Effects of Stimulation Frequency on Myocardial Extensibility

Transcription

1 Effects of Stmulaton Frequency on Myocardal Extensblty By Erc O. Fegl, M.D. ABSTRACT Whether a change n myocardal eontracthty s accompaned by a change n dastolc extensblty was studed by alterng stmulaton frequency, ncludng pared stmulaton, as the notropc nterventon. Isometrc and sotonc contractons of solated cat papllary muscles were examned. Apparent changes n dastolc extensblty were observed wth pared stmulaton n sometrc preparatons. Rapd changes were seen only n muscles that had spontaneous aftercontractons between drven beats. These changes were beleved not to reflect true extensblty changes but rather a change n tmng between the relaxaton of a beat drven by a pared stmulus and the onset of an aftercontracton. In contnuous sotonc (not afterloaded) preparatons, end-dastolc length depended on beat frequency. The muscle crept to a longer length when dastole was prolonged by decreasng the heart rate. In sotonc experments wthout aftercontractons myocardal extensblty remaned unchanged durng pared electrcal stmulaton and changes n beat frequency. ADDITIONAL KEY WORDS cardac tone myocardal elastcty muscle mechancal propertes myocardal complance aftercontractons papllary muscle postextrasystolc potentaton pared stmulaton cat Downloaded from by on January, 209 A characterstc property of cardac muscle s that the contractle vgor s dependent on the muscle fber length. Ths s the Frank- Starlng law of the heart. Myocardal dastouc extensblty s mportant because t s one of the determnants of muscle fber length. For a gven dastolc pressure the myocardal fber length s determned by the elastc propertes of the heart and ts geometry. Extensblty has been defned as the recprocal of the elastc modulus (). It s used here n that sense to descrbe the passve elastc property of cardac tssue n contrast to any change n muscle propertes resultng from contractons or aftercontractons. The possblty that elastc propertes of the restng heart change wth notropc effects has been nvestgated many tmes (2-22). Some nves- From the Department of Physology, School of Medcne, Unversty of Pennsylvana, Phladelpha, Pennsylvana 904. Ths nvestgaton was supported by U. S. Publc Health Servce Research Grants -K3-HE-0, 627 and HE 0906 from the Natonal Heart Insttute. Accepted for publcaton February 9, 967. tgators have found changes n the dastolc propertes of the myocardum followng admnstraton of epnephrne or calcum, or stmulaton of the stellate ganglon (6,, 7) and others have found no change (8, 0, 2-4, 6, 2). Recently, changes n dastolc complance resultng from pared electrcal stmulaton have been reported by Bartlestone et al. (8), Koch-Weser (9), and Scherlag et al. (20). Properly tmed pared electrcal stmul to cardac muscle can produce a large postve notropc effect. The mechansm may be related to the starcase phenomenon or ntervalstrength relatonshp (9, 23). Changng the stmulaton frequency (ncludng pared stmulaton) has the advantages that t elcts a change n contractlty that can be extngushed n only a few beats and that the notropc changes are reproducble and can be elcted repettvely. Ths permts studes n short tme ntervals and mnmzes problems of baselne shft. Spontaneous aftercontractons are very mportant n the nterpretaton of the results; CrcuUon Rnrcb, Vol. XX, Aprl

2 448 FEIGL Downloaded from by on January, 209 they have been observed thus far only n solated n-vtro myocardal preparatons (24-28). They are dstnct, small, slow contractons that occur n the absence of a propagated acton potental and are most promnent at temperatures below 37 C. Experments were done at 22 C to study the effects of aftercontractons. Ths study was an examnaton of dastolc extensblty durng notropc changes elcted by changng the stmulaton frequency. An n-vtro preparaton of cat papllary muscle was used. Results smlar to those of Scherlag et al. (20) were obtaned but were related to the presence of aftercontractons, stress relaxaton, or both, n an sometrc preparaton rather than to a change n passve extensblty. Methods Cats and kttens were anesthetzed wth pentobarbtal, 25 mg/kg ntrapertoneally. Papllary muscles were quckly excsed from the rght ventrcle and placed n physologcal salt soluton. The composton of the soluton n mmoles per lter was: sodum chlorde, 90; potassum chlorde, 5; calcum chlorde, 2.5; sodum bcarbonate, 29; magnesum sulfate, ; sodum TEA/S/ O/V x g LULL phosphate, ; sodum fumarate, 5; sodum pyruvate, 5; sodum glutamate, 5; dextrose, 0; dsodum EDTA, 0.05; plus 5 unts of nsuln. The soluton was gassed wth 95% oxygen and 5* carbon doxde, and a ph of 7.3 at 37 C resulted. The bath was kept at constant temperature n a water jacket wth a crculatng pump. Experments were done at 22 or 37 C. The muscle was stmulated through the bath wth platnum electrodes that ran the length of the muscle but dd not touch t. The stmulator (Amercan Electroncs Laboratory 04) provded rectangular pulses through an solaton unt. The ntensty was adjusted to be just supramaxmal, usually 0$ to 50 greater than threshold. A second (pared) stmulus could be ntroduced wth a varable delay wthout changng the basc rate. The muscle was arranged so that muscle force and shortenng could be measured smultaneously. The lower end of the muscle was held n a specal sprng clamp whch s part of the force transducer. The force transducer (Honeywell) was entrely submerged n the bath and held by a sturdy post. The complance of the force gauge was 0.30 mm/00 g. The upper end of the muscle was attached to an sotonc lever (29) wth a length of straghtened, full, hard-temper stanless steel wre, whch was ted to the chorda tendneae wth 4-0 slk suture just long enough to make a knot. The knot was constantly below the bath surface. The fct LLL.I U UU UJ.L!!T. L.n'Jll "'lttluljl.'. ' ' M '.I I MT I I! TEWS/OA/ X / sec FIGURE A prompt fall n dastolc sometrc tenson followed the frst pared stmulaton. Ths was an apparent ncrease n dastolc extensblty. Note the aftercontractons between drven contractons. The perod between the onset of a stmulated contracton and the subsequent aftercontracton was.7 sec, whch promptly ncreased to 2.2 sec wth pared stmulaton. Temperature, 22 C; dastolc muscle length, 8.3 mm; cross-sectonal area, 2X)5 mm'. Stmulus rate was 23/mn; duraton, 5 msec; pared delay, 743 msec. CrcmUto* Kttrcb, VoL XX, Aprl 967

3 MYOCARDIAL EXTENSIBILITY 449 lever was used to record nstantaneous muscle length. The electronc crcut was modfed to mprove the stablty and lnearty. The equvalent mass of the lever was less than 80 mg. The lever was equpped wth an adjustable mcrometer stop. The length sgnal was dfferentated by an operatonal amplfer (Phlbrck P65) to obtan shortenng velocty. Wth ths arrangement, the muscle could be studed under true sotonc, sotonc afterloaded, and sometrc condtons by smply adjustng the load and the movable stop. Calbratons of all expermental varables were made after each expermental run. Length was calbrated wth the mcrometer stop on the lever, the force transducer wth weghts. Velocty was calbrated by a trangular wave generator (Hewlett Packard 3300A), whch gave a trace on the calbrated length record, and the dervatve on the velocty record. Recordng was on an oscllograph (Brush 707). At the end of the experment, the muscle was weghed and cross-sectonal area calculated on the bass of a cylnder of unt densty. Muscle cross-sectonal areas ranged from.40 to 2.6 mm 2. Ths paper reports the results from 5 techncally satsfactory preparatons; eght muscles were studed at 22 - C and seven at 37 C. Results Isometrc Contractons wth Ajtercontractons. When aftercontractons were present at 22 C, a decrease (Fg. ), ncrease, or no change n sometrc dastolc tenson could accompany pared stmulaton. Whether the sometrc dastolc tenson ncreased or decreased wth pared stmulaton was dependent on the tmng of the extra stmulus. Fgures 2 through 4 are records taken from the same muscle. In Fgure 2, when the pared stmulus was delayed 550 msec, the dastolc tenson ncreased, ndcatng an apparent decrease n dastolc extensblty. In Fgure 3, the delay was ncreased to 650 msec, and there was no apparent change n restng extensblty. In Fgure 4, a further ncrease TENS/ON /O Downloaded from by on January, g TENS/ON X / 2 0 /O sec FIGURE 2 Increase n dastolc sometrc tenson accompanyng pared stmulaton. There was an apparent decrease n dastolc extensblty. Note the aftercontractons between drven contractons. The perod between the onset of a stmulated contracton and the subsequent aftercontracton was.3 sec, whch promptly ncreased to.5 sec wth pared stmulaton. Temperature, 22 C; dastolc muscle length, 7.5 mm; cross-sectonal area, 2.3 mm'. Stmulus rate was 25/mn; duraton, 4 msec; pared delay, 550 msec. Fgures 2, 3, and 4 are from the same muscle. CrcmUuon Rtarcb, Vol. XX, Aprl 967

4 : 450 FEIGL n delay to 740 msec gave a fall n restng tenson and an apparent ncrease n extensblty. The dastolc portons of the records n Fgures through 4 are not flat. In each case there s a small spontaneous aftercontracton between the larger contractons drven by the stmulator. Aftercontractons were also present durng the perod of pared stmulaton. The aftercontractons are clearly seen n Fgure 2, where the slower aftercontracton was on the down slope at the tme the drven contracton began. Aftercontractons can be seen on close examnaton n Fgures, 3, and 4; tenson developed slowly and was nterrupted by the rapd development of tenson of the stmulated beat. The "shoulder" between the up slope of the aftercontracton and the rapd begnnng of the drven contracton s readly apparent n Fgure 3 and less apparent n Fgures and 4. The tme between the onset of a drven contracton and begnnng of the subsequent aftercontracton was lengthened durng pared stmulaton. In Fgure the perod between the begnnng of the drven beat and the subsequent aftercontracton was.7 sec before and after pared stmulaton. Durng pared stmulaton the aftercontracton began 2.2 sec after the drven contracton. For the muscle shown n Fgures 2, 3, and 4 the tme between the onset of drven and aftercontracton was.3 sec durng control perods. Wth pared stmulaton, ths ncreased to.5 sec n Fgure 2,.8 sec n Fgure 3, and.9 sec n Fgure 4. Ths ndcates that the second depolarzaton of pared stmulaton n some way alters the onset of the spontaneous aftercontractons. Eght muscles wth aftercontractons were studed sometrcally at 22 C. In three, dastolc sometrc tenson fell (an apparent ncrease n extensblty) wth pared stmulaton of the type seen n Fgures and 4. Aftercontractons dsappear at low stmulaton frequences (24-28). It was not possble to obtan the rght TEA/S/O/V X /O Downloaded from by on January, g ;! A ' /! V! : j :! I / I' TENS/ON X / 2g A ft V r r h! ; V ' : :!! : ; ; I!. j U! I! ~L _ I r +J-MH-! A \ V. '! A ]'I _ft s r A V /' J\ rvi A u ' : I /O sec FIGURE 3 Unchanged dastolc sometrc tenson durng pared stmulaton. The perod between the onset of a stmulated contracton and the subsequent aftercontracton was.3 sec, whch promptly ncreased to.8 sec wth pared stmulaton. Stmulus rate was 25/mn; duraton, 4 msec; pared delay, 650 msec. CrcuUto* Rumrcb, Vol. XX. Aprl 967

5 MYOCARDIAL EXTENSIBILITY 45 combnaton of aftercontracton, wth basc beat frequency, or wth proper pared delay nterval to demonstrate a fall n dastolc sometrc tenson n all muscles. At 22 C an ncrease n dastolc sometrc tenson (an apparent decrease n extensblty) was observed n all eght muscles wth aftercontractons. Isotonc Contractons wth Aftercontractons. Sx muscles wth aftercontractons were studed sotoncally at 22 C. In all sx, pared stmulaton decreased dastolc length (an apparent decrease n extensblty). Ths effect was observed at hgh stmulaton frequences when aftercontractons followed each beat (three muscles) and also at low basc stmulaton frequences when aftercontractons were elcted by pared stmulaton (sx muscles). These effects are more completely descrbed below n the secton on aftercontractons. Decreased sotonc dastolc length resultng from pared stmulaton n the presence of aftercontractons s llustrated n Fgure 9. Increases n dastolc length accompanyng pared stmulaton were never observed n an sotonc preparaton. Isometrc Contractons tohhout Aftercontractons. Seven muscles were studed sometrcally at 37 C wthout aftercontractons. None had rapd changes n dastolc tenson wth pared stmulaton. When restng tenson was kept low (below 0.3 g) lttle stress relaxaton was observed (2). An experment of ths type s llustrated n Fgure 5. Isotonc Contractons wthout Aftercontractons. Seven muscles wthout aftercontractons were studed sotoncally at 37 C. Under completely sotonc (not afterloaded) condtons, end-dastolc muscle length was dependent on the stmulaton frequency the longer the dastolc perod, the longer the end-dastolc length the muscle would creep TEA/S/ON X /O Downloaded from by on January, g TENS/ON X / 2g /O sec FIGURE 4 Decrease n dastolc sometrc tenson durng pared stmulaton. The perod between the onset of a stmulated contracton and the subsequent aftercontracton was 3 sec, whch promptly ncreased to.9 sec wth pared stmulaton. There was an apparent ncrease n dastolc extensblty. Stmulus rate teas 29/mn; duraton, 4 msec; pared delay, 740 msec. Crculaton Ruurcb, Vol. XX, Aprl 967

6 452 FEIGL TENS/ON X /O 0.3 g "II < r _ TEA/S /OA/ X / 3 g Downloaded from by on January, 209 / > sec FIGURE 5 Unchanged dastolc sometrc tenson durng pared stmulaton. Note the absence of aftercontractons. Temperature, 37 C; dastolc length, 7.5 mm; cross-sectonal area, 0.93 mm. Stmulus rate was 8/mn; duraton, 4 msec; pared delay, 22 msec. LENGTH x 20 : : I I I ' I I ': ',; n rr [ I H I I I 4- LENGTH X / IT Ill' r T ITTT t,!' x - ^ 4 -j- ; -t- \ III! sec : ' ' - t -T -HMH+H I l l f! m It - I ; j I. I f j ll [ I t,! - ; - J-: 4- l t ] [_ '. L- R A T E 6 /ms FIGURE 6 Isotonc contractons. End-dastolc length was dependent on the duraton of dastole. Increased stmulaton frequency abbrevated dastole preventng the muscle from creepng to a longer length before the next contracton. Shortenng downward; dastolc muscle length, 93 mm; cross-sectonal area, 0.56 mm ; temperature, 37 C; duraton, 4 msec. Load toas 0.4 g. Orc m Uton Rnftrcb, Vol. XX, Aprl 967

7 MYOCARDIAL EXTENSIBILITY 453 LENGTH X 20 r r < LENGTH f X I f f f f f f r" \ f 4 T\ J.I.- ṟ\ f r f s c ' SHORTENING VELOCITY mm/sec /0 sec Downloaded from by on January, 209 FIGURE 7 sofon contractons. Essentally no change n dastolc length was observed wth two perods of pared stmulaton. The potentaton due to pared stmulaton was manfest by ncreased shortenng and shortenng velocty. Shortenng downward; dastolc muscle length, 7.5 mm; cross-sectonal area, 0.93 mm'; temperature, 37"C. Rate was 30/mn; duraton, 4 msec; pared delay, 22 msec. Load was 0.3 g. LENGTH x /O VELOCITY hortlnng 6-'; \ mm/sec / mn I ' :{tll l: lngthtnng 6 RUE J /»! FIGURE 8 Isotenc contractons. AftercorUractons whch were not apparent at low stmulaton frequency were elcted at hgher stmulaton frequency. Shortenng downwards; dastolc muscle length, 6.2 mm; cross-sectonal area, 2.42 mm*; temperature, 22 C. Load was 0.5 g. CrcmUto* Rturcb, Vol. XX, Aprl 967

8 FEIGL 454 LEMGTH x /O tc ^C\f]'f\f jr-t ±: FIGURE 9 Isotonc contractons. Aftercontractons were elcted by pared stmulaton. From left to rght, the stmulator was turned off for pauses after regular stmulaton, after a sngle pared stmulus, after two pared stmul, after three pared stmul, and agan wthout pared stmul. Note that the dastolc length was shorter after the frst pared stmulus n each case. Wthout a pause n stmulaton the slow aftercontractons can be mssed. Both the drven contractons and the aftercontractons were potentated over several beats wth pared stmulaton. Shortenng downward; dastolc muscle length, 7.3 mm; cross-sectonal area,.64 mm'; temperature, 22 C. Rate was 5/mn; duraton, 4 msec; pared delay, 800 msec. Load was 0.4 g. Downloaded from by on January, 209 to. Conversely, the shorter the dastolc perod, the shorter the end-dastolc length because of the vscous creep observed n dastolc muscle. These effects are llustrated n Fgure 6. Pared stmulaton resulted n a very slght decrease n end-dastolc muscle length because of the shorter dastolc perod when the muscle s stmulated twce. An ncrease n sotonc dastolc length (whch would ndcate an ncreased extensblty) wth pared stmulaton was never observed n these studes. The effects of pared electrcal stmulaton are shown n Fgure 7. Aftercontractons. Aftercontractons were a complcaton n ths study. They were regularly present n some muscles followng each stmulated beat as shown n Fgures through 4. However, they could be elcted by ncreases n the stmulaton frequency, and f they had not been recognzed, an erroneous concluson of a decreased extensblty wth ncreasng stmulaton frequency mght have been made. Ths s llustarted n Fgure 8. At a stmulaton of 3/mn, the aftercontracton was not readly recognzed though the muscle dd not show a smooth dastolc lengthenng. When the stmulaton frequency was ncreased to 6/mn, the dastolc length decreased because of the aftercontracton. After the stmulaton frequency was further ncreased to 2/mn, a clear aftercontracton wth dstnct shortenng was observed. Compare Fgure 8 wth aftercontractons to Fgure 6 wthout aftercontractons. In some muscles, pared stmulaton would generate aftercontractons that were not prevously present at the same beat frequency wth sngle stmulaton. Under sotonc condtons ths could be erroneously nterpreted as a decreased extensblty. Fgure 9 llustrates the development of aftercontractons wth pared stmulaton; ther presence mght be overlooked f the stmulator had not been turned off for a pause. They were potentated by pared, stmulaton over several beats smlar to the potentaton of the stmulated CmmUton Rts*.rcb, Vol. XX, Aprl 967

9 MYOCARDIAL EXTENSIBILITY 455 Downloaded from by on January, 209 beats. Potentaton of regularly occurrng aftercontractons by pared stmulaton can be seen n Fgures 2 and 3. Dscusson Four problems appear to be nvolved n the determnaton of myocardal dastolc complance. These are: () ncomplete relaxaton at hgher heart rates; (2) alteratons n the shape or geometry of ntact ventrcles; (3) vscous effects n solated or ntact cardac preparatons; and (4) aftercontractons n solated muscle preparatons. The mportance of slow heart rates has been commented on by others (9, 22). If the dastolc propertes of cardac muscle are beng studed t s apparent that heart rate must be slow enough to prevent mechancal fuson of beats. Partal mechancal fuson wth a rate of 24/mn at 22 C s shown n Fgure 8. Durng dastole, the relatonshp between pressure and volume of a ventrcle s determned not only by ts extensblty, but also by ts geometry or shape. It has been ponted out that the left ventrcle changes shape throughout the cardac cycle (30, 3). Mtchell, Lnden and Samoff (8) measured a segment length of the free left ventrcular wall wth ntraventrcular pressures durng sympathetc and vagal stmulaton. They found no change n the relatonshp between pressure and dastolc segment length wth altered notropsm. Hefner and co-workers () measured left ventrcular crcumference wth a mercury-n-rubber gauge wth and wthout a norepnephrne nfuson. They found a small change n the pressure-crcumference relaton wth norepnephrne, an ndcaton of ncreased extensblty. The possblty that the left ventrcle changed shape wth norepnephrne, and thus ts pressure-crcumference relaton, cannot be ruled out n ther experments. It s possble that the relatve pressures n the rght and left ventrcles change wth norepnephrne and that a relatve movement of the nterventrcular septum mght alter the shape of the left ventrcle. If ths were the case, the segment length recorder on the free wall of the ventrcle used by Mtchell, CrcmUtwu Rtvnb, Vol. XX, Aprl 967 Lnden and Sarnoff mght be less affected by shape changes than a crcumference gauge. Vscous behavor has been reported n skeletal muscle (32, 33) and n frog (34) and cat (7, 2) myocardum. Sonnenblck and co-workers (2) have recently demonstrated vscous stress relaxaton (decreasng tenson at constant length) resultng from ncrease n contractle force n sometrc papllary muscles and sochorc ventrcles. Snce sometrc preparatons show stress relaxaton, an unequvocal demonstraton of ncreased extensblty accompanyng an ncrease n contractlty cannot be made wth an sometrc preparaton. However, the rapd fall n sometrc dastolc tenson after a sngle pared stmulus as reported by Scherlag et al. (20) and as shown n Fgures and 4 s very unlkely to result from vscous stress relaxaton. In the present study, a rapd change n sometrc dastolc tenson followng the frst pared stmulus was observed only when aftercontractons were present. The rapd ftcfease n dastolc sometrc tenson wth pared stmulaton shown n Fgure 2 cannot be attrbuted to stress relaxaton, snce the change s n the opposte drecton from stress relaxaton. Rapd changes n dastolc sometrc tenson wth pared stmulaton when aftercontractons were present were beleved to result from an alteraton n the relatve tmng between drven contractons and aftercontractons. The extent to whch the sometrc tenson fell was dependent on the duraton of relaxaton of the drven beat before the aftercontracton began. In effect ths was a mechancal fuson between the end of the drven beat and the onset of the spontaneous aftercontracton. The observaton that sometrc dastolc tenson could be made to ncrease, decrease, or reman constant as a functon of the tmng of the pared stmulus supports ths nterpretaton. Also, the perod between the begnnng of a drven contracton and the subsequent aftercontracton lengthened and shortened n the expected manner. Ths resulted n delayed or earler fuson of the drven contracton and aftercontracton and accounted for the change n dastolc tenson.

10 456 FEIGL Downloaded from by on January, 209 Katzung (28) has studed aftercontractons n cardac muscle from several speces and found spontaneous ncreases and decreases n restng sometrc tenson followng perods of stmulated contractons. Snce the term aftercontracton dd not seem approprate for a fall n tenson he named the phenomenon "dastolc oscllaton." Katzung equated postve oscllaton wth aftercontractons descrbed by others (24-26). A spontaneous fall n tenson had not been reported prevously. Katzung used an sometrc preparaton, and the decreases n tenson he llustrated (Fgs. IB and C) may be due to stress relaxaton. Hs Fgure IB shows a rather rapd fall n dastolc sometrc tenson at the onset of a perod of stmulated beats. The fall s less abrupt than t appears because dastole followng the frst beat s mechancally fused wth the second beat and s off scale. In any case, the rapd fall s n keepng wth the rapd recovery at the end of the seres of beats and ndcates a short "tme constant" for the vscous element. Katzung's Fgure C shows a perod of rest nterrupted by a seres of rapd contractons wth mechancal fuson followed by a fall n restng tenson wth a slow recovery to the prestmulaton restng tenson. These two experments show what would be expected n an sometrc preparaton showng stress relaxaton. The nterpretaton of a decreased sometrc tenson due to aftercontractons n the present paper s based on altered tmng between drven contractons and aftercontractons. Ths dffers from Katzung's negatve dastolc oscllaton or "hyper-relaxaton." An sotonc preparaton s not subject to stress relaxaton. Muscles examned sotoncally n the present study dd not show "hyper-relaxaton" when aftercontractons were present. All observers agree that aftercontractons are more promnent at temperatures below 37 C and when Ca ++ s ncreased n the bath (24-28). The rapd dastolc changes assocated wth aftercontractons n ths study were observed at 22 C. The rapd fall n sometrc dastolc tenson wth pared stmulaton reported by Scherlag et al. (20) was n a cat papllary muscle at 37 C. However, ther Fgure 2 shows unmstakable aftercontractons at 37 C. Fgure n ther paper does not have suffcent tme resoluton to determne f aftercontractons are present. Katzung (28) reports aftercontractons at 35 C wth ncreased Ca". In one of the sotonc preparatons studed at 37 C, the Ca~ was ncreased to n w th aftercontractons were elcted by pared stmulaton smlar to the experment shown n Fgure 9. The relaton between aftercontractons and the strength of subsequent drven contractons has been nvestgated by Braveny, Sumbera and Kruta (27). They found that the greater the shortenng due to an aftercontracton, the smaller was the next stmulated contracton. Ths was related to the Frank- Starlng length-tenson relatonshp. That s, f the muscle had shortened by an aftercontracton and then a stmulated contracton was superposed, the stmulated contracton was smaller because t began from an already shortened length. However, t would be msleadng to descrbe the results n terms of a change n the passve extensblty of the muscle. Fgure 8 llustrates that aftercontractons are potentated by ncreasng the stmulaton frequency. Ths has been reported by several other workers (24-28). Elctng aftercontractons by pared stmulaton as shown n Fgure 9 has not been prevously reported. The dffculty of makng nterpretatons concernng dastolc dstensblty when aftercontractons are present s ponted up n Fgures 8 and 9. Even when an sotonc preparaton s used, slow aftercontractons may not be recognzed unless the stmulator s turned off. It s concluded that an unequvocal demonstraton of a change n dastolc extensblty accompanyng a postve notropc effect should be free from: () mechancal fuson found at hgh heart rates, (2) shape changes found n ntact ventrcles, (3) vscous stress relaxaton found n sometrc and sochorc preparatons, and (4) aftercontractons found wth n vtro preparatons. Wthn the lmts Crculate* Rumrcb, Vol. XX, Aprl 967

11 MYOCARDIAL EXTENSIBILITY 457 Downloaded from by on January, 209 of the sotonc method used, a change n dastolc extensblty was not observed to accompany the notropc effects of altered beat frequency or pared stmulaton. References. LANDOWNE, M., AND STACY, R. W.: Glossary of terms. In Tssue Elastcty, edted by J. W. Remngton. Washngton, D. C, Amercan Physologcal Socety, 957, p MEEK, W. J.: The queston of cardac tonus. Physol. Rev. 7: 259, WIGGEBS, C. J.: Studes on the cardodynamc acton of drugs: II. Mechansm of cardac stmulaton by epnephrne. J. Pharmacol. Exptl. Therap. 30: 233, JOHNSON', V., AND KATZ, L. N.: Tone n the mammalan ventrcle. Am. J. Physol. 8: 26, BOZLER, E.: Tonus changes n cardac muscle and ther sgnfcance for the ntaton of mpulses. Am. J. Physol. 39: 477, RUSHMEB, R. F.: Pressure-crcumference relatons of left ventrcle. Am. J. Physol. 86: 5, BUCKLEY, N. M., AND ZEIC, N. J.: Acute unlateral ventrcular falure n the solated dog heart. Am. J. Physol. 97: 247, MITCHELL, J. H., LINDEN, R. J., AND SAHNOFF, S. J.: Influence of cardac sympathetc and vagal nerve stmulaton on the relaton between left ventrcular dastolc pressure and myocardal segment length. Crculaton Res. 8: 00, BBAUNWALD, E., FHYE, R. L., AND ROSS, J., JR.: Studes on Starlng's law of the heart: Determnants of the relatonshp between left ventrcular end-dastolc pressure and crcumference. Crculaton Res. 8: 254, MONROE, R. C, AND FRENCH, G. N.: Left ventrcular pressure-volume relatonshps and myocardal oxygen consumpton n the solated heart. Crculaton Res. 9:.362, 96.. HEFNER, L. L., COGHLAN, H. C, JONES, W. B., AND REEVES, T. J.: Extensblty of the dog left ventrcle. Am. J. Physol. 20: 97, LAFONTANT, R. R., FEINBEHC, H., AND KATZ, L. N.: Pressure-volume relatonshps n rght ventrcle. Crculaton Res. : 699, SONNENBLICK, E. H.: Force-velocty relatons n mammalan heart muscle. Am. J. Physol. 202: 93, SONNENBLICK, E. H., SIECEL, J. H., AND SAR- NOFF, S. J.: Ventrcular dstensblty and pressure-volume curve durng sympathetc stmulaton. Am. J. Physol. 204:, SALISBURY, P. F., CROSS, C. E., AND RIEBEN, P. A.: Integrarve study of the crculaton n CucuUw* Rtsrcb, Vol. XX, Aprl 967 moderate hypotherma. Am. J. Cardol. 2: 84, MONROE, R. C, STRANC, R. H., LAFARCE, C. G., AND LEVY, J.: Ventrcular performance, pressure-volume relatonshps, and O 2 consumpton durng hypotherma. Am. J. Physol. 206: 67, LEACH, J. K., AND ALEXANDER, R. S.: Effect of epnephrne on stress relaxaton and dstensblty of the solated cat heart. Am. J. Physol. 209: 935, BARTELSTONE, H. J., SCHERLAG, B. J., HOFFMAN, B. F., AND CRANEFTELD, P. F.: Demonstraton of varable dastolc complance assocated wth pared stmulaton of the dog heart. Bull. N. Y. Acad. Med. 4: 66, KOCH-WESER, J.: Potentaton of myocardal contractlty by contnual premature extra-actvatons. Crculaton Res. 8: 330, SCHERLAG, B. J., BARTELSTONE, H. J., WYTE, S. R., AND HOFFMAN, B. F.: Varable dastolc ventrcular complance: A general property of mammalan cardac muscle. Nature 209: 246, SONNENBLICK, E. H., Ross, J., JR., COVELL, J. W., AND BRAUNWALD, E.: Alteratons n restng length-tenson relatons of cardac muscle ntroduced by changes n contractle force. Crculaton Res. 9: 980, BLINKS, J. R., AND KOCH-WESER, J.: Physcal factors n the analyss of the actons of drugs on myocardal contractlty. Pharmacol. Rev. 5: 53, KOCH-WESER, J., AND BLINKS, J. R.: Influence of the nterval between beats on myocardal contractlty. Pharmacol. Rev. 5: 60, REITER, M.: "After-contractons" under the acfon of cardac-glycosdes and calcum. In Proceedngs of the Frst Internatonal Pharmacologcal Meetng, vol. 3, edted by W. Wlbrandt. New York, Macmllan Co., 963, p REITER, M.: De Entstehung von "Nachkontraktonen" m Herzmuskel unter Enwrkung von Calcum und von Dgtalsglykosden n Abhanggket von der Rezfrequenz. Arch, exptl. Path. Pharmakol. 242: 497, KAUFMANN, R., FLECKSTEIN, A., AND ANTONI, H.: Ursachen und Auslosungsbedngungen von Myokard-Kontraktonen ohne regulares Aktonspotental. Arch. Ges. Physol. 278: 435, BRAVENY, P., SUMBERA, J., AND KRUTA, V.: After-contractons and resttuton of contractlty n the solated gunea pg aurcles. Arch. Intem. Physol. Bocbem. 74: 69, KATZUNC, B.: Dastolc oscllaton n muscle tenson and length. J. Cellular Comp. Physol. 64: 03, 964.

12 458 FEIGL 29. NORIUS, G., AND CARMECI, P.: Isotonc muscle transducer. J. Appl. Physol. 20: 355, RUSHMER, R. F.: Length-crcumference relatons of the left ventrcle. Crculaton Res. 3: 639, HAWTHORNE, E. W.: Instantaneous dmensonal changes of the left ventrcle n dogs. Crculaton Res. 9: 0, BUCHTHAL, F., AND ROSENFALK, P.: Elastc propertes of strated muscle. In Tssue Elastcty, edted by J. W. Remngton. Washngton, D. C, Amercan Physologcal Socety, 957, p ABBOTT, B. C, AND LOWY, J.: Stress relaxaton n muscle, Proc. Roy. Soc. Ser. B (London) 46: 28, LUNDIN, C: Mechancal propertes of cardac muscle. Acta Physol. Scand. 25: (suppl. 20), 947. Books Receved Books receved by CIRCULATION RESEARCH are hereby acknowledged. Downloaded from by on January, 209 Catecholamnes. Rchard J. Wurtman, M.D., Boston, Lttle, Brown and Co., 966, pages, 6 llustratons, $6.75. Conflct n Socety. CIBA Foundaton Symposum. Anthony De Reuck, M.Sc, D.I.C., A.R.C.S., and Jule Knght, B.A. (Eds.). Boston, Massachusetts, Lttle, Brown, and Company, 966, 467 pages, llustrated, $3.00. Comparatve Leukaema Research. Wenner- Gren Center Internatonal Symposum Seres, Vol. 6. G. Wnqvst (Ed.). London, Pergamon Press, pages, llustrated, $3.50. Heparn and Lpd Metabolsm: An Annotated Bblography. Myer M. Fshman, Ph.D. Rver Edge, N. J., Techncal Servce Laboratores, 966, 95 pages, $5.50. Balstocardography and Cardovascular Dynamcs (Proceedngs of the Frst World Congress on Balstocardography and Cardovascular Dynamcs). A. A. Knoop (Ed.). Baltmore, Maryland, Wllams and Wlkns Company, fgures, 3 tables, 347 pages. $9.25. Der Sauerstoffverbrauch des normound hypothermen Hundeherzens vor und wahrend verschedener Formen des nduzerten Herzstllstandes. Bblotheca Cardologca, No. 8. Karl Bonhoeffer. Basel, New York, S. Karger A.-G., 967, 3 fgures, 4 tables 74 pages. sfr./dm 20. Proceedngs of the Internatonal Symposum on the Cardovascular and Respratory Effects of Hypoxa. /. D. Hatcher and D. B. Jennngs (Eds.). Basel, New York, S. Karger A.-G., 408 pages, llustrated, $7.50. Engneerng n the Practce of Medcne. Bernard L. Segal, M.D., and Davd G. Kdpatrck, P.E. (Eds.). Baltmore, Maryland, Wllams and Wlkns Company, 967, 482 pages, llustrated. CrtmUswn Rssarcb, Vol. XX, Aprl 967