Effect of Physical Training on the Mechanical and Metabolic Response of the Rat Heart to Hypoxia

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1 Effect f Physical Training n the Mechanical and Metablic Respnse f the Rat Heart t Hypxia By James Scheuer and S. William Stezski ABSTRACT T study the effects f physical cnditining n cardiac functin and metablism during hypxia, rats we cnditined by swimming. Their islated hearts and hearts f sedentary rats we studied under isvlumic cnditins and als while perfrming external wrk. During isvlumic perfrmance nly minimal imprvement in hypxic cardiac perfrmance was bserved because f cnditining. While perfrming external wrk during hypxia cardiac utput and cardiac wrk we apprximately twice as gat in hearts frm cnditined rats as in thse frm sedentary rats. The we als slightly higher peak systlic pssus and mean left ventricular systlic pssus during hypxia. Oxygen delivery and lactate prductin during hypxia we the same in hearts frm cnditined and sedentary rats as we mycardial NADH fluscence, sidual high-energy phsphate sts, and mycardial glycgen levels. External efficiency in experiments n wrking rat hearts was twice as gat during hypxia in hearts frm cnditined rats as in thse frm sedentary rats. The data suggest that hearts f cnditined rats have enhanced pumping capacity when subjected t hypxia cmpad with hearts f sedentary rats. Oxygen delivery and energy frmatin during hypxia a nt imprved in hearts f cnditined animals. The majr asn fr imprved perfrmance appears t be m efficient energy utilizatin fr external cardiac wrk. KEY WORDS lactic acid catine phsphate mycardial metablism cnditining glycgen Pvius studies frm ur labratry (1) have demnstrated that islated hearts frm cnditined rats have enhanced cardiac serve capacity when they a stssed by incasing the heart rate r raising the atrial filling pssu. Hearts f cnditined rats appear t have imprved mechanisms f xygen delivery and als incased cardiac actmysin adensinetriphsphatase activity (2). Thus, at least tw pssible adaptive mechanisms may accunt fr the gater Frm the Mycardial Metablism Labratry, University f Pittsburgh Schl f Medicine, Pittsburgh, Pennsylvania This wrk was supprted by U. S. Public Health Service Research Grant HE frm the Natinal Heart Institute, American Heart Assciatin Grant , and in part by the Max Baer Heart Fund f the Fraternal Order f Eagles. Dr. Scheuer is a cipient f the Natinal Institutes f Health Caer Develpment Award HE Received Octber 4, Accepted fr publicatin January 28, adensine triphsphate mycardial mechanics intrinsic cardiac perfrmance that sults frm the cnditining prcess. Because f the prbable beneficial rle f physical training in patients with established r ptential ischemic heart disease (3, 4), it was cnsided imprtant t determine whether physical cnditining wuld alter the cardiac spnse t hypxia. Hearts frm cnditined rats we studied in tw diffent types f islated heart perfusin systems. Hearts we studied in an isvlumic apparatus, because in the absence f ejectin infences can be made abut the tensin and velcity characteristics f the heart as a muscle. Hearts we studied in a wrking (ejecting) heart apparatus t furnish infrmatin abut the heart as a pump. The sults indicate that during hypxia hearts f cnditined rats maintain enhanced cardiac utput and cardiac wrk but that isvlumic perfrmance is nly minimally prtected by prir physical cnditining. The imprved external 418

2 PHYSICAL TRAINING AND CARDIAC PERFORMANCE 419 perfrmance cannt be attributed t incased xidative r glyclytic metablism but may be explained by incased cardiac efficiency as expssed by wrk utput per unit f xygen uptake. Methds Cnditining Prgram. Male Wistar rats, with an riginal weight f g, we made t swim 90 minutes per day fr 5 days a week. A deep tank kept at a temperatu near 33 C was used fr swimming. The surface aa f the tank was 375 inch 2, and five t seven rats swam at ne time. This gemetry ensud enugh interactin between rats s that they culd nt passively flat. The swimming prgram was cntinued fr 8 weeks bef the hearts we studied. A series f rats taken frm the same initial grup as the swimmers, but kept at nrmal cage activity, we used fr sedentary cntrls. Heart Perfusin Systems. The isvlumic perfusin apparatus has been described and diagramed pviusly (5). Fr isvlumic studies hearts we perfused trgrade thrugh the arta in a gravity-flw system. In the curnt experiments, the left atrium and atrial appendage we tied with a ligatu t ensu against any gurgitatin frm the left ventricle. The perfusin medium cntained 143 mm sdium, 124 mm chlride, 25 mm bicarbnate, 6 mm ptassium, 1.2 mm calcium, 1.2 mm magnesium, and 0.4 mm sdium EDTA. Glucse, 5 mm, was included at all times. During cntrl perids the perfusin medium was bubbled with 95% O 2-5% 2, which maintained an xygen tensin abve 600 mm Hg and a ph f 7.4. During hypxic perids, the same medium was bubbled with a mixtu f 95% rm-air 5% 2, which maintained the xygen tensin at abut 140 mm Hg. The perfusin apparatus was arranged with the gravity-flw servirs 88 cm abve heart level. The we tw parallel perfusin systems, either f which culd be alternately switched int the perfusin line by a stpcck just abve the artic perfusin cannula. Thus, fully xygenated and hypxic medium culd be changed abruptly. Perfusin flw rates we mnitd by cllectin f all the cardiac effluent slutin with a fractin cllectr. Fr studying the wrking heart, the system was a nncirculating, islated, wrking rat heart apparatus f the type described and diagramed by Neely et al. (6) In this apparatus the heart is perfused thrugh the left atrium, and it ejects fluid frm the left ventricle int the arta. The atrial filling pssu fr cntrl perids was 10 cm. The verflw f the arta dripped int a calibrated artic chamber that was used t measu artic flw. The effluent fluid that dripped ut f the right ventricle was the crnary flw, and this was als measud in a calibrated chamber. The perfusin medium cntained 143 mm sdium, 123 mm chlride, 25 mm bicarbnate, 6 mm ptassium, 1.2 mm magnesium, 1.2 mm phsphate, 2.0 mm calcium, 0.5 mm disdium EDTA, and 5 mm glucse. The gas bubbled thrugh the slutin was 95% O 2-5% 2 fr aerbic perids. This maintained the xygen tensin f the perfusate abve 600 mm Hg and the ph clse t 7.4. T maintain cardiac utput during hypxia tw mdificatins we made. A lesser dege f hypxia was used than in isvlumic experiments. Fr perids f hypxia the perfusate was bubbled with 45% N 2-50% O 2-5% 2, which maintained the xygen tensin near 350 mm Hg. The height f the artic clumn was 62.5 cm, which was lwer than we used pviusly in this apparatus (1). Als, as with the trgrade apparatus the we tw parallel systems either f which culd be switched int the atrial cannula fr an abrupt change frm fully xygenated t hypxic medium. In bth systems the apparatus was in a water jacket s that perfusin was at 37 C. Left ventricular pssus we mnitd thrugh a flanged 17-cm plyethylene-90 catheter which pierced the left ventricular wall (1). The catheter was attached t a Statham P23Gb strain gauge. The system had a fquency spnse f 21 cps. The rate f left ventricular pssu rise (dp/dt) was crded with a sistance-capacitance diffentiating channel n an Electrnics-fr-Medicine phtgraphic crder. The time cnstant fr the diffentiating circuit was 0.5 msec, and the spnse was linear within 5% frm 1 57 cps. Althugh the fquency spnse f the crding system may be brderline fr the measument f dp/dt at rapid heart rates, such a limitatin wuld tend t mask any ptential diffences between cntrl and cnditined hearts. The system was sensitive enugh t demnstrate significant diffences in this apparatus in ur pvius studies (1). Recrdings we made at a paper speed f 200 mm/sec. Peak systlic pssus we mnitd n a full scale f mm Hg fr trgrade experiments and mm Hg fr wrking experiments. Oxygen tensin in the influent and effluent perfusin media was mnitd as described pviusly (1, 7). T avid bradycardia during hypxia, hearts we paced thrugh a platinum wi attached t a Grass SD 5 stimulatr. The active lead was placed n the right ventricle fr trgrade studies and n the right atrium fr wrking studies, and the grund lead was placed n the

3 420 SEUER, STEZOSKI artic cannula. The cnstant pacing rate was 330 beats/min, which is the minimal rate necessary t cnstantly take ver the pacemaker rle in perfused rat hearts. The stimulus had an amplitude f 5 v and a duratin f 4 msec. Fr trgrade studies epicardial NADH fluscence was mnitd with a Chance type f cmpensated micrflurmeter (8). Experimental Prcedu. Animals we sted the day bef their hearts we mved fr perfusin. Hearts frm sedentary rats and frm cnditined rats we paid and perfused alternately n the same day. Hearts we mved and munted as described pviusly (1, 5). Bef perfusin the heart was cleaned and weighed in a tad beaker which cntained cld medium. The heart was perfused trgrade thrugh the arta while the catheters and cannulas we placed. In trgrade perfusin studies pacing was begun after 10 minutes f perfusin. Tw grups f experiments we perfrmed. In grup 1, hypxic slutin (equilibrated with 95% rm air) was switched int the perfusin line after 20 minutes f aerbic perfusin. After 5 minutes f hypxia, fully xygenated slutin (equilibrated with 95% O 2 ) was std fr 5 minutes. In this grup, dynamics we cafully crded t determine if any diffences in isvlumic dynamics we psent during hypxia and cvery in hearts frm cnditined rats. Lactate utput and epicardial fluscence we als measud in this grup. In grup 2, the purpse was t determine m cmphensively the metablic changes during hypxia alne. The hearts in this grup we perfused in the same manner as thse in grup 1, except that the experiments we terminated at the end f the hypxic perid by crushing the hearts with clamps pviusly cled in liquid nitrgen. Measuments f mycardial glycgen, adensine triphsphate (ATP), and catine phsphate we made in these hearts. In grup 2, xygen, lactate, and pyruvate metablism and epicardial fluscence we als measud. In experiments n wrking rat hearts (grup 3), antegrade perfusin and pacing we begun after 10 minutes f trgrade perfusin. After a 5-minute cntrl antegrade perid, the hearts we perfused fr successive 5-minute perids at 10 cm f atrial pssu with 95% O 2, 10 cm f atrial pssu with 50% O 2, 20 cm f atrial pssu with 50% O 2, and 10 cm f atrial pssu with 95% O 2. Measuments f xygen tensin and dynamics we perfrmed during the fifth minute f each perid and samples f fluid we taken fr measument f lactate and pyruvate. After these measuments we made, the artic tubing was clamped just abve the artic cannula t determine cardiac serve during cntractin against a "clsed valve." In this situatin cntractin shuld be isvlumic. When the heart had ached a stable isvlumic ventricular pssu, the clamp was leased. Analysis f the Experiment. At the end f the experiment hearts we mved and a prtin f the ventricles was then taken fr determining the dry weight. In hearts which had been clamped, ratis f dry t wet weight we determined in the undamped prtin. Glycgen was ppad in KOH extracts by the methd f Walaas and Walaas (9), and the glucse was quantified enzymatically (10). ATP and catine phsphate we determined by the methds f Lampcht et al. (11, 12). Fr lactate and pyruvate determinatins, perfusate was delived int tubes cntaining 1 ml f cld 6% perchlric acid, and the substances we determined enzymatically (13, 14). The percent change in epicardial fluscence was determined by crding the deflectin caused by a standard amplificatin signal frm the flurmeter fr each heart. The amplificatin deflectin was designated as 100% change and the base line as 0% change. This standard deflectin was quite cnstant amng diffent hearts. Cardiac wrk and external efficiency we calculated as described pviusly (1). Mean left ventricular systlic pssu was btained by planimetry and is the average f the develped pssu curves at each pint. Statistical significance was determined by analysis f variance, and when paid data we cmpad interactin was emplyed (15). Regssin equatins and crlatin cefficients we determined by standard frmulas (15). All flw-lated data a expssed per gram dry heart weight. Results Table 1 shws the weight latinships in cnditined and sedentary rats. In all grups the bdy weights we lwer and the ratis f heart weight t bdy weight we higher in cnditined animals. Heart weights a usually similar in cntrl and physically trained rats (1, 16, 17). In grup 3, heart weights tended t be gater in cnditined rats than they we in sedentary rats. Results in Isvlumic Pparatins. Figu 1 shws the dynamic spnses f grup 1 t hypxia and xygenatin. Crnary flw was higher and left ventricular end-diastlic pssu tended t be lwer in hearts frm cnditined rats tward the end f the hypxic perid and during early cvery.

4 PHYSICAL TRAINING AND CARDIAC PERFORMANCE 421 Weight Relatinships in Cnditined and Sedentary Rats TABLE 1 Grup 1 Grup 2 Grup 3 N. hearts 00 CD Results a means *P < fp > 0.2. \P < P < ± 8 ± 16 ± 8 Rat wt (g) ± 9* 250 ± 9t 260 ± =*= 5 ± 10 ± 16 Dry heart wt (mg) ± SE. = = hearts frm sedentary rats; = hearts frm cnditined rats. 248 ± 10t 259 ± 8t 328 ± Dry heart wt bdy wt (mg/g) ± ± ± ± 0.014J ± 0.011* ± 0.049J Develped left ventricular systlic pssu and maximum rate f left ventricular pssu rise we nt diffent fr hearts frm cnditined and sedentary rats. Peak left ventricular systlic pssu, which is nt shwn in Figu 1, was als nt significantly diffent in the tw types f hearts. The ratis f maximum dp/dt t the simultaneusly I 2000 IOOO - NDITIONED 19) SEDENTARY (9) i TIME (MINUTES) FIGURE 1 Effects f hypxia and cvery n the dynamics f hearts frm cnditined rats (grup 1). Each pint psents a mean ± SE. The number f hearts is shwn in pantheses. CF = crnary flw/g dry weight; DVLSP = develped left ventricular systlic pssu; LVEDP = left ventricular end-diastlic pssu; MAX dp/dt = maximum rate f left ventricular pssu rise. ** indicates that P < 0.01; * indicates that P < 0.05; ( ) indicates that P < 0J0. Circulatin Research, Vl. XXX. April 1972

5 422 SEUER, STEZOSKI 0.60 r SEDENTARY (91 NDITIONED 19) SEDENTARY 19) NDITIONED (9) 0? TIME (MINUTES) FIGURE 2 Metablic findings during hypxia and cvery in perfused hearts f cnditined rats (grups 1 and 2). Grup 1 is indicated by the circles and grup 2 is indicated by the triangles. Oxygen cnsumptin (qo 2 ) and ratis f lactate t pyruvate (L/P) we measud nly in grup 2. qo s and lactate prductin a per gram dry weight. Fluscence indicates the percent change in NADH fluscence. The frmat and all ther symbls a the same as in Figu 1. V measud develped systlic pssu we similar during hypxia in hearts frm cnditined and sedentary rats but tended t be higher at the end f the experiment in hearts frm cnditined animals. Figu 2 shws the sults f metablic and fluscent measuments in grups 1 and 2, and Tables 2 and 3 shw sme additinal metablic values fr grup 2. The we n significant diffences in xygen cnsumptin, lactate prductin, r rati f lactate t pyruvate in the effluent perfusin medium r in fluscence during hypxia. After 5 minutes f cvery, lactate prductin turned t the cntrl value in hearts frm cnditined animals but mained slightly elevated in hearts frm the sedentary cntrls. Oxygen cnsumptin and pyruvates we nt measud during cvery. Oxygen extractin (influent-effluent xygen cntent) (Table 2) and effluent P 2 we nt significantly diffent in hearts frm cnditined and sedentary rats in grup 2. The was virtually cmplete extractin f xygen frm the perfusing slutin during hypxia. Table 3 shws the sults f glycgen and high-energy phsphate analysis after hypxic perfusin in grup 2. Althugh mycardial glycgen is higher in hearts frm cnditined rats than it is in thse frm sedentary cntrls in the in viv state (18), this diffence did nt persist during hypxia in cntracting hearts. As wuld be expected in hypxia, catine phsphate levels we als depssed cmpad with thse during in viv r aerbic perfusin (18, 19). They we nt significantly diffent after hypxic perfusin in hearts frm cnditined and sedentary rats. ATP was nt depssed significantly frm in viv levels. T determine the usefulness f fluscent change in pdicting changes in lactate r

6 PHYSICAL TRAINING AND CARDIAC PERFORMANCE 423 m e a..111 Trie IN >c >c IM 05 IN 1O <N O i 4) 1 +1 & i i 41 IN rt r-l (N i H Oi O * I 00 ^-i C<) IN O i> -* IN t^ i-< ) 4) 41 T t- c H I I I 41 41,-i 4) t~ T io ic O O io c; c^ c-i i i '.I X s g. >> p 5b if T3 O GJ **" II -a 35 >> M a c 5 J: sis = II V ratis f lactate t pyruvate, crlatins fr these variables we calculated fr hearts frm cnditined and sedentary rats. Fluscence change crlated significantly with lactate utput in hearts f bth cntrl and experimental rats (P<0.01, r = 0.55), and ratis f lactate t pyruvate crlated in hearts frm cnditined rats (P<0.05, r = 0.41). Hwever the pdictive value f fluscence change was nt quantitatively useful. Lactate prductin crlated highly with the rati f lactate t pyruvate (P<0.001, r=0.80) in this experimental mdel. NADH fluscence was useful fr timing the metablic changes sulting frm hypxia. N diffences we bserved between hearts frm cnditined and sedentary rats in the nset f fluscent change during either hypxia r cvery. An incase in fluscence was nted an average f 8 secnds frm the nset f hypxia, and a decase ccurd an average f 2.5 secnds after the beginning f xygenatin. Results in Wrking Hearts. Figu 3 shws the dynamic sults in wrking rat hearts (grup 3). Perfrmance tended t be better in the aerbic state in hearts frm cnditined rats as has been nted pviusly (1). With hypxia, left ventricular systlic pssu, maximum dp/dt, and cardiac utput fell. Hwever, cardiac utput was twice as high during hypxia in hearts frm cnditined rats as it was in hearts frm sedentary rats. Hypxia ablished the pssu, velcity, and cardiac utput spnses f the heart t a dubling f the atrial pssu. In the aerbic state this prcedu incases all f these functins (1). During hypxia the left ventricular enddiastlic pssu exceeded the value that was pdicted frm the height f the atrial servir. These values a shwn in Table 4. Hwever, the was n significant diffence in end-diastlic pssu between hearts frm cnditined and sedentary rats during either full xygenatin r hypxia. Figu 4 shws the latinship between wrk, mean (integrated) left ventricular systlic pssu, xygen cnsumptin, lactate

7 424 SEUER, STEZOSKI Residual Energy-Related Cmpunds in Perfused Hearts Grup 2 Grup Residual glycgen* ((imles/g) ± ± ± ± TABLE 3 Catine phsphate ATP Gunles/g) G<mles/g) 18.1 ± ± =*= ± 1.6 Results a means =*= SE/g dry heart weight. = hearts frm sedentary rats; = hearts frm cnditined rats. *In glucse equivalents. SEDENTARY NDITIONED IS) ATRIAL PRESSURE (cml 95 OXYGEN [%] FIGURE 3 Effects f hypxia n the perfrmance f cnditined hearts in the wrking rat heart apparatus (grup 3). PLVSP = peak left ventricular systlic pssu. = cardiac utput. Fr PLVSP and MAX dp/dt, a shws perfrmance during isvlumic clamping and b shws perfrmance while the hearts we ejecting. All ther symbls a the same as in Figu 1. prductin, and cardiac efficiency in grup 3. Bth wrk and mean left ventricular systlic pssu we higher in hearts frm cnditined rats than they we in hearts frm sedentary rats during the initial aerbic perid and during hypxia. As was nted pviusly (1) lactate prductin tended t be higher under aerbic cnditins in the hearts frm the sedentary cntrls. Cardiac efficiency was the same in hearts frm cnditined and sedentary rats under aerbic cnditins but was twice as high in hearts frm cnditined rats during hypxia. In grup 3 xygen extractin and P 2 in the effluent medium we higher than in grup 1 (Table 2), suggesting sme serve capacity fr xygen extractin by these wrking hearts. Hwever the was n significant diffence between hearts frm cnditined and sedentary rats in grup 3 garding xygen cnsumptin, xygen extractin, r P 2 in the effluent medium. During hypxia, the rati f lactate t pyruvate was slightly higher in hearts frm cnditined rats than in thse frm sedentary rats at 20 cm f atrial pssu. Glycgen levels (Table 3) we similar in hearts frm cnditined and sedentary rats in grup 3 at the end f the study. Discussin Dynamics in the Isvlumic Pparatin. The studies in grups 1 and 2 we

8 PHYSICAL TRAINING AND CARDIAC PERFORMANCE 425 O >v Ct </) ^^ li X z e < E z UJ -J ^ SEDENTARY (8) --- NDITIONED (8) u. UJ ATRIAL PRESSURE (cm) OXYGEN (%) FIGURE 4 95 Cardiac wrk and metablism in cnditined hearts during hypxia in the wrking rat heart apparatus (grup 3). The symbls and frmat have been described in the legends t Figus 1 and 3. Wrk, qo z, and lactate utput a per gram dry weight. designed t investigate the mechanic and metablic perfrmance f hearts cntracting isvlumically in an attempt t derive sme infrmatin abut lative changes in tensin and cntractility in hearts frm cnditined and sedentary rats. That hearts we cntracting isvlumically is supprted by the bservatin that the peak left ventricular pssu during cntrl and cvery perids just ached the level f the artic perfusin pssu (Fig. 1). Thus ejectin during full xygenatin must have been insignificant. During hypxia the peak left ventricular systlic pssu did nt ach the artic perfusin pssu. The left atrium was ligated s that significant mitral gurgitatin culd nt ccur. Althugh individual cntractins we thef essentially isvlumic, gradual changes in diastlic pssu ccurd during hypxia. This was prbably due t thebesian flw r a small amunt f artic gurgitatin. The pssu change tended t be gater in hearts frm sedentary rats than in thse frm cnditined rats, and the diffences we particularly prnunced in the early cvery perid. The diffences in end-diastlic pssu must psent alteratins in diastlic cmpliance r vlume f these ventricles. Althugh it is pssible that the cmpliance latinships between hearts frm sedentary and cnditined rats became alted during hypxia, length-tensin latinships have been prted t be the same in hearts frm sedentary and cnditined animals (20, 21). If isvlumic perfrmance during hypxia was markedly imprved by cnditining, we wuld have expected hearts frm cnditined rats t maintain higher peak left ventricular systlic pssus and a gater maximum dp/dt than hearts frm sedentary rats. Similar changes have been demnstrated during anxia in this same apparatus in hearts with high glycgen sts (19), indicating that the system is sensitive enugh t detect changes in isvlumic perfrmance. In the psent studies the we n significant diffences between hearts frm cnditined and sedentary rats in either peak r develped left ventricular systlic pssus. Hearts frm cnditined rats tended t develp the same systlic pssus frm lwer end-diastlic pssus; this suggests but des nt prve the pssibility f a gater intrpic state in hearts frm cnditined rats during hypxia. Thef, the isvlumic studies suggest slightly imprved perfrmance during hypxia in hearts frm cnditined rats, as psented by a lesser end-diastlic pssu, and pssibly vlume, during hypxia.

9 426 SEUER, STEZOSKI End-Diasllic Pssu in Wrking Rat Hearts Atrial servir height (cm) TABLE 4 Pdicted end-diastlic pssu (mm Hg) Observed end-diastlic pssu (mm Hg) 7.5 ± 1.6 T 6.5 ± 1.2* T i i 15.0 ± 2.0 <- t -» 13.4 ± 0.7 T T t 1 i 20.1 ± 0.8 <- t -* 19.3 ± 0.3 t T * * I i > 9.5 ± 1.4 <- J -» 7.3 ± 1.5* Results a means = = SB. = hearts frm sedentary rats; = hearts frm cnditined rats. *P < cmparing values at the end f the arrws. fp < 0.05 cmparing values at the end f the arrws. %P > 0.05 cmparing values at the end f the arrws. Dynamics in the Wrking Rat Heart. As was pviusly nted, dynamic perfrmance was gater during xygenatin in hearts frm cnditined rats than in hearts frm sedentary rats (1). During hypxia left ventricular enddiastlic pssus exceeded values pdicted frm the height f the atrial servir (Table 4). In pvius studies during full xygenatin end-diastlic pssu was similar t the pdicted value. The mechanism f this pssu diffence is nt clear but may be lated t atrial cntractin ccurring against a latively nncmpliant left ventricle during hypxia. During hypxia small diffences between hearts frm cnditined and sedentary rats we nted in peak pssu develpment, mean left ventricular systlic pssu, and maximum dp/dt (Figs. 3 and 4). These slight diffences in perfrmance cnfirm the minimal changes seen in the trgrade perfusin studies (grups 1 and 2). The majr dynamic diffences nted during hypxia we that cardiac utput and cardiac wrk per gram f heart we apprximately twice as high in hearts frm cnditined rats as in thse frm sedentary rats during hypxia. It has been pviusly prted that perfrmance f islated rat hearts crcted fr heart weight is inversely lated t their size (6). Thus, gater perfrmance in grup 3 in hearts frm cnditined rats with larger hearts implies an even gater effect f cnditining n these hearts. If the utput and wrk data in Figus 3 and 4 we expssed per whle heart r per unit bdy weight, the diffences between hearts frm cnditined and sedentary rats in their capacity t deliver utput r perfrm external wrk wuld be accentuated. The pssibility must be raised that the dynamic advantage f hearts frm cnditined rats in grup 3 depends n cardiac hypertrphy. Althugh this cannt be firmly denied, pvius studies with hearts with cnditined rats demnstrate that imprved dynamics and enzymatic changes a nt the sult f hypertrphy (1,2). During hypxia hearts frm cnditined and sedentary rats failed t incase ventricular pssu, dp/dt, r cardiac utput with incasing atrial pssus. During full xygenatin, Starling spnses had been shwn pviusly t be quite adequate (1). This suggests that the limits f cardiac serve capacity f hearts frm bth cnditined and

10 PHYSICAL TRAINING AND CARDIAC PERFORMANCE 427 sedentary rats had been ached. The view is further supprted by the failu f left ventricular systlic pssu and maximum dp/dt t rise significantly during isvlumic clamping (Fig. 3). During full xygenatin, this prcedu prduced marked changes in these measuments. Our pvius studies had indicated a gater crnary flw spnse in aerbic hearts frm cnditined rats (1). This diffence had pviusly been brught ut during full xygenatin by raising the atrial pssu t high levels. This bservatin was cnsistent with pvius anatmic and crnary-cast studies (17, 22). In the psent investigatin an incased crnary serve f hearts frm cnditined rats was nly bserved during hypxia in isvlumic studies. The asn fr nt detecting such changes in the wrking apparatus is nt clear. In the isvlumic experiments 20% xygen was used in the hypxic perfusin slutin, and in wrking experiments 50% xygen was emplyed. With 20% xygen all the xygen was extracted frm the perfusin medium and the P 2 f the effluent fluid apprached 0 mm Hg. With 50% xygen the P02 was in the range f 50 mm Hg in the effluent medium. Mycardial P 2 was als prbably much lwer in isvlumic studies. The level f mycardial xygenatin is thught t be an imprtant cntrl factr in the spnse f the crnary vasculatu t hypxia (23). In wrking studies mycardial P 2 may nt have been lw enugh t fully stimulate crnary vasdilatatin. Metablism and Energetic Relatinships. It has been suggested that islated perfused rat hearts have brderline xygenatin, and may in fact be hypxic even when they a perfused with a slutin bubbled with 95% O L. (24). This suppsitin appears t be based n studies in which intraventricular ballns we used. In thse studies, crnary perfusin rates we lwer than in the psent studies. Lactate utput and ratis f lactate t pyruvate in the effluent perfusin medium seem t be abnrmally high, cmpad with studies prted he and pviusly prted frm this labratry (19). Furtherm, we have pviusly demnstrated that in ur trgrade perfusin systems mycardial glycgen and high-energy phsphate levels a maintained at r near in viv levels during aerbic perfusin (19). Neither the psent studies f isvlumic r f wrking perfrmance demnstrated any diffences in energy delivery between hearts frm cnditined and sedentary rats during hypxia as measud by xygen cnsumptin, lactate prductin, ratis f lactate t pyruvate, r sidual glycgen r high-energy phsphates in the mycardium. In skeletal muscle, enzymatic adaptatin t cnditining appears t ccur in the pathways f aerbic energy prductin (25). The same des nt appear t ccur in hearts f cnditined animals (26, 27). Thef, diffences in rates f energy frmatin prbably d nt accunt fr the diffences in cardiac wrk bserved during hypxia. This suppsitin is supprted by the bservatin that the tw majr determinants f energy cnsumptin, tensin and cntractility (28), appead t be nly minimally diffent in hearts frm cnditined and sedentary rats during hypxia. The majr diffence between hearts frm sedentary and cnditined rats during hypxia seems t late t fiber shrtening (strke vlume). The ability t demnstrate diffences during hypxia in wrking hearts and nt in isvlumic hearts lates t the lesser metablic cst f fiber shrtening as cmpad with tensin develpment in mycardium. Thus hypxic hearts frm cnditined animals culd achieve much higher cardiac utputs than hypxic hearts frm cntrl animals with latively little added energy cst. If this ccurs in viv, it wuld be a highly imprtant adaptive alteratin in the spnse f cnditined hearts. Cardiac efficiency, as calculated frm the calric equivalent f xygen cnsumptin and the calric equivalent f external wrk fell during hypxia but mained higher in hearts frm cnditined rats than it did in hearts frm sedentary rats. During hypxia, lactate utput frm hearts frm cnditined and

11 428 SEUER, STEZOSKI sedentary rats was similar. Anaerbic glyclysis wuld have cntributed the same amunt f energy t hearts frm cnditined and sedentary rats and thus cannt accunt fr the appant gater external efficiency in hearts frm cnditined rats during hypxia. The psent studies indicate that the pumping capacity f hearts frm cnditined rats has gater sistance t hypxia than des that f hearts frm sedentary rats. Whether ischemic r hypxic hearts in intact physically trained humans act similarly is nt knwn. Acknwledgment We a grateful fr the technical assistance f Miss Patricia Pisanelli and fr the sectarial assistance f Miss Carl Gundlach. Refences 1. PENPARGKUL, S., AND SEUER, J.: Effect f physical training upn the mechanical and metablic perfrmance f the rat heart. J Clin Invest 49: , BHAN, A.K., AND SEUER, J.: Effect f physical cnditining n cardiac actmysin ATPase (abstr.). Circulatin 44:11-132, PAFFENBARCER, R.S., JR., LAULIN, M.E., GIMA, A.S., AND BLACK, R.A.: Wrk activity f lngshmen as lated t death frm crnary heart disease and strke. N Engl J Med 282: , BRUNNEH, D., AND MEULAM, N.: Pventin f curnt mycardial infarctin by physical exercise. Isr J Med Sci 5: , SEUER, J., AND STEZOSKI, S.W.: Discrdance between the electrcardigram and ATP levels in the islated rat heart. Am J Med Sci 257: , NEELY, J.R., LlEBERMEISTER, H., BATTERSBY, E.J., AND MORGAN, H.E.: Effect f pssu develpment n xygen cnsumptin by islated rat heart. Am J Physil 212: , PENPARCKUL, S., AND SEUEH, J.: Metablic cmparisns between hearts arsted by calcium deprivatin r ptassium excess. Am J Physil 217: , ANCE, B., WILLIAMSON, J.R., JAMIESON, D., AND SOENER, B.: Prperties and kinetics f duced pyridine nucletide fluscence f the islated and in viv rat heart. Bichem Z 341: , WALAAS, O., AND WALAAS, E.: Effect f epinephrine n rat diaphragm. J Bil Chem 187: , SAIFER, A., AND GERSTENFELD, S.: Phtmetric micrdeterminatin f bld glucse with glucse xidase. J Lab Clin Med 51: , LAMPRET, W., AND STEIN, P.: Catine phsphate. In Methds f Enzymatic Analysis, edited by H. U. Bergmeyer. New Yrk, Academic Pss, 1963, pp LAMPRET, W., AND TRAUTSOLD, I.: Determinatin with hexkinase and glucse-6-phsphate dehydrgenase. In Methds f Enzymatic Analysis, edited by H. U. Bergmeyer. New Yrk, Academic Pss, 1963, pp HOHORST, H.J.: L-( + )-Iactate: Determinatin with lactic dehydrgenase and DPN. In Methds f Enzymatic Analysis, edited by H. U. Bergmeyer. New Yrk, Academic Pss, 1963, pp SECAL, S.A., BLAIR, A.E., AND WYNCAARDEN, J.B.: Enzymatic spectrphtmetric methd f the determinatin f pyruvic acid in bld. J Lab Clin Med 48: , SNEDER, G.W.: Statistical Methds, 5th ed. Ames, Iwa, Iwa State University Pss, GOLLNICK, P.D., STRUCK, P.J., AND BOGYO, T.P.: Lactic dehydrgenase activities f rat heart and skeletal muscle after exercise and training. J Appl Physil 22: , STEVENSON, J.A.F., FELEKI, V., RENITZER, P., AND BEATON, J.R.: Effect f exercise n crnary te size in the rat. Circ Res 15: , SEUER, J., KAPNER, L., STRINCFELLOW, C.A., ARMSTRONG, C.L., AND PENPARGKUL, S.: Glycgen, lipid, and high energy phsphate sts in hearts frm cnditined rats. J Lab Clin Med 75: , SEUER, J., AND STEZOSKI, S.W.: Prtective rle f incased mycardial glycgen sts in cardiac anxia in the rat. Circ Res 27: , WHTTEHORN, W.V., AND GRIMMENGA, A.S.: Effects f exercise n prperties f the mycardium (abstr.). J Lab Clin Med 48:959, GRIMM, A.F., KUBOTA, R., AND WHITEHORN, W.V.: Prperties f mycardium in cardimegaly. Circ Res 12: , BLOOR, CM., AND LEON, A.S.: Interactin f age and exercise n the heart and its bld supply. Lab Invest 22: , BERNE, R.M., BLACKMON, J.R., AND GARDNER, T.H.: Hypxemia and crnary bld flw. J Clin Invest 36: , HENDERSON, A.H., CRAIC, R.J., GORLIN, R., AND SONNENBLICK, E.H.: Fe fatty acids and

12 PHYSICAL TRAINING AND CARDIAC PERFORMANCE 429 mycardial functin in perfused rat hearts. Cardivasc Res 4: , OSCAI, L.B., MOLE, P.A., BHEI, B., AND HOLLOSZY, J.O.: Cardiac grwth and spiratry enzyme levels in male rats subjected t a running prgram. Am J Physil 220: , HOLLOSZY, J.O.: Bichemical adaptatins in muscle: Effects f exercise n mitchndrial xygen uptake and spiratry enzyme activity in skeletal muscle. J Bil Chem 242: , SIMON, L.M., SEUER, J., AND ROBIN, E.D.: Cytchrme xidase and pyruvate kinase changes in the chrnically exercised rat (abstr.). Clin Res 19:340, SEUER, J. AND MCDONALD, R.H.: Curnt status f mycardial mechanical-energetic latinships. Mt Sinai J Med NY 37: , 1970.