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    Jpn Cire J 1998; 62: 517-526 Effect of Preischemic Catecholamine Treatment on Ischemia-Reperfusion Injury of the Myocardium - Subtype, Dose, and Temperature Dependency — Yasuyuki Shimada, MD*; Fumio Yamamoto, MD: Hiroshi Yamamoto, MD“*; Takahiro Oka, MD* Preischemic adrenergic stimulation may affect postischemic cardiac function, Using an isolated working heart model, we investigated the effects of preischemic catecholamine treatment on postischemic recovery. Hearts from Wistar rats were perfused in working mode for 20 min, in Langendorff mode for 15 min, and again in ‘working mode for 20min (W2). Hearts were treated with isoproterenol (8.0 and 40.0 nmol/L), phenylephrine (0.06, 0:30, and 1.50 mol/L), or epinephrine (16 and 80 nmol/L) during the W2 period and then arrested with ‘St Thomas’ Hospital cardioplegic solution (STH) and subjected to global ischemia (37°C or 20°C), followed by reperfusion. At 37°C, isoproterenol had a beneficial effect at the lower dose but a harmful elfect at the higher dose; phenylephrine and epinephrine had a harmful effect at all doses. At 20°C, isoproterenol and epinephrine had a harmful effect at a high dose; phenylephrine had no harmful effect’at any dase, In a separate study, the influence of calcium modulators (diltiazem and ryanodine, added in the STH) on the catecholamine effect was investigated. The harmful effect of preischemic treatment with isoproterenol (24.0 rmolL) or phenylephrine (0.9 molIL) was abolished by the calcium modulators. Thus, preischemic 2. adrenergic or a-+2-adrenergic stimulation has a deleterious effect on postischemic recovery of the myocar- dium. The effect could be altered depending on the subtype and dase of catecholamine and the ischemic temperature. Intracellular calcium movement could be involved in the mechanism responsible for the harmful effect of preischemic catecholamine treatment (pn Cire J 1998; 62: 517526) Key Words: Ischemnia-reperfusion-induced injury; Catecholamine; Rat sometimes required preoperatively for patients with unstable hemodynamics caused by valvular or ischemic heart disease. In addition, most heart trans- plantation donors undergo medical treatment with pos tive inotropic agents before their hearts are harvested! Some of those patients occasionally suffer from severe Tow cardiac output syndrome as @ result of ischemia- reperfusion injury of the myocardium even after a satis. factory operation? Catecholamines may alter the extent of myocardial damage during ischemia and reperfusion when given before or during myocardial ischemia. Little is known, however, about the effect of preischemic catecholamine treatment upon ischemia-reperfusion in jury of the myocardium and, in particular, the appropriate choice of catecholamines and their optimal doses. We have previously demonstrated, using an jsolated rat heart preparation, that a f-adrenergie agent (isoprotere- nol), phosphodiesterase inhibitor (milrinone), and an exogenous cyclic AMP agent (dibutyryl cyclic AMP) have P sitive inotropic agents such as catecholamines are (Received Sepomber 17,197; ressed manuscript recived Desember 2, 1997; aceped January 29, 198) Deparmen of Cardiovascular Surgery, Naional Cardovaeaar Center, Sule, Osaka, Japon "Socond Deparmen of Surgery, Kyoto Prefeenel University of Medng, Kyoto, Kyo, Japan "Fini Deparment of Surgery, Auhilawa Medical Collge, Asahitawa, Holbatd, Japan Mailing adres Fumio Yamamoto, MD, Department of Cacdiovesula Surgery, National Caniovsela C T Fujehirods, Suita, Osaka 565, Tspan Japanese Caton Jour Vol. 62, July 1998 deleterious effects on postischemic recovery when given before ischemiat suggesting that_an inerease in cyclic AMP might accelerate myocardial injury during ischemia and reperfusion. Cyclic AMP is known to enhance trans- sarcolemmal calcium intlux through cyclic AMP-depen- dent protein kinase activation, An a-adrenergic agent is known to have some inotropic effect on the myocardium, although the mechanism of its inotropism is different from that of a f-adrenergic agent, which may alter the extent of myocardial damage during ischemia and reperfusion. Hypothermic cardioplegia with topical cooling of the heart is an important method of myocardial. protection in open heart surgery. Tt is @ crucial point in a clinical setting to determine how catecholamines work when given before hypothermic ischemia ‘Questions that arise are: (1) Is there dose dependency in the deleterious effect of preischemic -adrenergic stimulation on the ischemia-reperfusion injury? (2) Is there any effect of preischemic a-adrenergic stimulation fon the ischemia-reperfusion injury? (3) Is there dose dependency in the effect of calcium modulators on the catecholamincsinduced injury? (4) Ts there temperature dependency in the effects of catecholamines or caleium modulators? The objectives of the present study were to determine: (1) the effect of catecholamines (adrenergic agent, a-adrenergic agent, and a-+ ?-adrenergic agent) at different concentrations on ischemia-reperfusion injury; (2) whether calcium modulators (diltiazem and ryanodine) influence the effect of preischemic catecholamine treat ment; and (3) whether there are differences in those effects between normothermic ischemia (37°C) and hy- ee eee ratocot ‘perfusion || catecholamine || pertusion we rrowcus [wr | Serer tn] om || cemarena| zaesee]| | W2 with, ‘STH with Langerdertt mowete [om Wega] woes | euch |] cnn] HERSEY] moweto [we [Spare] ccm | ua cone] BREE] Fel. Expinenal pote, Ate he sgn wei penne), ears ne Lang etl lowe the second 20-min working perfusion (W2) with various catecholamines. Feats were then arrested with 8 i infusion of St ‘Thomas’ Hospital cardioplegic solution (STH) and subjected to normothermic (37°C) or bypotbermic (20°C) global Schemia. ‘This was followed by [5 min of Langendort reperfusion and the thied20-min working perfusion (WS). Procol A: Time-matched ‘controls; protocol B,C, and D: global schema and reperfusion (diem was added to STH in protocol C; ryanodine was ndded to STH in protocol D), pothermic ischemia (20°C). ‘Materials and Methods Animals Hearts were obtained from male Wistar strain rats, weighing 250-350 g. The animals were taken care of according to the Principles of Laboratory Animal Care of the National Society for Medical Researeh and the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication No 80-23, revised in 1978). Peifusion Methods ‘The isolated perfused working heart model, which has been described in detail by Hearse et alf is a left heart Preparation, in which an oxygenated perfusion medium ‘enters the cannulated left atrium at a hydrostatic pressure of 12emH,O and is passed into the left ventricle, from which it is spontaneously ejected via an_aortic cannula against a hydrostatic pressure of 100emH0. Coronary clfluent leaving from the right heart can be sampled for the measurement of creatine Kinase (CK) leakage or pooled and recirculated with the aortic flow. Langendorlt non-working perfusion is introduced by clamping the left atrial cannula and introducing perfusion medium into the aorta from a reservoir located 100m above the heart, Ischemic cardiac arrest can be induced inthis preparation by clamping the aortic cannula. The cardioplegic solution is infused using a reservoir located 6 emHl,O above the hicart. ‘The perfusion medium was a modified Krebs- bicarbonate buffer (KHBB) of the following ion (in mmoVL): NaCl, 118.5; NaHCOs, 25.0; Mg8Ox, 1.2; KHaPO,, 1.2; CaCl, 1-4; and glu- cose, ILO. The bulfer was filtered before use and was gassed with 95% oxygen and 5% carbon dioxide. St ‘Thomas’ Hospital cardioplegic solution was used as a ear= dioplegic solution, and has the following composition (in mmol/L): NaCl, 110.0; NaHCOs, 10.0; KCI, 16.0; MgCl, 16.0; and CaCk, 1.2. ‘The pH of the eardioptegie solution was adjusted to 7.8 at any temperature before use. ‘The rats were anesthetized with diethyl ether, and heparin (200 IU) was injected into the femoral vein. The hearts were placed into a 4°C KHBB solution after rapid extirpation, and cannulation of the aorta was performed ‘within I min, Hearts were subjected to 5 min of aerobic Langendorff perfusion, followed by a first working perfu- sion (20min), a Langendorff perfusion (15 min), and a second working perfusion (20min). Hears were then arrested with a 3min infusion of St Thomas’ Hospital cardioplegie solution and subjected to normothermic oF hypothermic global ischemia (30 or 33min at 37°C and 120 min at 20°C), This was followed by a Langendorif reperfusion (15min) and a third working perfusion (20 min). The duration of ischemic arrest was selected from the preliminary experiments, which identified the periods resulting in about 70% of postischemic recovery of aortic flow at each temperature (the data are aot shown). CK leaked into the coronary effiuent during 15-min Langen- ddorff reperfusion was measured by the Oliver UV method? Experimental Protocols (Fig 1) Preischemic Treatment with a B-Adrenergic Stimulator Time-Matched Controls Isolated hearts were subjected to continuous aerobic perfusion without ischemia to serve a8 time-matched controls. Isoproterenol. (40.0 nmol/L) was treated during the second working perfusion (pro- tocol A). This was followed by aerobie perfusion (15-min Langendorff perfusion and the third 20-min working perfusion). The dose of isoproterenol was chosen accord- ing (0 our previous studies! Global Ischemia and Reperfusion Two different levels of concentration (ie a low dose and a high dose) were employed. Isoproterenol (8.0 and 40.0 nmol) was used for preischemie treatment during the second working perfusion (protocol B). Hearts were arrested with St ‘Thomas’ Hospital cardioplegic solution and then sub- jected to global ischemia (37°C or 20°C), followed by reperfusion. In a separate study, the effect of diltiazem (protocol C) ‘or ryanodine (protocol D) on the preischemic catechol- _Jepanese Cination Journal Vol.62, July 1998 (Catecholamines and Myocardial Ischemia ‘Table 1 Changes in Indices of Cardiac Function During und After Isoproterenol or Phenylephrine Treatment (Time-Matched Contras) “onic flow Coronary flow “Heart rate “one presure Gece wawr wawi waiver Wawr~ waws— Wawi~ walw? __Walwr cy mm) (HH) HD Conrad WIS215 6216 989230 987222 WOL2I WOLIS 1OLIS09 97.9309 Leoproterenol (M0.0nmolL) 242434" $R.2LIM TBRILOT? 95.7432 IMI42S 975429 UOTLLS 949410 Phenylephrine (150 molL) 1289426" GRS41.7 IBL7242* 172243 29229" 1043469 1156425" 96.3222 Vales are expresed as mean sandard eror ofthe mean. °p<0.0 vs the contol group. WI, the contol value measured daring de fost working perfusion: W2, the value measured during the second working perfesion; WS, the value measured during the third working perfusion. 519 n= amine treatment was examined. Isoproterenol (24.0 nmol/L) was used for preischemic treatment during the second working perfusion. Hearts were then arrested with St Thomas’ Hospital cardioplegic solution containing diltiazem (0, 0.5, 1.0 and 5.0 zmolL) or ryanodine (0, 0.175, 1.750 and 8.750 nmol/L) and subjected 10 global ischemia 37°C or 20°C), followed by reperfusion. ‘The doses of diltiazem and ryanodine were chosen according to our previous studies® Preischemic Treatment With an a-Adrenergic Stimulator Time-Matched Controls. Isolated hearts were subjected to continuous acrobie perfusion without ischemia to serve 4 timesmatched controls. Phenylephrine (1.50 pamoV/L) ‘was used in treatment during the second working perfa- sion (protocol A). This was followed by aerobic perfusion (iS-min Langendorff perfusion and the third 20-min work- Ing perfusion). The dose of phenylephrine was chosen according to our previous studies? Global Ischemia and Reperfusion Three different levels of concentration were employed. Phenylephrine (0.06, 0.30, and 1.50 emo/L) was used for preischemic treat- ment during the second working perfusion (protocol B) Hearts were arrested. with St Thomas’ Hospital car- digplegic solution and then subjected to global ischemia (37°C oF 20°C), followed by reperfusion. In a separate study, the effect of diltiazem (protocol C) or ryanodine (protocol D) on the preischemic catechol- amine treatment was examined. Phenylephrine (0.90 emolil.) was used for preischemic treatment during the Second working perfusion. Hearts were then arrested with St Thomas’ Hospital cardioplegic solution containing diltiszem (0, 0:5, 1.0, and 5.0 pmolfL.) or ryanodine (0, 0.175, 1.750, and 8.750 nmol/L) and subjected to global ischemia (37°C), followed by reperfusion, Preischemic Treatment with a->A-Adrenergie Stimulator Global Ischemia and Reperfusion Two different levels of concentration (je a low dose and a high dose) were employed in preischemie catecholamine treatment. Ad- renaline (16.0 and 80.0 nmol/L) was used for preischemic treatment during the second working perfusion (protocol B). Hearts were arsested with St Thomas’ Hospital car dioplegic solution and then subjected to global ischemia, (20°C or 37°C), followed by reperfusion. The concentra- tions in the lower dose group andl the higher dose group, were equivalent to respectively twice and 10-fold that of the serum concentration in patients administered as an initial dose in a clinical seting.1° Iepanee Creation Joumal Vol 62, Jy 1998 Expression of Results ‘Change in Cardiac Function The following indices were ‘measured as the cardiae function: aortic flow (AF), coro= nary flow (CF), heart rate (HR), and aortic pressure (AP). The change in cardiac function during adrenergic stimulation was calculated by the following equation. Change during catecholamine treatment = ‘WWI x 100 (%) ‘The postperfusion change (ie, recovery) in cardiac fune- tion in groups of time-matched controls was calculated using the following equation: Postperfusion recovery =W3/W1 x 1 (%o) ‘The postischemic change (ie, recovery) in cardiac function in groups treated with global ischemia and reperfusion ‘was calculated using the following equation: W3WLX 100 (%) he value of AF, CF, HR, or AP measured during the first working perfusion period; W2=the value of AF, CE, HR, or AP measured during the second work- ing perfusion period; and W3=the value of AF, CF, HR, or AP measured during the third working’ perfusion period. Statistical Analysis Data ate reported as _means-tstandard error of the mean, All levels of statistical significance were calculated with I-way analysis of variance in each study and multiple comparison (Dunnet'st test) was then performed. Values of p<0.05 were considered statistically significant Results Preischemic Treatment With a Adrenergic Stimulator Time-Matched Controls The change in AF during iso- proterenol treatment (W2WI in Table 1) was significantly greater than for the control group. There was no differ- ence in the postperfusion recovery of AF (W3/W1 in Table 1) between the control group and the treatment group. CK leakage resulted in no difference between the control group and the treatment group (4.61.0 and 5.50.9 TU/15 min per g dry weight, respectively). Global Ischemia and Reperfusion At 37°C, the change in AF during the preischemic treatment (W2/W1 in Table 2) was significantly greater than in the control group in 520 SHIMADA ¥ eval ‘Table 2 Changes in Indes of Cardiac Function During Isoproterenol Treatment and After Ischemia (Global Ischemia and Reperfusion) Tinperonse TnproenotAdrieflow Coronary flow Hear rate “Aor pressive during, concenraion woivy wow -WoWT WW? (WW? —WSIWT = WWIII Lschemia °C) (amo) (sy ey) YY) Conmol — WO428 650426 94329 ~2THIO 4nd ALI6 M5222 OF6RIE 3780 sri 87424 sops227% otro msoets HIL3s 1030209 MSZ 40 U7ESO 26452 TMTES6" GIEII I2HOLS6 5004205 101225 IB7EISS Como! 2741.7 073423 MMLLL6 $2430 PLT 97420 WOES 98.3439 2 BO” S747 T9428 09d HIER? W_7E07 HOLST —NOSS22 928220 $0 123452" SERPS TETON S79LI6S" 120DiSO" BILE 124234 SHIRT Values are expressed as mean: standard ror of he mean. °p<0.05 v the contol group. W, the cond value measured during he flat rorking perfusion; W2, the value mesure ring the second working prison W3, the rae mesured during the rd working pefon ae a i - Dag igo 0 &2 is of = a9 : 20 : am ae os s so Mag E60 wae is fail a : : Co £* ~~ a eeroar Fig. Posschemic recovery of aortic flow (AF) and creatine kinase (CK) leskage alter normothermic (37°C) or Rypothermic (G0°C) fschemia in hears treated with isoproterenol during the second 2smin working perfusion, Values are expressed a rmean-standard enor of the mean. “p<0.0S vs the contol group. Open columns: recovery of AF; hatched columns: CK leakage the 8.0nmolL group but not in the 40.0 nmoVL. group. However, the changes in CF, HR, and AP in the 40.0, moW/L group were significantly greater than in the con- trol group (W2/W1 in Table 2). At 20°C, the change in AF during the preischemic treatment (W2/WI in Table 2) \as significantly greater than in the control group. At 37 °C, the postischemic recovery of AF (W3/W1 in Table 2) was significantly greater in the 8.0 nmol/L group but sig- nificantly less in the 40.0 nmoVL group when compared with the control group (Fig 2, top). CK leakage tended to be greater in the 40.0 nmol/L. group than in the control group (Fig2, top). At 20°C, the postischemic recovery of AF (W3/WI in Table 2) was significantly less in the 40.0, moV/L group than in the control group (Fig 2, bottom). CK leakage was significantly greater in the 40.0 nmol. g70up than in the contro! group (Fig 2, bottom). In hearts arrested with the cardioplegic solution con- taining diltiazem or ryanodine, the change in AF during the preischemic treatment before the cardioplegic arrest (W2/W1 in Table 3 or Table 4) was significantly greater than in the control group at both ischemic temperatures, ‘AC 37°C, the postischemic recovery of AF (W3/WI in ‘Table 3) was significantly less in the 0, 0.5, and 5.0 nmoVL diltiazem (plus 24.0 nmoUL isoproterenol) groups than in the control groups but was similar in the 1.0 samolL diltiazem (plus 24.0 nmol/L isoproterenol) group and the control group (Fig 3A, top). There was a signi ceant increase in CK leakage in the OsrmoV/L diltiazem (plus 24.0 nmoVL isoproterenol) group than in the control ‘group, but CK leakage was decreased to the contro level in the 0.5, 1.0, and 5.0zmolL diltiazem (plus 240 nmol/L. isoproterenol) groups (Fig3A, top). ‘The post- ischemic recovery of AF (W3/WI in Table 4) was sini cantly less in the OnmoV/L ryanodine (plus 24.0 nmol/L, isoproterenol) group than in the control groups, but AF in the 0.175, 1.750, and 8.750 nmol/L ryanodine’ (plus 24.0 mol isoproterenol) groups recovered to a level similar to that in the control group (Fig 3B, top). There was a significant increase in CK leakage in the O nmol/L ryano- dine (plus 240 nmol. isoproterenol) group compared withthe control group, but CK leakage was decreased 10 the control level in the 0.175, 1.750, and 8.750 nmol/L ryanodine (plus 24.0 nmol. isoproterenol) groups (Fig, 3B, top). ‘At 20°C, the postischemic recovery of AF (W3/W1 in Table 3) was significantly less in the 0, 0.5, 1.0, and 5.0 umoVL diltiazem (plus 24.0 nmol/L. isoproterenol) ‘groups than in the control group (Fig 3A, bottom). ‘There was no difference in CK leakage between the control group and any other group (Fig3A, bottom). The post- ischemic recovery of AF (W3/W1 in Table 4) was signifi- cantly Jess in the 0, 0.175, and 8.750 nmol/L ryanodine (plus 24.0 nmoVL isoproterenol) group than in the control sroups, but AP in the 1.750 nmoVL ryanodine (plus 24.0 moll isoproterenol) group recovered to a level similar to that in the control group (Fig 3B, bottom). There was a significant increase in CK leakage in the Onmol/L ryanodine (plus 24.0 nmol/L isoproterenol) group com- pared with the control group, but CK leakage decreased to the control level in the 0.175, 1.750, and 8.750 nmoVL. ryanodine (plus 24.0 nmol/L. isoproterenol) groups (Fig 3B, bottom). Preischemic Treament With a-Adrenergic Stimulator ‘Time-Matched Controls The change in AF during the phenylephrine treatment (W2/WL in Table 1) was signii- cantly greater than in the control group. There was n0 difference in the postperfusion recovery of AF (W3/W1 in ‘Table 1) between the control group and the treatment group. CK leakage resulted in no difference between the control group and the treatment group (4.61.0 and 5.72.0 1U/I5 min per g dry weight, respectively) _Iepanese Cirlation Journal Val.62, July 1998 (Catecholamines and Myocardial schema sat ‘Table 3 Changes in Indices of Cardiac Function During Isoproterenol Treatment and Aer Ischemia in Heats Arrested With St Thomas? Hospital Cardioplegc Solution Containing Various Concentrations of Ditizem (Global Ischemia and Reperfusion) Tenperoure “rte fom Coronary fw Hearse Toric prsive oprtren Dilan “2% fom___Coroaryflow__Hewtrae__fris presnre_ ing rere Pieces wat wali Want —walWi —Waiwr —Walwi War Wanvi seca) BD Conmol <0 —«TONSLe. e805 %sz28 GEIS 1535 ImOLI2 90K so 0 in7si2d autre Sovis4 magia ot4a7 Ii7aea 7 o79ata” MO os haat Maser fmeate Baetd Imse20 O1ss40 lanos2e weslor 20 0 dardahse artes 129859 19433 1ID3i10 Ba841 ligo42D 3817 240 $0. BBWAA A236" HBIATS an BEeS IST koL ¥zK0 E4s29 STALE Conrol 058419 689522, OLLS SRO WHEE 959422 1057525 M2213 so 0 indase Sore SOIER6 089439" ORPES4 TIS/sA2" SBoIH a mo OS BI1462 BLA 143222 BILLS UDILIM D043? 1USBs26" 89215 260 1D MSI62° 353425" 125431" 778152 1073436" ILS M162S1.0" S4Z3S 240 50 W720435" PEAS M6842 H4167 1129135* WSESS TS3AI8 8ST Values are expresed as mean standard eror ofthe mean. *p<0.05 vs the contol group. WI, the contol value measured during the frst working perfusion; W2, the value measured diving the second working perfusion; WS, the value measured during the third working perfusion. m6, ‘Table 4 Changes in Indices of Cardiac Funton During Isoproterenol Treatment and After Ischemia in Hearts Arrested With St Thomas’ Hospital Cardlopleie Solution Containing Varlous Concenratons of Ryanodine (Global Ischeala and Reperfusion) ae “ora fow Gonna Tow Tet rae hor pane prael Ruadee —eo —waWi Wow WANN WANT WT WON) WaT seem) (oy (%) 0). Conrol—«0—« WLS 16 8023.2 1044130 HI128 946135 919455 D012 93.9108 20 0 9279422 424n28" 15242" $6 7ESA NGAEIS 14427 74a IT 879E1I° OOS MBB? OSSESS IBITZAT 3453 NOTE GS427 145233" 91S=23 260 LIS IWNG4SI ISZ] 1Wosss ASAD WSI464 942419 106229" 240 8780“ BTOEIS 678250 MOSES2 HIEKT 1129EIS° 93.0416 153218" Como! 0381.9 68.9522 MOIS M0430 SLI 959422 07225 27413 20 0 TBLSHSS $6122.48" 150.5259" 881436 1OS345S" URIS USTS32° 88.9554 2 Oats DOZEAE ST ELO DSOESH OES U3E3O" IOLT=22 52235 473416 20 175) IMBS39" 690530 1230376" B50431 1057462 1027260 WS 2816 888223 240 8780 BS 7E4O $3262 ASLO SISEKI M5023" G80E47 U4TE3T 88424 Values ave expressed as mean:zstandard eror ofthe mean. °p<0.08 vs the contol group_ WI, the control value measured during the frst working perfusion; W2, the vlue measured daring the second working perfusion; WS, the value measured durin the third working perfusion me A . FE] 0 10 HE] 10 100 5 © Bag 5 & ®e ae . 0 2 Ek e0 . cy g fk 0 fa a 8 40 os PTC ties SL ial * ° ° ° ° BE] 00 100 [BE] 10 190 3 . Mag 5 © ® so ge . . feSh Feely a a2 So 5 oft ie #3 as fh Sees teres P 28 0 ° ° ° convo! [Teepioene 2 ani contol esi 240 rm ] %s ih 8 ‘iazom molA) anode (nei | Fig3. _Postschemic recovery of aortic low (AF) and creatine kinase (CK) leakage after normothermic (37°C) or hypothermic (20 “O jachemis in heats treated ith soproterenol daring the second 20-in working perfusion and arrested with St Thomas’ Hospital catcioplegic solution eonsaining dikazem (A) or ryanodine (B). Values are expressed as mean-tstndard error of the mean, "p< 0.08 ws the contrl group. Open columas: recovery of AF; hatched columns: CK leakage Japanese Cirelaton Journal Vol 62, July 1998 522 SHIMADA ¥ ecal ‘Table 5 Changes in Indices of Cardioe Function During Phenylephrine Treetment and After Ischemia (Global Ischemia and Reperfusion) Tenporanse. Phenylephrine Arte flow Coronary flow ear ae Aric pressure dhring_| concentration WWE WIN wi Walwi Wawa? WaT —(W3IWT ischemia °C) wmollL) "Ys &) ca) )_® (9) (5) a Control MILER OTI418 97120 MHL27 97.923 969426 8413 H7RIT e 0.05 1003224" 76x80" 00224 O48 9S SS143S 1040422 89.3220 030 OSEAS S104KS 169232" 1007538" 100. DLT M2B2T §RVA1S 150 U3TS33" W243 1248s" 8022129 98 WAIT 96468" 778512.) Convo! 12.7217 67.3423 a2et0 95 97.4220 1040325 95.3239 » 030°“ U66413" T6=25 U00L2T 81539 99II4 1097422 MOSEKo 905316 130 98s" WVSEIT DIELT 117260" MOIKKD UDL=26 91.8422 Values are expressed as mean:zstundard error ofthe mean. °p<0.05 ws the conol group. WA, the control value measured during the fist working perfusion; W2, th vale measured during the second working perfusion, WS, the value measured daring ie shird working persion. = aE] s © . tee : * L l, (L ¥ = 2 : Cm: ae] oh a ° ee i « ® q = 40 0 =, 2 20 5 : : ont [5 ao Birstall Fig, Postichemie recovery of sorte flow (AF) and creatine Kinase (CK) leakage after normothermic (37°C) or hypothermic (20°C) ischemia in hears rated with phenylephrine during the Second 20-min working perfusion and arrested with St Thomas" Hospital cardioplegic solution. Values ate expresed as moans: SMandard exror of the mean. *p<0.05 vs the contol group ‘Open columns: recovery of AF; Hatched columns: CK leakage Global Ischemia and Reperfusion At both ischemic temperatures (37°C and 20°C), the change in AF during the pretreatment (W2/W1 in Table 5) was. significantly greater than in the control group. At 37°C, the postische= mie recovery of AF (W3/WI in Table 5) was significantly less in the 0.06, 0.30, and 1.50 moV/. groups than in the control group (Fig, top). CK leakage was significantly ‘gxcater in the 1.50 mol/L group than in the control group (Fig, top). At 20°C, there was no difference between the control groups and any other group in the postisehe- mic recovery of AF (W3/'WI in Table 5; Fig, bottom). CK leakage resulted in no difference between the control group and any other group (Fig 4, bottom), In hearts arrested with the cardioplegic solution con- taining diltiazem or ryanodine, the change in AF during the preischemic treatment before the cardioplegic arrest (W2/W1 in Table 6 or Table 7) was significantly greater than in the control group at an ischemic temperature of 37°C. The postischemic recovery of AF (W3/W1 in Table 6) was less in the O mol/L diltiazem (plus 0.9 emoUL, phenylephrine) group than in the control group but was similar in the 0.5, 1.0, and 5.0 pmoVL diltiazem (plus 0.9 nmol/L phenylephrine) groups and the control group (Fig 5A). There was a significant increase in CK leakage in the 0 amoVL diltiazem (plus 0.9 amoVL phenylephrine) ‘group compared with the control group, but CK leakage decreased to the control level in the 0.5, 1.0, and 5.0 eanoVL diltiazem (plus 0.9 mol. phenylephrine) groups (Fig 5A). The postischemic recovery of AF (W3W1 in Table 7) was Significantly less in the O nmol ryanodine (plus 0.9 pmol phenylephrine) group than in the control groups, but AF in the 0.175, 1.730, and 8.750 nmol ryanodine (plus 0.9 moVL. phenylephrine) groups recov ered {0 level similar to that in the control group (Fig 5B). There was a significant increase in CK leakage in the Onmol/L ryanodine (plus 0.9 mol/L phenslepheine) {group compared with the control group, but CK leakage decreased to the control level in the 0.175, 1.750, and 8.750 nmol/L ryanodine (plus 0.9 »mol/L phenslepheine) r0ups (Fig 5B). Preischemic Treatment With an a+ a-Adrenergie Stimulator Global Ischemia and Reperfusion ‘The. change in AF during the pretreatment (W2/W1 in Table 8) was signif cantly greater than in the control group at both ischemic temperatures. At 37°C, the postischemic recovery of AF. (W3/W1 in Table 8) was significantly less in the 16 and 80 nmol/L groups than in the control group (Fi 6, top). CK leakage in the 8 nmol/L group was significantly greater than that in the control group (Fig6, top). At 20°C, the postischemic recovery of AF (W3/Wi in Table 8) was sis- nificantly fess in the 80 amoVL group than in the control group (Fig6, bottom). There’ was no difference in CK Teakage between groups (Fig 6, bottom), Discussion Intracellular calcium overload is, in general, a key ‘mechanism of ischemia-reperfusion injury, and the posi tive inotropic action of catecholamines can be induced by an increase in intracellular calcium!'-'? Therefore, there is a possiblity that preischemic treatment with catechola- mines may aggravate calcium overload during ischemia and reperfusion and then accelerate ischemia-reperfusion injury. Our previous studies were able to confirm the dose-dependent acceleration of ischemia-reperfusion in- jury induced by preischemic treatment with either a phos- phodiesterase. inhibitor (milrinone) or a f-adrenergic stimulator (isoproterenol)* Most of the catecholamines such as dopamine, epinephrine, norepinephrine, and Japanese Ciltion Jornal Vol 62, uly 1998 (Catecholamines and Myocacial Ischemia 3 ‘Table 6 Changes in Indices of Cardiac Function During Phenylephrine Treatment and After Ischemia in Hearts Arrested With ‘SU Thomas’ Hospital Cardioplege Solution Containing Various Concentrations of Dilazer (Global Ischemia and Reperusion) Tempers “rts fow Coronas Fw Tear re Toric pemere Plesephie Dicom Ate Ben___Cormary flow __Hewrate_ ————s ing Oitci) Wii Wai? Wa? — won’ Wanvi Want" Wav WINE achemiaC) (=) Convo! WISA16 680432 1064230 943328 946435 120212 93.9%05 os USTED” 3435" 112238" §9.4229 97529 ua7es3 g.0412 v O9 D3 3E3L BBLIG IMIL2M S144 974408 913420 09 BO 237" TELIA 120 JOLG33 1039409 Us0s13* 1314 09) WITEIT 47229 IBOEKT BIEdd 9.0440 M39810" 946417 Values ave expressed as meansstandard eror ofthe mean. “P<0.05 vs the contol group- WI, the convo value measured daring the frst working perfusion; W2, the vale measured dung the second working pefason; WS, the volue measured during the third working perfusion ‘Table 7 Changes in Indices of Cardiac Function During Phenylephrine Treatment and After Ischemia in Hearts Arrested With ‘St Thomas" Hospital Cardioplegic Solution Containing Various Concentrations of Ryapodine (Global Ischemia and Reperfusion) a “ore low Coronary flow ear rate one presare Tempera pheryephrine Ryaodne —— “7% Fam _ aah = diving Mamet) fmol) WWE WSIW! —W2IW) WAM WOW] Wali —Wa1W1—_WaIWT ‘schema 70) PY) Conrol—0«FOISS 1.6 8053.2 1044420 143428 SOLIS VEILS MBOLIZ 989408 oo 0 MB7a2I° FERS" 12438" $4229 975229 G24 MTS GOEL? a O8 O17 D8IHSH BSHIS DELEAO' 06828 92214 3427 1219322 97.726 09 1790 68231" 72421 IBIELT WOETO 143] 985240 1196220" V3.5 09 8.750 132.6222" 44259 DDVAEIT GS5233 W4RIA MALI 1200810" HELIS Vales are expresed as mean: standard eror ofthe mean. °p-<0.05 vs the contol group. WI, the contol value measured during the frst working perfusion; W2, the value measured during the second working perfusion; WS, the value meatured during the third working perfusion. ‘Table 8 Changes in Indices of Cardiac Function During Adrenaline Treatment and After Ischemia (Global Ischemla and Reperfusion) Tonperanne Adrenaline Adri flow ewe during" concentation “Wows walwi Wan WNT WWE -WaIWT WOO scheieec) “toot” “By! “eay! “ee! Nay“ ew Coronary flow Hear vate Aortic pressure Conpol 96.1811 735427 W21E50, WS12 969228 BALD? VOLLA ” 6 W21s32 2251 S740 SED? OVER! NIO4RIS 878429" »” IMIEST WHSH 13446" HEI DIAM 905429 ILLS 87 941.5* Control 12.7=17 673423 NI416 SB24IO IIS 974420 1040425 953420 20 16 WDO4249" S78HI3 IOIE2I $50S58 G76tIF GEDA NOTES] 887421 » DI2G7H 89A7H MISE WSIEISO WALL MSLISS DBOLSE GVOLILO Values are expressed as mean‘ sandard error ofthe mean. “p<0.05 vs the contol group. WI, the control value measured during the frst working perfusion; W2, the vale measured during the Second Working perfusion; WS, he value measoe during the hrd working perfusion. a 8 BFE] 100 100 [BFE] 100 100 © 0 © © . eae geo off feel) : 052 eo 08% B «0. . « 3 a) 2 3% 2. 20 ° ° ° ° como! [-prenfaree 09 met] conv! [-phenyenhe 08 pratt 7g 10, 80 os 1750-070 Phaze uma) anes Fig. Postschemic reovery of aortic ow (AF) ad creatine kinase (CK) leakage after normothermic (37°C) ischemia in hears tteated with phenylephrine daring the second 20-nin working periusion and arrested wih St Thomas’ Hospital eardopleic solution ‘containing ditiazem (A) of ryanodine (8). Values ate expressed as ean-estandard error of the mean. "p

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