS ble period without nemi. In dog Nos. 4-7, t the end wk of nemi, 25 mg of iron (Imferon, Lkeside L bor- Observtions were mde with the dogs lying t rest. Initil tories, Inc., Milwukee, Wis.) nd 4-6 ml of m tched number is the verge of four dogs (Nos. 4-7). Numbers in blood were given, nd recovery control observtions: mde. We studied the dogs while they ly t rest in the prentheses represent the rnge of men vlues for seprte bsorptive stte. Immeditely fter his dily 5 min me postg dogs. P vlues indicte significnce of difference from control irning v wlk, the dog entered quiet room where he ly, ifcing (pired t test). NS = not significntly different. the wll, on his side on low bench. Smpling tubes were connected to his ctheter dpters nd the dog relxed for observtions ws mde before exercise with the dog stnding 1-15 min before observtions begn. The dog ws ignored t rest on the tredmill. Finlly, exercise, performed for throughout. No restrint, sedtive, or ressurnce w! s em- periods of 8 min with intervening rest periods of 5 min, ployed, nd the dog seldom moved. consisted of running up 1 grde t tredmill speeds Exercise experiments were performed in dog Nos. 9-12, rnging from 2 to 5 miles/hr. Aortic blood smples for first on 2-4 dys with the dogs not nemic nd then t lctte nd pyruvte nlyses were obtined t 4 min, crdic incresingly severe levels of nemi, induced in four steps output determined t 5 min, nd blood smples for systemic of 1 dy ech. After observtions were mde s bove with (-v)o2 difference were obtined from 6 to 7 min of exerd ws cise. the dog lying t rest, the dog entered nother room n( hrnessed to motor-driven tredmill. A second s;et of = red blood cell component; = whole blood. Techniques Simultneous ortic nd mixed venous blood smples for ood 2 determintions were obtined from the ctheters over 6- to 9-sec periods. The hemoglobin concentrtion ws L/P determined spectrophotometriclly. In the chronic nemi experiments blood 2 concentrtion ws determined by the mnometric method (15) nd 2 sturtion ws clcu lted. In the exercise experiments 2 concentrtion ws 5.1 clculted from: blood Po2 nd ph (Rdiometer Co., Copen hgen, Denmrk), hemoglobin concentrtion, nd n 2 dissocition curve. Crdic output ws estimted by the dye 7.92 dilution method by injecting 1 mg Indocynine green into 7.25 the pulmonry rtery ctheter nd withdrwing blood from 7.37 the ortic ctheter through GME densitometer. Systemic 2 consumption rte ws clculted from the product of 16.2 crdic output nd systemic blood (-v) 2 difference. 11. Blood smples for lctte nd pyruvte were rpidly with drwn from the ortic ctheter into disposble syringes in stndrdized mnner, injected immeditely into trichlor cetic cid t C, nd nlyzed by modifictions of the 11.3 methods of Brker nd Summerson nd Friedemnn nd 11.6 Hugen (16). Duplicte determintions checked within 2%. If the LIP were higher in the plsm thn in the red 15.3 blood cells, the greter proportion of plsm in nemic blood 13.9 would be expected to increse the LIP of whole blood, even 14.3 if the plsm nd red cell LIP ech remined constnt. To investigte this possible explntion for rise in blood LIP during nemi, on five occsions freshly shed whole blood Tissue Hypoxi nd the Blood Lctte: Pyruvte Rtio 1863

3 TABLE III Arteril Blood Lctte, Pyruvte, nd LIP: Vrition during Control nd the Effect of Anemi Dog Condition Lctte Pyruvte L/P mmole/liter 1 Control, n =6 Anemi, n ± ±.68 NS NS P <.5 2 Control, n ± :±:.24 Anemi, n S ±.66 P <.2 P <.2 P <.2 3 Control, n =7.59 ±.38 Anemi, n = ± ± ±.68 NS NS NS 4 Control, n = ±-1.47 Anemi, n = ± NS NS NS 5 Control, n =32 Anemi, n = ± ± ± ± ±2.54 P <.1 P <.1 P <.1 6 Control, n = ± Anemi, n= ± NS NS P <.1 7 Control, n ±-.223 Anemi, n = ± ± ±.84 NS P <.1 P <.1 8 Control, n ± ±.72 *Control, n = ± ±.54 NS NS NS n - number of observtions. Vlues represent men ±SD. Control dt include observtions before nemi nd fter recovery from nemi. Sttistics clculted by nonpired I test. * Seril observtions in dog No. 8 crried out over period of time equl to tht of the nemi period in the other dogs (5 wk). ws seprted s rpidly s possible by centrifugtion into two components: one contining minly plsm nd the other minly red blood cells. An liquot of the sme blood smple ws set side for n equl time (4 min) without centrifugtion. The results pper in Tble I. The L/P ws lowest in the plsm component, highest in the red cell component, nd intermedite in whole blood, indicting tht the higher proportion of plsm in nemic blood should slightly decrese, but not increse, the L/P of whole blood. These results confirm similr reported dt (16). RESULTS Chronic nemi. All observtions were mde with the dogs lying t rest. Control nd nemi hemodynmic dt were obtined in four dogs (Tble II). Hert rte nd crdic output incresed, nd mixed venous blood sturtion decresed during nemi. The slight increses in stroke volume nd systemic O2 consumption were not sttisticlly significnt. These vribles returned to the initil control levels fter the dogs recovered from the nemi. Arteril blood lctte nd pyruvte dt for ll eight dogs re presented in Tble III. Control lctte nd pyruvte concentrtions in ech dog vried gretly from 3. r '4 Q O 1.5 I4 1. 't.5 - I.O 8. - '5. \ *.. *:. * CONTROL C CONTROL2 I 5 months FIGURE 1 The vribility of blood lctte nd L/P in dog No. 6 during 5 months. Dots represent vlues on seprte dys, nd the horizontl lines represent mens for ech period indicted. Blood lctte concentrtion fluctuted widely but ws not significntly ffected by nemi (shded re). Blood L/P vried less nd incresed during nemi (P <.1). dy to dy, nd the men control vlues differed from dog to dog. Blood L/P ws more constnt, men vlues in ll but one dog flling between 5.14 nd The coefficients of vrition (sd/men) for control vlues for ll dogs were: lctte 4%, pyruvte 35%, nd L/P 13%. There were significnt (P <.5) increses in rteril blood L/P during nemi in five of seven dogs. In the other two, smller increses in L/P were not significnt. Although significnt chnges in blood lctte nd pyruvte concentrtions occurred during nemi in few instnces, the directions of these chnges were inconsistent between different dogs. Therefore, the increse in L/P did not depend upon ny specific chnges in either lctte or pyruvte concentrtion. There were no significnt chnges in lctte, pyruvte, or L/P in dog No. 8, which ws not mde nemic. The comprison between chnges in rteril blood lctte nd L/P is illustrted in Fig. 1 for dog No. 6, 1864 W. A. NeiU, P. E. Jensen, G. B. Rich, nd l. D. Werschkul

4 TABLE IV Hemodynmic Dt in Exercise Experiments Control (rest, lying) Stnding rest Mximum exercise Hert rte per minute 6 (52-7) 88 (74-13) 176 (155-28) P <.1 P <.1 Crdic output, ml/kg per min 115 (96-138) 147 ( ) 356 (294-45) P<.2 P<.1 Stroke volume, ml/kg per bet 1.91 ( ) 1.7 ( ) 2.1 ( ) P <.5 NS Mixed venous blood 2, % sturtion 69 (62-78) 6 (48-71) 37 (3(49) P <.2 P <.1 Systemic 2 consumption, ml/kg per min 6.1 (5.6-7.) 1.3 ( ) 45.8 ( ) P <.1 P <.1 Initil number is the verge of four dogs. Numbers in prentheses represent the rnge of seprte men vlues for the different dogs, except for "mximum exercise," where numbers represent observtions during mximum level of exercise for ech dog. Sttistics s in Tble II. in which observtions extended for 5 months. The dily vribility in lctte concentrtion ws reltively gret, nd the differences between the vlues during the initil two control periods, the nemi period, nd the finl recovery control period, were not significnt. For L/P, the dily vribility ws less. Moreover, the L/P vlues for the initil two control nd recovery periods were comprble, nd they differed significntly from the nemi vlues (P <.1). While nemic, the dogs were less eger to run but otherwise remined helthy. While resting observtions were being mde, their behvior ws the sme s tht during the control period. After the dogs recovered from the nemi, their originl vigor returned. Exercise. Rest nd exercise hemodynmic dt for dog Nos when they were not nemic re given in Tble IV. Fig. 2 shows the reltionship between crdic output nd systemic 2 consumption by the tissues. This reltionship did not pper to be entirely uniform in the different dogs, i.e., crdic output ws reltively high in dog No. 1 (squre symbols) nd low in dog No. 9 (circle symbols). Men rteril blood ph ws.t% e 4- k 3 i v I f A VO& O A 4 2 qb.%3 C- 1 1 JO o go I I I I Consumption-mI/kg/min FIGURE 2 The reltionship between crdic output nd systemic 2 consumption when the dogs were not nemic. Resting observtions re to the left nd exercise observtions extend to the right. (O = dog No. 9, = dog No. 1, A = dog No. 11, V-dog No. 12.) Tissue Hypoxi nd the Blood Lctte: Pyruvte Rtio 1865

5 lb I 6r 12f 7.4 lying t rest, 7.43 stnding t rest, nd during exercise reched mximum vlues rnging from 7.44 to 7.51 in the four dogs. Chnges in rteril blood L/P during exercise re shown in Fig. 3. Dt obtined when dogs were not nemic, represented by open symbols, differed in seprte dogs. In two dogs (No. 11 nd No. 12, Fig. 3, lower pnels), L/P consistently incresed during exercise which ws strenuous enough to increse systemic consumption by four to five times the resting level. In-dog No. 9 (upper left pnel), L/P did not increse until 2 consumption reched 8-1 times the resting level, nd in dog No. 1 (upper right pnel), L/P consistently decresed during exercise when he ws not nemic. To determine the effect of restriction in the supply of 2 to tissues while their 2 consumption ws cutely incresed, we repeted the exercise studies t four levels of nemi, with hemoglobin concentrtions of pproximtely 8, 6, 4, nd 2.5 g/1 ml. The results during nemi re represented in Fig. 3 by solid symbols (two dogs would not run on the tredmill t the most severe nemi level). Irrespective of their differ t) ol -4 \ 16 % 12 4g t69 l~t I I I Dog 9 ences when not nemic, s the dog's bility to ugment cutely tissue Os supply ws restricted by incresingly severe nemi, progressively lrger increses in blood L/P ppered during exercise t progressively lower rtes of Os consumption. Moreover, the dogs whose L/P incresed most redily when they were not nemic hd the most pronounced effect from nemi. Corresponding chnges in mixed venous blood Pos re shown in Fig. 4. Anemi decresed the venous blood Po. t ll levels of systemic Os consumption during rest nd exercise, nd the mgnitude of the decrese in Po2 ws proportionl to the degree of nemi. In the presence of severe nemi, mixed venous blood Po2 fell during exercise to s low s 12 mm Hg (11-12% 2 sturtion) in three dogs. DISCUSSION Huckbee showed tht moment-to-moment chnges in blood lctte nd pyruvte concentrtions occurred for no pprent reson or could be redily induced by vriety of fctors, mny of which were unrelted to O. supply (17). Blood L/P, however, remined nerly -e,. o g 89 Dog 1 2.5g Dog 12 4g Av~~~v 7; 6g 9 _ 6; I I Consumption - ml / kg / min FIGURE 3 Per cent chnges in rteril blood L/P relted to chnges in systemic 2 consumption during musculr exercise. Ech pnel represents seprte dog. Open symbols re observtions mde when the dogs were not nemic; solid symbols, observtions during nemi. There were four levels of nemi (Hb = 8, 6, 4, nd 2.5 g), nd the lines join observtions mde t ech different level W. A. NeiU, P. E. Jensen, G. B. Rich, nd I. D. Werschkul

6 constnt s long s O. supply ws not chnged. In our experiments, repeted determintions of blood lctte nd pyruvte concentrtions during the control period estblish the rnge of fluctutions in these substrtes nd in blood L/P- which normlly occur, not cutely s previously studied, but spordiclly from dy to dy over n extended period. It is worth emphsizing the bsl stte of these dogs. From externl ppernces they lwys ppered relxed. As evidence, their hert rtes nd systemic 2 consumption vlues (Tble II) were consistent from dy to dy (men dy-to-dy vrition of ech, 12%) nd lower thn most vlues previously reported for wke dogs (18-21). Under these conditions, their blood lctte nd pyruvte concentrtions vried over wide rnge while L/P remined reltively constnt. Thus, vritions in unidentified fctors which do not pper to be relted to Os supply vigorously influenced lctte nd pyruvte concentrtions but hd little effect on blood L/P. In view of their mrked fluctutions even during the control period when we ttempted to keep the condition of the dogs stble, it is not surprising to find chnges in the blood concentrtions of both lctte nd pyruvte when the dogs were mde nemic. In some instnces these chnges were sttisticlly significnt; their direction, however, ws completely inconsistent in different dogs. Thus, whtever effect nemi itself my hve hd on the blood concentrtions of these substrtes, it ws lrgely overshdowed by other unidentified fctors, perhps by the sme ones responsible for the fluctutions in control lctte nd pyruvte concentrtions. With blood L/P, the result differed. Although blood L/P on some dys during nemi equled the control vlues, other nemi vlues were clerly bove the previously estblished control rnge (e.g. Fig. 1), nd the direction of chnge in men L/P during nemi ws consistently upwrds. One possibility is tht nemi regulrly incresed the L/P; nother is tht nemi mde the niml more susceptible to other fctors influencing L/P which were inconstntly present. The overlp between control nd nemi L/P vlues provides n explntion for the previous inconsistent reports of the effect of chronic hypoxemi or nemi on blood L/P (8-13). With enough observtions, however, the effect of nemi on blood L/P is specific enough to be detected even in the presence of vribles in ddition to 2 supply which my slightly influence dy-to-dy blood L/P vlues. We hve no proof tht tissue hypoxi ws the 5r Dog 9 Dog 1 4-3F % Z. 2 I- hb -2.5g. 6g :> I -I '^ 5 j~ xi 21 1 IF 1-4g 6g 8g Dog II v -~~~ VV4 Bg F~4# 2.5g Dog 12 I I I II I I. I I I Consumption - ml/ kg/min FIGURE 4 Mixed venous blood Po during rest nd exercise. Explntion s for Fig. 3. Tissue Hypoxi nd the Blood Lctte: Pyruvte Rtio 1867

7 specific feture of nemi responsible for the incresed blood L/P, but it seems the most plusible explntion. These findings coincide with Huckbee's conclusion from his cute experiments tht blood&l/p, rther thn lctte or pyruvte concentrtion, is regulrly ffected by chnges in On supply. We would not expect the circultory djustments during nemi to be uniform throughout the body; therefore, neither would we nticipte tht hypoxi ws evenly distributed mong different tissues. The lctte nd pyruvte concentrtions in rteril blood represent mixture of the concentrtions in venous blood drining the different body tissues. Thus, from the increse in rteril blood L/P, we hve no informtion regrding the distribution of tissue hypoxi in nemi, nor cn we distinguish diffuse from focl tissue hypoxi. Normlly, n cute increse in the rte of 2 consumption by tissue is compensted, t lest prtly, by simultneous increse in 2 delivery vi incresed blood flow to the tissue. Since 2 delivery is ugmented, the increse in 2 consumption might not result in tissue hypoxi. Nevertheless, rteril blood L/P increses during mild musculr exercise in norml but sedentry humns (22-24), which suggests tht O vilbility for metbolism in the tissues is not mintined t constnt level in these subjects even when O2 consumption is only modestly incresed. Among subjects who regulrly engge in vigorous physicl ctivity, the increse in rteril blood L/P is considerbly less (25, 26). In certin pthologic conditions, the cpcity for cute increse in tissue On delivery is impired by limited blood flow. In some ptients, hert disese limits the cpcity for incresed systemic blood flow; in others, nrrowed rteries interfere with blood flow loclly. Under these conditions, cute increse in O2 consumption by the potentilly ischemic tissue is ccompnied by n exceptionlly lrge increse in blood L/P: either the locl venous blood in locl ischemi, e.g., myocrdium (27) or leg (28, 29); or the rteril blood in systemic ischemi, e.g., crdic filure (22. 3). The explntion which hs been given for the exceptionl increses in blood L/P is tht when the increse in blood flow in response to incresed 2 consumption is less thn norml, the fll in On vilbility for metbolism is greter, i.e., more mrked tissue hypoxi occurs. The purpose of the exercise experiments in the dogs is to exmine the significnce of blood L/P chnges which ccompny incresed 2 consumption in tissue under somewht different experimentl conditions. In ech of the dogs we studied, when he ws not nemic, the increse in rteril blood L/P during exercise ws substntilly less thn tht reported for sedentry humns, even though the degree of exercise s judged by increse in O consumption rte ws greter in the 1868 W. A. Neill, P. E. Jensen, G. B. Rich, nd l. D. Werschkul dogs. In fct, in two dogs the L/P did not regulrly increse even when systemic O consumption reched seven times the resting level. These results suggest tht tissue O supply is better mintined during exercise in dogs thn in most humns, perhps due to species differences or to differences in physicl ctivity. Crdic output is one fctor governing tissue O supply, nd there is evidence tht crdic output reltive to 2 consumption is higher during exercise in dogs (Fig. 2 nd references 18 nd 19) thn in humns (31-34). Thus, the more stble blood L/P in the dog cn be explined prtly by superior tissue supply due to higher crdic output. Anemi in the dogs limited the extent to which they could ugment O2 delivery to their tissues during exercise. In these experiments, On delivery ws limited not by ischemi but by low blood concentrtion. The presence of nemi enhnced the increse in blood L/P during exercise, nd this effect of nemi ws proportionl to its severity. The more tht ugmented 2 delivery ws inhibited, the greter the increse in blood L/P for ny level of systemic O2 consumption (Fig. 3). These experiments show tht exercise chnges in blood L/P re responsive in predictble mnner to concurrent ltertions in tissue O. supply; therefore, the chnges in blood L/P pper to be relted to chnges in the vilbility of 2 to the respirtory enzyme system in the tissue rther thn to some other effect of exercise. The results of these experiments lso substntite the interprettion presented in the previous studies of ptients with ischemic disese tht their exceptionlly lrge increses in blood L/P were due to tissue hypoxi. ACKNOWLEDGMENTS John Oxendine, Stephen Moore, Sndr Hor, nd Mrilyn Pul provided vitl technicl help. The blood O2 dissocition curves were determined by members of Dr. Jmes Metclfe's lbortory. The uthors re grteful to Dr. Richrd L. Dobson, who criticlly reviewed the mnuscript. This work ws supported by Public Helth Service Grnt HE REFERENCES 1. Friedemnn, T. E., G. E. Hugen, nd T. C. Kmiecik Pyruvic cid. III. The level of pyruvic nd lctic cids, nd the lctic-pyruvic rtio, in the blood of humn subjects. The effect of food, light musculr ctivity, nd noxi t high ltitude. J. Biol. Chem. 157: Huckbee, W. E Reltionships of pyruvte nd lctte during nerobic metbolism. III. Effects of brething low-oxygen gses. J. Clin. Invest. 37: Gudbjrnson, S., nd R. J. Bing The redoxpotentil of the lctte-pyruvte system in blood s n indictor of the functionl stte of cellulr oxidtion. Biochim. Biophys. Act. 6: Cin, S. M Appernce of excess lctte in nesthetized dogs during nemic nd hypoxic hypoxi. Amer. J. 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