Haemodynamic and metabolic effects of atenolol

Transcription

1 Br Hert J 198; 43: Hemodynmic nd metbolic effects of tenolol in ptients with ngin pectoris D S THOMPSON, N NAQVI, S M JUUL, D J COLTART, B S JNKINS, M M WBB-PPLO From the Deprtments of Crdiology nd Medicine, St Thoms's Hospitl, London SUMMARY Myocrdil substrte extrction, coronry sinus flow, left ventriculr pressure, nd crdic output were mesured in 11 ptients with ngin pectoris t three pcing rtes before nd fter tenolol (.2 mg/kg). Left ventriculr pressures, nd the product of systolic pressure time index nd hert rte did not chnge, but mx dp/dt nd KV mx fell fter tenolol. Only t the lowest pcing rte did the drug reduce crdic output. Coronry sinus blood flow nd myocrdil oxygen uptke did not chnge fter tenolol. At the highest pcing rte before tenolol four ptients developed ngin, ccompnied by rise in end-distolic pressure. After tenolol ngin ws bolished in three, but the end-distolic pressure still rose t the highest pcing rte. Myocrdil lctte extrction rtio fell s hert rte incresed, nd ws lower in the ptients who developed ngin. After tenolol, lctte extrction rtio incresed significntly t the highest nd lowest pcing rtes. Myocrdil pyruvte extrction rose fter the drug. Arteril concentrtions ofhydroxybutyrte nd cetocette fell fter tenoldl, but the decrese in their extrction ws not significnt. Myocrdil extrction of free ftty cids ws relted to rteril concentrtion, which fell fter tenolol. The chnges in lctte nd pyruvte extrction fter tenolol were relted inversely to chnges in rteril free ftty cid concentrtion suggesting tht the improvement in myocrdil metbolism could hve been secondry to reduced peripherl lipolysis. The increse in lctte extrction ws ssocited with reliefofngin, but did not bolish the rise in end-distolic pressure induced by pcing. The beneficil effect of bet-drenergic blocking drugs in ngin hs been ttributed to reduction in myocrdil oxygen demnd secondry to their hemodynmic ctions.1-3 When hert rte is controlled by tril pcing, bet blockde hs little effect upon myocrdil oxygen consumption.45 Studies in which ptients with ngin hve been pced before nd fter bet-blocking drugs hve yielded conflicting results; some hve shown no beneficil effect,3 6 while others hve shown n improvement in nginl threshold or lctte extrction,4 suggesting tht bet blockde my modify myocrdil metbolism independently of its hemodynmic ctions. The possible direct effects of bet-blocking drugs upon the humn myocrdium re poorly understood, nd though their ctions upon peripherl metbolism re well documented8 the relevnce of these to the hert hs not been estblished. Atenolol is crdioselective bet-drenergic ntgonist without intrinsic sympthomimetic c- Received for publiction 12 November 1979 tivity,9 nd is effective in the tretment of ngin.' When hert rte is controlled, tenolol does not chnge myocrdil oxygen consumption or coronry blood flow.5 This study describes the effects of tenolol upon myocrdil substrte extrction, coronry sinus blood flow, nd systemic hemodynmics during pcing in 11 ptients with ngin, nd ttempts to identify the mechnisms by which it might improve the metbolism of the ischemic myocrdium. Ptients nd methods leven men (ged 4 to 59) were studied. All were limited by ngin nd were undergoing dignostic crdic ctheteristion nd coronry ngiogrphy. The ptients gve written consent, nd the hospitl ethicl committee pproved the study. Bet-blocking drugs were stopped 48 hours before ctheteristion. All studies were performed in the morning fter n over-pight fst. Atropine 3 mg nd dizepm 1 mg intrmusculrly, nd heprin 45 units/kg intrvenously, were given one 668

2 Hemodynmic nd metbolic effects of tenolol in ptients with ngin pectoris hour before ctheteristion. Right nd left hert ctheteristions were performed vi the right femorl vein nd rtery. Immeditely fter rteril ctheteristion blood ws tken for substrte concentrtion, nd second dose of heprin (45 units/kg) given. Coronry rteriogrphy ws performed using the Judkins technique, fter which the ptient ws sked if he wished to continue with the metbolic stuy. A Gnz thermistor nd pcing ctheter (7Fr CCS 7U, Wilton Webster Inc) ws introduced vi left ntecubitl vein nd positioned in the coronry sinus. Its position ws confirmed by injection of contrst medium. Cold sline ws injected into the right trium to ensure tht the thermistors were unffected by reflux of tril blood.11 A Schwrzer Swn-Gnz ctheter ws positioned in the pulmonry rtery, nd ctheter tip micromnometer, either no. 5 Millr or no. 8 Telco (MM52), introduced into the left ventricle. No mesurements were mde until t lest 2 minutes fter coronry rteriogrphy. Coronry sinus pcing ws estblished just bove bsl hert rte. Crdic output, left ventriculr pressure, nd coronry sinus blood flow were mesured, nd left ventriculr nd coronry sinus blood were smpled simultneously. The procedure ws repeted t three pcing rtes. Pcing ws stopped nd tenolol -2 mg/kg ws given intrvenously. Twenty minutes lter, mesurements were repeted t the sme three pcing rtes. Left ventriculr cinengiogrphy ws performed fter the metbolic study. The pressure nd coronry sinus thermistor signls were displyed on Cmbridge 12-chnnel recorder, nd stored on tpe. The micromnometer signl ws differentited either electriclly or on-line by computer. KV mx ws derived from the plot of log d (developed pressure)/dt ginst pressure'2 by n electronic processor13 or by computer. Systolic pressure time index ws clculted from plnimetric integrtion of the ventriculr pressure trce. Crdic output ws mesured by dye dilution. Indocynine green ws injected in the right trium, nd its concentrtion in the pulmonry rtery smpled. The dye curve ws nlysed by n IVH3 Schwrzer crdic output computer. Coronry sinus blood flow ws mesured by constnt infusion thermodilution.14 Left ventriculr volume, ejection frction, nd mss were estimted from the right nterior oblique projection of the cinengiogrm using computer-light pen system.13 Blood ws dded to n liquot of 1 per cent perchloric cid for deproteinistion nd subsequent enzymtic photometric determintion of lctte nd pyruvte,'5 cetocette nd hydroxybutyrte,'16 nd glycerol.17 For mesurement of free ftty cids'8 blood ws dded to sequestrine tubes, mixed, nd centrifuged. All smples were put on ice, nd then stored t -2'C. Heprinised smples were tken for determintion of oxygen content upon Lex 2 Con-TL (Lexington Instrument Corportion). xtrction of substrte is defined s the difference in concentrtion between rteril nd coronry sinus blood (A-V). xtrction rtio is tht difference expressed s percentge of rteril concentrtion [(A-V)/A %]. Myocrdil oxygen uptke is clculted s the difference between rteril nd coronry sinus blood oxygen content multiplied by coronry sinus flow. In ddition to the 11 ptients to whom tenolol ws dministered, one ptient followed the sme procedure, but ws given sline insted of the drug. The effect of heprin upon rteril free ftty cid concentrtion ws investigted in seprte group of 21 ptients who were undergoing dignostic left hert ctheteristion. In this lbortory ll ptients re given heprin (45 units/kg) fter the introduction of the rteril ctheter. Arteril free ftty cid concentrtion ws mesured immeditely before, nd five, 1, nd 3 minutes fter heprin dministrtion. Of the 21 ptients, 11 hd received heprin t the time of premediction. Sttisticl nlysis is by Student's t test nd liner regression; p < 5 is considered significnt. Vlues re expressed s men ± stndrd error of the men. Results 669 Ten of the 11 ptients hd bnorml coronry rteriogrms, nd the ngiogrphic dt re listed in the Tble. One ptient hd ngiogrphiclly norml coronry rteries, but history of ngin nd lctte extrction rtio of less thn 1 per cent t the highest pcing rte. As bsl hert rte differed between individuls, the pcing rtes used were not identicl in ll ptients. In ech individul the pcing rtes before nd fter tenolol were in close greement. The men hert rtes mesured from the pressure records were 86 ± 2, 114 ± 3, nd bets/min before, nd 87 ± 2, 114 ± 3, nd 139 ± 4 bets/min fter tenolol. The hemodynmic effects of tenolol re summrised in Fig. 1. Left ventriculr systolic nd enddistolic pressures did not chnge significntly fter tenolol. Crdic output ws reduced significntly only t the lowest pcing rte: '22 1/min compred to 4-57 ±-32 1/min (p < 5). The mximum rte of pressure rise ws lower fter tenolol t ech pcing rte, flling from 1667 ± 11 mmhg/s to 151 ± 1 mmhg/s t the first plcing

3 67 Tble Detils of coronry rteriogrphy nd left ventriculr cinengiogrphy Thompson, Nqvi, Juul, Coltrt, Jenkins, Webb-Peploe rte (p <.1), from 1878 ±17 mmhg/s to 1551 ± 1 mmhg/s t the second (p <1), nd from to 1567 ±146 mmhg/s (p < 1) t the third pcing rte, nd KV mx fell from 75 ±4 to 65 ±3/s (p < 1), 79 ±4 to 64 ±4/s (p < 1), nd from 63 ±6 to 54 ±4/s (p < 5) t the sme three pcing rtes. Four ptients developed ngin t the highest pcing rte before tenolol nd, in these ptients, between the lowest nd highest pcing rtes, enddistolic pressure rose by men of 11 mmhg, wheres in the other seven ptients there ws men fll of 1 mmhg. After tenolol, three of the four did not hve pin t the highest pcing rte, but end-distolic pressure still rose by men of 11 mmhg, compred with rise of 1 mmhg in the other seven. Coronry sinus flow nd myocrdil oxygen consumption did not chnge fter tenolol (Fig. 2). Arteril nd coronry sinus blood oxygen content Cse no. Age (y) RCA LAD Cx jection frction LV mss (g) o 5%o 1% %o.8% 8%/ % 1% 4%/o * 53 7o 9/f Norml 1% Norml * 48 1% 9% 8%// Norml 8% Norml * 4 Norml 1% 7% * 43 1% 1% 7 / Norml Norml Norml Norml 8% Norml RCA, right corony rtery; LAD, nterior descending brnch of left coronry rtery; Cx, circumflex brnch of left coronry rtery; * ptient developed ngin t the highest pcing rte. The percentge denotes the severity of the mior lesion in tht coronry rtery, or its mjor brnches LV systolic pressure b LV end-distolic pressure e Pcing rte Mx dp/dt 16 X Pcing rte C'4 e c KV mx SPTI x HR 5s-~~~~~~~~~~~CU Crdic output Fig. 1 Hemodynmic observtions t ech pcing rte. Men ± SM ofll 11 ptients. Open circles: before tenolol. Closed circles: fter tenolol. () Left ventriculr systolic pressure. (b) Left ventriculr end-distolic pressure. (c) Crdic output. (d) Mximum rte of rise of left ventriculr pressure (mx dp/dt). (e) KV mx. (f) Product of systolic pressure time index nd hert rte. * p < 5, ** < 1, when pre- nd post-tenolol vlues re compred.

4 Hemodynmic nd metbolic effects of tenolol in ptients with ngin pectoris did not chnge with incresing hert rte or fter the drug, so coronry sinus flow closely followed myocrdil oxygen uptke. Oxygen uptke/1 g myocrdium ws relted to the product of systolic pressure time index nd hert rte before tenolol, r=-68 (p<1) nd fter tenolol, r=62 (p<{5), nd the slopes of the two regression lines were similr (Fig. 3). No differences in coronry sinus flow or myocrdil oxygen consumption were pprent between the ptients who developed ngin, nd those who did not. Myocrdil lctte extrction rtio fell s pcing rte incresed; from 15-4 per cent ±2-7 t the first, to -8 per cent ±5A4 (p < 5) t the third before tenolol, nd from 26-6 per cent ±3-8 to 18- per cent ±4-2 (p <-5) fter tenolol (Fig. 4). The men lctte extrction rtio of the 11 ptients ws higher fter tenolol t ech pcing rte, significntly so t the first, 26-6 per cent +3-8 compred with 15-4 per cent ±217 (p<.2), nd t the third, 18 per cent ±42 compred with +8 per cent ±5A * Coronry sinus blood flow Myocrdil oxygen uptke Pcing rte Fig. 2 Upper pnel: coronry sinus blood flow, men ± SM t ech pcing rte. Lower pnel: myocrdil oxygen uptke, men ± SM t ech pcing rte. Open circles: before tenolol. Closed circles: fter tenolol. (p <-1). There ws smll increse in rteril lctte concentrtion from 575 ±O35 mmol/l to -661 ± 4 mmol/l (p <.1) fter tenolol. At the highest pcing rte before tenolol men lctte extrction rtio in the four ptients with ngin ws per cent ±8-6, compred with 9-6 per cent ±4-2 in the ptients without pin. Arteril concentrtion nd extrction of pyruvte, cetocette, hydroxybutyrte, nd free ftty cids did not chnge s hert rte rose, so the results t ech pcing rte re not considered seprtely. After tenolol rteril pyruvte concentrtion rose from -29 ±O3 mmol/l to 39 ±O2 mmol/l (p <1), nd extrction rose from -5 ±-1 mmol/l to -12 ±O2 mmol/l (p <.1). The increse in extrction rtio from 17 per cent +7'5 to 31 per cent ±8 ws not significnt. xtrction ws relted to rteril concentrtion before, r = Before tenolol 16.c 8 v _x g'c 24 2 V O 16 > 8 1 r=-68 p<1 O After tenolol r=-63 p<.5. * SPTI x HR Fig. 3 Reltion between oxygen uptke/min per loog myocrdium nd the product of systolic pressure time index nd hert rte (mmhg s/min). Upper pnel: before tenolol. Oxygen uptke/min per 1 g= 38+ O8 (SPTI x HR) Lower pnel: fter tenolol. Oxygen uptke/min per 1g= 32± 8 (SPTI x HR)

5 672 Thompson, Nqvi, Jenkins, Juul, Coltrt,Webb-Peploe o 3 c 2 * 1 Fig. 4 Myocrdil lctte extrction rtio t ech pcing rte. Open circles: before tenolol. Closed circles: fter -t-1. n = 1 1 tenolol. () Men ± SM of -2 ll 11 ptients. (b) Men ± SM of seven ptients who did Pcing rte b C not develop ngin. (c) Men 4+ SM offour ptients who ge 3 I 1: 3 developed ngin t the highest = 2. 2 pcing rte before tenolol. d *p <.2, **p < 1 when prend post-tenolol vlues re o 1 ic compred. O x n=7 n= 4 -& I - i Pcing rte Pcing rte (p <.1) nd fter tenolol, r=-74 (p <'1) -18 mmnol/l (p <.1), but the fll in extrction (Fig. 5). Arteril cetocette concentrtion fell from mmol/l to ' mmol/l from '87 ±O12 mmol/l to 75 ± 111 mmol/l, ws not significnt. xtrction rtios were 29 per nd extrction from 39 mmol/l to 33 mmol/l cent ±4 nd 32 per cent ±4 before nd fter the fter tenolol, but these chnges were not significnt. drug. xtrction ws closely relted to rteril xtrction rtios before nd fter tenolol were 45 concentrtion; r=-88 (p< 1) nd r=-96 per cent ±5 nd 44 per cent +6 (NS), nd extrction ws relted to rteril concentrtion before nd Arteril free ftty cid concentrtion fell fter (p<l). fter the drug, r=-8 (p< 1) nd r=-98 tenolol from mmol/l to (p <.oo1). -52 mmol/l (p <.1). Men extrction fell from After tenolol, rteril hydroxybutyrte concentrtion fell from mmol/i to 111 ± -1), but the decrese in extrction rtio from -172±-2mmol/l to '1±-2mmol/l (p< Pyruvte 4 Before tenolol r=-58 p < After tenool r=-74 P< *'/~~~~~~~~~~~~~~~ I *1 Arteril concentrtion (mmol/l) Fig. 5 Reltion between myocrdil pyruvte extrction nd rteril concentrtion of pyruvte. Left-hnd pnel: before tenolol. xtrction=-255± 66 (rteril concentrtion) Right-hnd pnel: fter tenolol: extrction = -415 ± 35 (rteril concentrtion) - 4.

6 Hemodynmic nd metbolic effects of tenolol in ptients with ngin pectoris 17-6 per cent ±1-6 to 13-5 per cent ±2-6 ws not significnt. xtrction ws relted to rteril concentrtion before nd fter the drug; r=-57 (p < -1), nd r =-44 (p < -2) (Fig. 6). In Fig. 7 the chnge in myocrdil lctte extrction observed in ech ptient t ech pcing rte fter tenolol hs been plotted ginst the corresponding chnge in rteril free ftty cid concentrtion. The chnges in lctte extrction were relted inversely to the chnges in rteril free ftty cid concentrtion; r= --63 (p < -1). A similr reltion ws found between chnges in pyruvte extrction nd chnges in free ftty cid concentrtion; r= --67 (p < -1) c. 2 x O j - 2 Before tenolol r= 57 p ' Arteril free ftty cid con centrtion ( mmoll/) Arteril glycerol concentrtion decresed fter tenolol from -6 ±-3 mmol/l to -45 ±-3 mmol/l (p <-1). xtrction ws not relted to rteril concentrtion, nd glycerol relese from the hert ws common. At the lowest pcing rte fter tenolol extrction ws -8 ±-3 mmol/l, compred with --7 ±-2 mmol/l (p < -1) before the drug. At the higher pcing rtes there ws no significnt chnge fter the drug. In 1 of the 11 ptients rteril substrte concentrtions were mesured immeditely before the second dose of heprin, pproximtely one hour before the metbolic study. Concentrtions of hydroxybutyrte, cetocette, nd free ftty cids * i After tenol ol r = -44 p<-2 * Fig. 6 Reltion between myocrdil extrction nd rteril concentrtion offree ftty cids. Left-hnd pnel: before tenolol. xtrction = -225 ± -69 (rteril concentrtion) Right-hnd pnel: fter tenolol. xtrction =-17±-61 (rteril concentrtion) r w l Lj - O *t Lctte r= --63 p<.1-4 O C Li -2 - * * O~~~~-f.U+ 1 - v. cn r_ b Pyruvte * r = p <-1 ': I * \ ~~~~~~~~~~~~~~~I Chnge in rteril free ftty cid concentrtion (mmol/l) Fig. 7 Left-hnd pnel: reltion between the chnge in myocrdil lctte extrction seen in ech ptteni t ech pcing rte fter tenolol, nd the chnge in rteril free ftty cid concentrtion. Chnge in lctte extrction = --252±-43 (chnge in rteril free ftty cid concentrtion) Right-hnd pnel: reltion between the chnge in myocrdil pyruvte extrction seen in ech ptient t ech pcing rte fter tenolol, nd the chnge in rteril free ftty cid concentrtion. Chnge in pyruvte extrction = ± -7 (chnge in rteril.free ftty cid concentrtion) -.5..*S L 673

7 674 Fig. 8 Arteril concentrtion (men ± SM) of ydroxybutyrte, cetocette, nd free ftty cid before the second dose of heprin, t the three pcing rtes before tenolol, nd the three pcing rtes fter tenolol. The times t which these smples were tken in reltion to heprin nd tenolol dministrtion re shown on the bsciss were higher t the beginning of the metbolic study thn before the second dose of heprin (Fig. 8). Their concentrtions t the three pcing rtes before tenolol showed little vrition. Similrly, fter tenolol concentrtions were stble over the three pcing rtes, though lower thn pre-drug levels. Arteril concentrtion of lctte, pyruvte, nd glycerol t the beginning of the metbolic study did not differ significntly from levels before the second dose of heprin. The ptient who followed the sme procedure, but received sline insted of tenolol, proved to hve only minor irregulrities in the coronry rteries, nd pcing did not precipitte pin. At the three pcing rtes before sline myocrdil lctte extrction rtios were 26, 3, nd 32 per cent, nd fter sline, 24, 22, nd 3 per cent. Arteril free ftty cid concentrtions were -57, -63, nd -56 mmol/l before, nd -64, 53, nd -56 mmol/l fter sline. Fig. 9 summrises the effects of heprin upon rteril free ftty cid concentrtion in the 21 ptients undergoing routine ctheteristion. The initil rteril free ftty cid concentrtions were similr in both groups. In the 1 ptients who hd not been pretreted with heprin men concentrtion rose from -69 ±-48 mmol/l to ±-186 mmol/1 (p<-1) five minutes fter heprin, nd ws still significntly rised t 1 minutes, ± -16 mmol/l (p < 1), though t 3 minutes, -982 ±-157 mmol/l, ws not significntly different from the pre-heprin level. In contrst, in the ptients who hd received heprin t the time of premediction, rteril concentrtion did not rise 5 Hydroxybutyrte FT t Thompson, Nqvi, Juul, Coltrt, Jenkins, Webb-Peploe I AcetocetteT - ~ F -ll lb - Free ftty Qcids A - _ T 1lhr -m 15min ti- 2min- --*15min -- Heprrin Atenolol 45 uniits/kg 2 mg/kg significntly fter the second dose of heprin, nd men concentrtion ws similr before, 747 ± -67 mmol/l, nd 3 minutes fter heprin, -762 ±-122 mmol/l. 14 c c 8 C9 V 6. > 46 _c4 > w O "2o T T, T t Heprin min Fig. 9 ffects of heprin on rteril free ftty cid concentrtion in 21 ptients undergoing crdic ctheteristion. Open circles: men ± SM of 1 ptients given single dose. Closed circles: men ± SM of 11 ptients who received heprin t the time of premediction in ddition to the dose given fter rteril ctheteristion. **p < 1 compred to pre-heprin levels.

8 Hemodynmic nd metbolic effects of tenolol in ptients with ngin pectoris Discussion In this study we used coronry sinus pcing to investigte the effects of tenolol upon myocrdil metbolism nd hemodynmics t progressively incresing levels of myocrdil oxygen demnd. We did not delibertely seek to induce ngin, so the pcing rtes employed were comprtively low. In study using similr procedure, pcing-induced chnges in myocrdil lctte extrction in both norml subjects nd ptients with coronry rtery disese hve been shown to return to norml within 15 minutes of stopping pcing.4 To confirm this, one ptient ws given sline insted of tenolol, nd it ws found tht both lctte extrction rtio nd rteril free ftty cid concentrtion were comprble in the two periods of pcing. All our ptients were studied fter coronry rteriogrphy. Injection of contrst medi into the coronry circultion my increse myocrdil blood flow (though oxygen consumption does not chnge"9), depress myocrdil contrctility,2 nd produce smll rise in left ventriculr end-distolic pressure.2' These effects re short lived nd, s rteriogrphy did not precipitte ngin in ny of our ptients, it is likely tht the intervl of t lest 2 minutes between rteriogrphy nd the first metbolic mesurements ws dequte to llow recovery. Atril pcing of the norml hert hs little effect upon crdic output, reduces stroke volume nd end-distolic pressure,22 23 nd increses mx dp/dt nd KV mx.24 In some ptients with coronry rtery disese pcing my fil to induce ngin becuse the pcing rte required to produce pin is higher thn the hert rte t which ngin occurs during exercise; under these circumstnces the hemodynmic response to pcing my be norml.25 If ngin does occur during pcing there is often n ssocited rise in left ventriculr end-distolic pressure2 27 nd fll in V mx,28 though ugmenttion of mx dp/dt by hert rte my be preserved. The rise in end-distolic pressure hs been ttributed to cute filure,27 or reduced distolic complince.29 In our study the four ptients who developed ngin t the highest pcing rte before tenolol showed rise in end-distolic pressure, wheres in the other seven ptients enddistolic pressure fell s hert rte incresed. The smll number of ptients does not llow forml sttisticl comprison of the ptients with nd without ngin, but it is of interest tht fter tenolol end-distolic pressure still rose on pcing in the four ptients who hd experienced ngin before the drug, despite relief of ngin in three, nd incresed lctte extrction in ll four. It might be rgued tht wheres the increse in end-distolic pressure before tenolol ws result of reduced distolic complince secondry to ischemi, the rise fter the drug ws the result of ventriculr dilttion nd filure cused by bet blockde. This explntion is unlikely becuse end-distolic presure did not rise fter tenolol in the other seven ptients. These observtions rise the possibility tht when myocrdil oxygen consumption is controlled by pcing, tenolol my hve more fvourble effect upon lctte extrction thn upon the mechnicl properties of the ischemic myocrdium. One mechnism by which bet-blocking drugs relieve ngin is reduction of myocrdil oxygen demnd secondry to their hemodynmic ctions.2 The mjor determinnts of myocrdil oxygen demnd re hert rte, contrctility, nd left ventriculr wll tension.3 As clcultion of wll tension requires complex simultneous mesurement of ventriculr volume nd pressure, the product of systolic pressure time index nd hert rte hs been used to predict myocrdil oxygen demnd," but suffers the disdvntge of being insensitive to chnges in ventriculr volume nd contrctility.32 The hemodynmic effects of tenolol shown in this study re similr to those reported by Robinson et l.3 Crdic output fell t the lowest pcing rte; left ventriculr systolic nd end-distolic pressures did not chnge. Mx dp/dt nd KV mx were consistently lower t ll pcing rtes fter the drug, suggesting tht myocrdil contrctility ws reduced, though conclusions drwn from indices derived from isovolumic pressure rise re open to criticism in the presence of ventriculr synergy Indices of contrctility derived from quntittive ngiogrphy lso fll fter tenolol," but end-distolic volume rises, so tht reduction in myocrdil oxygen demnd resulting from decrese in contrctility my be offset by n increse resulting from higher wll tension cused by ventriculr dilttion. In greement with other work5 myocrdil oxygen uptke did not chnge fter tenolol when hert rte ws controlled, nd ws still relted to the product of systolic pressure time index nd hert rte. Reduced contrctility did not cuse fll in myocrdil oxygen consumption, possibly becuse of the counterblncing effect of incresed wll tension cused by ventriculr dilttion. The significnt improvement in myocrdil lctte extrction in our ptients fter tenolol occurred without reduction in oxygen uptke, or systolic pressure time index, nd cnnot be ttributed to ny hemodynmic chnge cused by the drug. Coronry sinus blood flow did not chnge fter tenolol nd remined closely relted to myocrdil

9 676 oxygen uptke. Redistribution of myocrdil blood flow in fvour of ischemic res hs been suggested s mechnism by which bet blockde relieves ngin.36 Atenolol does not increse venous dringe from the territory of stenosed coronry rtery,5 nor does it increse perfusion in dyskinetic segments of left ventriculr myocrdium.3 The metbolic effects of the drug re thus unlikely to hve been the results of direct ction upon the disesed coronry circultion. The energy requirements of the norml hert re met primrily by oxidtion of free ftty cids, glucose, nd lctte.37 The citric cid cycle is the finl common pth for complete oxidtion of ll these substrtes. Lctte by oxidtion, nd glucose by glycolysis, re both converted to pyruvte, which the hert cn lso extrct from rteril blood. The entry of pyruvte into the citric cid cycle is controlled by pyruvte dehydrogense, which is inhibited by high rtios of cetyl CoA: CoA nd NADH: NAD.38 High rtes of ftty cid ctbolism cuse ccumultion of cetyl CoA nd NADH nd inhibit pyruvte dehydrogense, thus slowing the entry of pyruvte into the citric cid cycle. Ischemi impirs the regenertion of CoA nd NAD nd my further inhibit pyruvte dehydrogense. If pyruvte cnnot be oxidised it is converted to lctte, nd production of lctte nd its relese into coronry venous blood re chrcteristic findings in myocrdil ischemi.39 In norml subjects there is wide individul vrition in myocrdil lctte extrction.4 As might be expected from the competition between pyruvte nd free ftty cid metbolites for entry into the citric cid cycle, in group of norml subjects myocrdil lctte nd pyruvte extrction re relted inversely to rteril free ftty cid concentrtion (r= -462),4 nd increse when free ftty cid concentrtion is reduced.4 Thus, pproximtely 4 per cent of the vrition in lctte extrction between norml individuls cn be relted to differences in rteril free ftty cid concentrtion, nd lctte extrction in individul subjects cn be chnged by ltering free ftty cid concentrtion. In group of ptients with coronry rtery disese differences in severity of ischemi led to even wider individul vrition of lctte nd/or production which my obscure extrction the reltion between lctte extrction nd free ftty cid concentrtion. It is not surprising, therefore, tht we found no reltion between myocrdil lctte extrction nd free ftty cid concentrtion in our ptients. But even in the presence of ischemi, chnges in rteril free ftty cid concentrtion might still ffect lctte metbolism; lctte production by the ischemic cnine myocrdium is Thompson, Nqvi, Yuul, Coltrt, Jenkins, Webb-Peploe incresed when rteril free ftty cid concentrtion is rised,4' suggesting n dditive inhibitory effect of ischemi nd high rtes of free ftty cid ctbolism upon erobic crbohydrte metbolism. In our ptients the chnge in lctte extrction fter tenolol bore significnt inverse reltion to the chnge in rteril free ftty cid concentrtion. After tenolol men free ftty cid concentrtion fell from 976 to 743 mmol/l, from which the published regression eqution [lctte extrction =Q37 - (FFA) ART x -31; r= -J62],4 predicts n increse in lctte extrction of 73 mmol/l, compred with the observed men increse of -81 mmol/l. Thus, the correltion coefficient nd the slope of the regression line of the reltion, which we found between chnge in lctte extrction nd chnge in free ftty cid concentrtion, re similr to those described for the reltion between lctte extrction nd rteril free ftty cid concentrtion in norml subjects. Studies upon humn myocrdil metbolism my be complicted by chnges in rteril substrte concentrtion. Free ftty cid concentrtion my increse becuse of prolonged fsting, the stress of the procedure, or the use of heprin. We believe tht dequte nticogultion is mndtory for left hert ctheteristion, nd ll the ptients in this study were given heprin. Heprin rises free ftty cid concentrtion by ctivting lipoprotein lipse,42 nd its mximum effect is within bout 1 minutes of dministrtion.43 The first dose of heprin, t the time of premediction, ws given in n ttempt to reduce circulting triglycerides, nd thus reduce the effect of the second dose of heprin. The results of our study upon the 21 ptients undergoing routine ctheteristion show tht heprin dministrtion t the time of premediction is effective in blunting the rise in free ftty cid concentrtion tht follows second dose, nd tht in 3 minutes levels hve returned to control vlues. The metbolic studies were mde pproximtely one hour fter the second dose of heprin, nd it is unlikely, therefore, tht rteril free ftty cid concentrtion mesured then ws influenced by the prior dministrtion of heprin. Tht levels were higher t the beginning of the metbolic study thn before the second dose of heprin my hve been the result of stress. Arteril concentrtion ws stble over the three pcing rtes before tenolol dministrtion; fter the drug, rteril concentrtion ws lower, but gin similr t ech pcing rte. In the ptient who did not receive tenolol, free ftty cid concentrtion ws comprble during both pcing runs. All these fctors suggest strongly tht the reduction in free ftty cid concentrtion observed fter tenolol dministrtion ws the result of

10 Hemodynmic nd metbolic effects of tenolol in ptients with ngin pectoris direct ction of the drug rther thn progressive decline in the ction of heprin. These results re in greement with the known peripherl ntilipolytic ction of tenolol.4 Although we were ble to relte chnges in lctte nd pyruvte extrction to chnges in rteril free ftty cid concentrtion, this sttisticl ssocition my not be cusl, even though physiologicl bsis exists for such reltion. Alterntive mechnisms should be considered by which tenolol might increse myocrdil lctte extrction without reducing myocrdil oxygen consumption. xperiments with lbelled plmitte hve demonstrted myocrdil lipolysis,45 which my provide n importnt source of free ftty cids for consumption by the myocrdium." Free ftty cids derived from this source might influence lctte nd pyruvte metbolism by competition for entry into the citric cid cycle, or, prticulrly in the presence of ischemi, by ccumultion of long-chin ftty cyl CoA esters which inhibit oxidtive metbolism.47 Myocrdil lipolysis is incresed by ctecholmines, nd inhibited by proprnolol.48 In this study the moderte correltion between free ftty cid extrction nd rteril concentrtion, the occsionl negtive extrction vlues, nd the frequent finding of glycerol relese ll myocrdil lipolysis ws tking plce. Atenolol incresed glycerol extrction only t the lowest pcing rte, but did not pper to hve ny consistent effect t higher hert rtes. Reduction in peripher. l lipolysis ws not, therefore, ccompnied by n obvious reduction in myocrdil lipolysis. Adrenline reduces the ctivity of pyruvte dehydrogense, nd this cn be prevented by proprnolol.4 In the present study the fll in suggest tht rteril free ftty cid concentrtion, nd its likely effect upon lctte nd pyruvte extrction, mde it impossible to distinguish ny similr direct ction of tenolol upon pyruvte dehydrogense. High ketone body consumption hs been reported to reduce lctte extrction by the cnine hert,5 but in this study there ws only modest reduction in rteril concentrtion of hydroxybutyrte nd cetocette fter tenolol. Coronry sinus blood contins venous effluent from both ischemic nd norml res of myocrdium. An increse in globl lctte extrction could therefore be the result either of reduced lctte production by severely ischemic res, or of incresed extrction by modertely ischemic nd norml res, nd these two mechnisms cnnot be redily distinguished. The improvement in pin in three of the four ptients with pcing-induced ngin suggests tht lctte production in ischemic res ws reduced fter tenolol, but the lck of effect upon end-distolic pressure rgues for the persistence of some ischemi. The increse in lctte extrction fter tenolol ws greter in the ptients in whom pcing hd produced ngin thn in the other seven ptients, but they lso sustined greter fll in rteril free ftty cid concentrtion fter the drug. Thus, the effects of tenolol were qulittively similr irrespective of the severity of ischemi. The reson" for the greter fll in free ftty cid concentrtion in these ptients is not cler, but it is possible tht they hd greter sympthetic drive, or higher levels of circulting ctecholmines, nd therefore showed greter chnges fter bet blockde. When hert rte is controlled by pcing the cute dministrtion of tenolol increses myocrdil lctte extrction without reduction of myocrdil oxygen consumption or the product of systolic pressure time index nd hert rte. This effect my be the result of reduction of rteril free ftty cid concentrtion rther thn of direct ction upon the myocrdium. Inhibition of peripherl lipolysis my dterefore contribute to the efficcy of tenolol in the relief of ngin. These results emphsise the importnce of mesuring rteril free ftty cid concentrtion during studies upon myocrdil lctte nd pyruvte extrction, prticulrly in the investigtion of ntinginl drugs tht my influence peripherl lipolysis. References 677 'Wolfson S, Heinle RA, Hermn MV, Kemp HG, Sullivn JM, Gorlin R. Proprnolol nd ngin pectoris. AmJ Crdiol 1966; 18: Robinson BF. The mode of ction of bet-ntgonists in ngin pectoris. Postgrd Med ; 47, suppl Advnces in drenergic bet-receptor therpy: Schng SJ, Pepine CJ. ffects of proprnolol on coronry hemodynmic nd metbolic responses to tchycrdi stress in ptients with nd without coronry disese. Cthet Crdiovsc Dign 1977; 3: Armstrong PW, Chiong MA, Prker JO. ffects of proprnolol on the hemodynmic, coronry sinus blood flow nd myocrdil metbolic response to tril pcing. Am 7 Crdiol 1977; 4: Simonsen S. ffect of tenolol (ICI 66 82) on coronry hemodynmics in mn. Br Hert J 1977; 39: Blcon R. Assessment of drugs in ngin pectoris. Postgrd MedJ7 1971; 47, suppl Advnces in drenergic bet-receptor therpy: Jckson G, Atkinson L, Orm S. Improvement of myocrdil metbolism in coronry rtery disese by bet blockde. Br Hert ; 39: Dy JL. The metbolic consequences of drenergic blockde: review. Metbolism 1975; 24: Brrett AM. The phrmcology of tenolol. Postgrd Med _r 1977; 53, suppl 3:

11 678 OJckson G, Hrry JD, Robinson C, Kitson D, Jewitt D. Comprison of tenolol with proprnolol in the tretment of ngin pectoris with specil reference to once dily dministrtion of tenolol. Br HertJ 1978; 4: 'Mthey DG, Chtterjee K, Tyberg JV, Lekven J, Brundge B, Prmley WW. Coronry sinus reflux: source of error in the mesurement of thermodilution coronry sinus flow. Circultion 1978; 57: Grossmn W, Brooks H, Meister S, Shermn H, Dexter L. New technique for determimng of instntneous myocrdil force-velocity reltions in the intct hert. Circ Res 1971; 28: "Kolettis M, Jenkins BS, Webb-Peploe MM. Assessment of left ventriculr function by indices derived from ortic flow velocity. Br Hert J 1976; 38: "Gnz W, Tmur CK, Mrcus HS, Donoso R, Yoshid G, Swn HJC. Mesurement of coronry sinus blood flow by continuous thermodilution in mn. Circultion 1971; 44: "Hohurst HJ, Kreutz FH, Bucher T. Metbolitgehlte und metbolit-konzentrtionen in der Leber der Rtte. Biochem Z 1959; 332: "Willimson DH, Melnby J, Krebs HA. nzymtic determintion of D(-) 3-Hydroxybutyric cid nd cetocettic cid in blood. Biochem J 1962; 82: 9-6. "Kreutz FH. nzymtische Glycerinbestimmung. Klin Wochenschr 1962; 4: "Crruthers M, Young DA. Free ftty cid estimtion by semi-utomted fluorimetric method. Clin Chim Act 1973; 49: "Griggs DM, Nkmur Y, Leunissen R, Ksprin H, Novk P. ffects of rdioopque mteril on phsic coronry flow nd myocrdil oxygen consumption (bstrct). Clin Res 1966; 14: 247. "Guzmn SV, West JW. Crdic effects of intrcoronry rteril injection of vrious roentgenogrphic contrst medi. Am Hert J 1959; 58: Rhimtool SH, Gu GT, Rphel MJ. Crdic performnce fter dignostic coronry rteriogrphy. Circultion 197; 41: "Linhrt JW. Pcing induced chnges in stroke volume in the evlution of myocrdil function. Circultion 1971; 43: "Prker JO, Khj F, Cse RB. Anlysis of left ventriculr function by tril pcing. Circultion 1971; 43: "Leighton RF, Zron SJ, Robinson JL, Weissler AM. ffects of tril pcing on left ventriculr performnce in ptients with hert disese. Circultion 1969; 4: 'Brien KP, Higgs LM, Glncy DL, pstein S. Hemodynmic ccompniments of ngin. A comprison during ngin induced by exercise nd by tril pcing. Circultion 1969; 39: Linhrt JW, Hildner FJ, Brold SS, Lister JW, Smet P. Left hert hemodynmics during ngin pectoris induced by tril pcing. Circultion 1969; 4: "Prker JO, Ledwich RT, West RO, Cse RB. Reversible crdic filure during ngin pectoris. Circultion 1969; 39: Thompson, Nqvi, Juul, Coltrt, J7enkins, Webb-Peploe 2"Grber JD, Conti CR, Lppe DS, Ross RS. ffect of pcing induced tchycrdi nd myocrdil ischemi on ventriculr pressure-velocity reltionships in mn. Circultion 1972; 46: "Brry WH, Brooker JZ, Aldermn L, Hrrison DC. Chnges in distolic stiffness nd tone of the left ventricle during ngin pectoris. Circultion 1974; 49: "Brunwld. Control of myocrdil oxygen consumption: physiologic nd clinicl considertions. Am J Crdiol 1971; 27: "Srnoff SJ, Brunwld, Welch GH Jr, Cse RB, Stinsby WN, Mcruz R. Hemodynmic determinnts of oxygen consumption of the hert with specil reference to the tension time index. Am Y Physiol 1958; 192: Grhm TP Jr, Covell JW, Sonnenblick H, Ross J Jr, Brunwld. Control of myocrdil oxygen consumption: reltive influence of contrctile stte nd tension development. J Clin Invest 1968; 47: Robinson C, Jckson G, Fisk C, Jewitt D. Hemodynmic effects of tenolol in ptients with coronry rtery disese. Br Hert J 1978; 4: Sonnenblick H, Prmley WW, Urschel CW, Brutsert DL. Ventriculr function; evlution of myocrdil contrctility in helth nd disese. Prog Crdiovsc Dis 197; 12: "Lichtlen P, Amende I, Simon R, ngel HJ, Hundeshgen H. Left ventriculr function nd regionl blood flow fter tenolol in normls nd ptients with coronry rtery disese. Postgrd Med Y 1977; 53, suppl 3: Wolfson S, Gorlin R. Crdiovsculr phrmcology of proprnolol in mn. Circultion 1969; 4: Bing, R. Crdic metbolism. Physiol Rev 1965; 45: "Kerbey AL, Rndle PJ, Cooper RM, Whitehouse S, Psk HT, Denton RM. Regultion of pyruvte dehydrogense in the rt hert. Biochem J 1976; 154: "9Gorlin R. vlution of myocrdil metbolism in ischemic hert disese. Circultion 1969; 39 & 4, suppl IV: "Lssers BW, Whlquist ML, Kijser L, Crlson LA. Reltionship in mn between plsm free ftty cids nd myocrdil extrction of crbohydrte substrtes. Lncet 1971; ii: ,"Kjekshus JK, Mjs OD. ffect of free ftty cids on myocrdil function nd metbolism in the ischemic dog hert. J Clin Invest 1972; 51: Korn D. Clering fctor; heprin-ctivted lipoprotein lipse. I. Isoltion nd chrcteriztion of the enzyme from the rt hert. Y Biol Chem 1955; 215: Rutstein DD, Cstelli WP, Nickerson RJ. Heprin nd humn lipid metbolism. Lncet 1969; i: Decon SP. The effects of tenolol nd proprnolol upon lipolysis. Br Y Clin Phrmcol 1978; 5: Most AS, Brchfeld N, Gorlin R, Whren J. Free ftty cid metbolism of the humn hert t rest. Y Clin Invest 1969; 48:

12 Hemodynmic nd metbolic effects of tenolol in ptients with ngin pectoris 4"Zierler KL. Ftty cids s substrtes for hert nd skeletl muscle. Circ Res 1976; 38: Schrgo. The effect of long chin ftty cyl CoA esters on the denosine nucleotide trnslocse nd myocrdil metbolism. Life Sci 1978; 22: "Lech JJ, Jesmok GJ, Clvert DN. ffects of drugs nd hormones on lipolysis in the hert. Fed Proc 1977; 36: Coore HG, Denton RM, Mrtin BR, Rndle BJ. Regultion of dipose tissue pyruvte dehydrogense 679 by insulin nd other hormones. Biochem 1971; 125: Bssenge, Wendt V, Schollmeyer P, Bluimchen G, Gudbjmson S, Bing RJ. ffect of ketone bodies on crdic metbolism. Am Physiol 1965; 28: Requests for reprints to Dr M M Webb-Peploe, Deprtment of Crdiology, St Thoms's Hospitl, London S1 7H. Br Hert J: first published s /hrt on 1 June 198. Downloded from on 5 April 219 by guest. Protected by copyright.