ischaemic preconditioning of the human heart. - Leicester Research ...

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the rat skeletal muscle and liver. Certainly, mitochondrial and sarcolernmal K,,, channels appear to exhibit minor differences in structure but the function of the mitochondrial KATP channels appear to be intimately involved in matrix volume control as opposed to electrical activity for sarcolemmal KATP channels. In this instance, opening of the mitoKATP channel leads to membrane depolarization, matrix swelling, slowing of ATP synthesis, and accelerated respiration [29]. There is good evidence that diazoxide and 5-HD show good selectivity for mitochondrial over cardiac sarcolemmal KATP channels [13,20] and our present study confirms that preconditioning can be mimicked with diazoxide and abolished with both 5-HD and glibenclamide. These results are in close agreement with those of Garlid et al. [30] and further suggest that the mitoKATP channels are the end-effectors of cardioprotection produced by ischernic preconditioning. To more clearly address this issue, we used a specific sarcolemmal KATP channel blocker, HMR 1883. The novel blocker HMR 1883 shows good selectivity for the cardiac sarcolemmal KATP channel over those of pancreatic beta cells and the vasculature [201. Further, a brief report suggests that HMR 1883 did not block the protection induced by ischemic preconditioning in the rabbit [211. Our results are in agreement with this, since we found that the protective effect of PC persisted in the presence of HMR 1883. Taken together with our findings with 5-HD and diazoxide, this suggests that HMR 1883 does not block mito KATP channels of human myocardium at the concentration used (10 ýLM), and that blockade of the sarcolemmal channel does not abolish protection. The mechanisms by which the opening of mitoKATP channels exert the cardioprotective effect of preconditioning are not fully understood. Consequences of opening of the mito KATP channel include depolarization of the intramitochondrial membrane as K+ enters leading to decreased calcium in-port and matrix swelling. The mechanism of how this ultimately stimulates mitochondrial respiration and consequently the cytoprotective effect is much less clear and warrants further research. A potential limitation of our study was the use of atrial tissue as opposed to ventricular myocardium and therefore any extrapolation must be conducted with caution; however, Yellon and colleagues have suggested that preconditioning exerts identical protection in both tissues [16,311. Undoubtedly, KATP channels are present in both atrium and ventricle [321, although their density in both tissues is unknown. Another possible limitation might be that right atrial appendages were obtained from patients subjected to various medical treatments (e. g. nitrates, P-blockers, calcium antagonists) and that in principle may have in- fluenced ischemia/reperfusion injury and the protection induced by preconditioning. However; it should be emphasized, that all medication was stopped the day before surgery when specimens were taken for the study and that a significant effect of the medication was unlikely since all S. Ghosh et al. / Cardiovascular Research 45 (2000) 934-940 939 preparations responded to ischemia/reperfusion with a similar degree of injury and preconditioning was protective in all instances when applied. It should be mentioned that the preparation used in this study was not electrically stimulated (i. e. non-beating) and therefore one should be cautious when extrapolating to the in vivo situation. It should also be emphasized, that in common with previous studies in non-human hearts [13,14,20], our evidence for the involvement of mitoKATp rather than sarcolemmal KATP channels depends strongly on the selectivity of the KATP channel openers and blockers used, in particular diazoxide, 5-HD, and HMR1883. In this context, the concentration of diazoxide that we used (100 l. LM) has been reported to activate mitoKATp but not sarcolemmal KATP in rabbit ventricular myocytes [14]. HMR 1883 should be an effective blocker of sarcolemmal KATP channels at 10 ýLM, since its reported Ki for these channels is 0.8 l. LM [21], though its effects on mitoKATP have not been tested directly. 5-HD is an effective blocker of mitoKATP provided that the channel is opened by a physiological or pharmacological opener [14,18], but its selectivity for mitoKATP over sarcolemmal KATP merits further study. Notsu et al. [331 reported block of sarcolemmal KATP channels in guinea pig myocytes by 5-HD, though more recently Hu et al. [34] have argued that 5-HD at a concentration of 0.5 mM selectively blocks mitoKATP without affecting sarcolemmal KATP channels of rabbit ventricular cells. Certainly, 5-HD at a concentration of I mM was an effective blocker of cardioprotection in our human model. In conclusion, the present study provides strong evidence that mitochondrial rather than sarcolemmal KATP channels are effectors of ischemic preconditioning in the human myocardium. The finding has obvious important clinical implications, however, the mechanism by which the opening of mito KATP channels is protective is not fully understood and merits further investigation. Acknowledgments This study was supported in part by grants from The Wellcome Trust, British Heart Foundation, Rhone-Poulenc Rorer (UK) and the University of Leicester. References [13 Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal injury in ischemic myocardium. Circulation 1986; 74: 1124-1136. [2) Schott RJ, Rohmann S, Braun ER, Schaper W Ischemic preconditioning reduces infarct size in swine myocardium. Circ Res 1990; 66: 1133-1142. [3] Miller DL, Van Winckle DM. Ischemic preconditioning limits infarct size following regional ischemia-reperfusion in in situ mouse hearts. Cardiovasc Res 1999; 42: 680-684.
940 S. Ghosh et al. [41 Goto M, Liu Y, Yang X-M et al. Role of bradykinin in protection of ischernic preconditioning in rabbit hearts. Cite Res 1995; 77: 611 - 621. [51 Yellon DM, Allchulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet 1993; 342: 276-277. [61 Carrol R, Yellon DM. Myocardial adaptation to ischernia - the preconditioning phenomenon. Int J Cardiol 1999; 68: S93-SIOI. [7] Grover G. Pharmacology of ATP-sensitive potassium channel (K- ATP) openers in models of myocardial ischemia and reperfusion. Can J Physiol Pharmacol 1997; 75: 309-315. [8] Gross GJ, Auchampach JA. Blockade of ATP-dependant potassium channels prevents myocardial preconditioning. Cite Res 1992; 70: 223-233. [9] Schulz R, Rose J, Hcusch G. Involvement of activation of ATP- dependant potassium channels in ischemic preconditioning in swine. Am J Physiol 1994; 267: HI341-1352. [10] Armstrong S, Liu G, Downey J, Ganote C. Potassium channels and preconditioning of isolated rabbit cardiomyocytes. Effects of glyburide and pinacidil. J Mol Cell Cardiol 1995; 27: 1765-1774. [111 Grover GJ, Dalonzo AJ, Parham CS, Darbenzio RB. Cardioprotec- tion with the KATP opener cromakalim is not correlated with ischemic myocardial action potential duration. J Cardiovasc Phar- macol 1995; 26: 145-152. [121 Grover GJ, Dalonzo Al, Dzwonczyk S, Parham CS, Darbenzio RB. Preconditioning is not abolished by the delayed rectifier K' blocker dofetilide. Am J Physiol 1996; 40: HI207-HI214. [13] Garlid K, Paucek P, Yarov-Yarovoy V et al. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels: a possible mechanism of cardioprotection. Circ Res 1997; 81: 1072-1082. [14] Liu Y, Sato T, O'Rourke B, Marban E. Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection? Circu- lation 1998; 97: 2463-2469. [151 Tomai F, Crea F, Gasparadone A. Ischernic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K' channel blocker. Circulation 1994; 90: 700-705. [161 Speechly-Dick ME, Grover GJ, Yeilon DM. Does ischemic preconditioning in the human involve PKC and the ATP-dependant K' channel. Circ Res 1995; 77: 1020-1035. [17] Ghosh S, Standen NB, Galifianes M. Preconditioning the human myocardium by simulated ischernia. Studies on the early and delayed protection. Cardiovasc Res: 1999; in press. [181 Jaburek M, Yarov-Yarovoy V, Paucek P, Garlid KD. State-dependent inhibition of mitochondrial K, channel by glyburide and 5- hydroxydecanoate. J Biol Chem 1998; 273: 13578-13582. [19) McCullough JR, Mormandin DE, Conder ML et al. Specific block of the anti-ischemic actions of cromakalim by sodium 5-hydroxydecanoate. Circ Res 1991; 69: 949-958. / Cardiovascular Research 45 (2000) 934-940 [20] Sato T, O'Rourke B, Marban E. Modulation of mitochondrial ATP-dependent K' channels by protein kinase C. Circ Res 1998; 83: 110-114. [211 Gogelein H, Hartung J, Engelbert H, Scholkens B. HMR 1883, a novel cardioselective inhibitor of the ATP-sensitive of the ATP- sensitive potassium channel. Part 1: effects on cardiornyocytes, coronary flow and pancreatic B-cells. J Pharmacol Exp Ther 1998; 286: 1453-1464. [22] Linz W, Jung 0, Englert HC, Sch6lkens BA. The benefit of ischaemic preconditioning is not abolished by the cardioselective K ATp blocker HMR 1883 in rabbits. Br J Pharmacol 1998; 24: SS25P. [231 Auchampach J, Grover G, Gross G. Blockade of ischemic preconditioning in dogs by novel ATP-dependent potassium channel antago- nist sodium-5-hydroxydecanoate. Cardiovasc Res 1992; 26: 1054- 1062. [24] Carr CS, Grover GJ, Pugsley WB, Yellon DM. Comparison of the protective effects of a highly selective ATP-sensitive potassium channel opener and ischemic preconditioning in isolated human atrial muscle. Cardiovasc Drugs Ther 1997; 11: 473-477. [25] Kelpzig H, Kobert G, Matter C et al. Sulfonyl ureas and ischemic preconditioning. Euro Heart J 1999; 20: 439-446. [26] Terzic A, Jahangir A, Kurachi Y Cardiac ATP-sensitive K' channels: regulation by intracellular nucleotides and K' channel opening drugs. Am J Physiol 1995; 269: H525-H545. [271 Hiroaka M, Furukawa T. Functional modulation of cardiac ATP- sensitive K' channels. News Physiol Sci 1998; 13: 131-137. [28] Suzuki M, Kotake K, Fujikura K et al. Kir 6.1: A possible subunit of ATP-sensitive K+ channels in mitochondria. Biochem Biophys Res Comm 1997; 241: 693-697. [29] Gross GJ, Fryer RM. Sarcolemmal versus mitochondrial ATP- sensitive K+ channels and myocardial preconditioning. Circ Res 1999; 84: 973-979. [30] Garlid K, Paucek P, Yarov-Yarovoy V, Sun X, Schindler P. The mitochondrial K TP channel as a receptor for potassium channel openers. J Biol Chem 1996; 27: 8796-8799. [31] Cleveland JC Jr, Wollmering MM, Meldrum. DR et al. Ischemic preconditioning in human and rat ventricle. Am J Physiol 1996; 271: HI786-HI794. [32] Heidbuchel H, Vereecke J, Carmeliet E. Three different potassium channels in human atrium: contribution to the basal potassium conductance. Circ Res 1990; 66: 1277-1286. [331 Notsu T, Takano 1, Takano, M, Noma A. Blockade of the ATP- sensitive K' channels by 5-hydroxydecanoate in guinea pig ventricular myocytes. J Phannacol Exp Ther 1992; 260: 1702-1708. [34] Hu H, Sato T, Seharaseyon J et al. Pharmacological and histO- chemical distinctions between molecularly defined sarcolemnual KATP channels and native cardiac mitochondrial K ATP channels. MOI Pharmacol 1999; 55: 1000-1005.
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ISCHAEMIC PRECONDITIONING OF THE HU
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ABSTRACT Ischaemic preconditioning
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andomised clinical study with the f
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CHAPTERI Introduction 35 Matefials
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Discussion 151 CHAPTER Vill Conclus
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44 CK leakage and MTT reduction on
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The Wellcome Trust and The British
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Presentations International "The Ef
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Abbreviations An attempt has been m
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1.1 Introduction Ischaernic heart d
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1.2 Myocardial Ischaemia Myocardial
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hours up to several days to complet
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phosphates and its influence on hyd
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1.4 Myocardial Protection This refe
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performed. This process is repeated
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1.6 Possible Mechanisms of Ischaemi
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kilodalton stress proteins. These p
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and these proteins have been sugges
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K vi-1, channels were initially fou
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tissues the K.. %,.,, channels are
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Subsequently, Jaburek et al 1145] i
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venous capacitance vessels. At ther
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preconditioning to be investigated
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In the angioplasty model, Tomai et
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patients were randomized into two g
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CHAPTER 11 THE HUMAN RIGHT ATRIAL T
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inexpensive. Briefly in this model,
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of each ischemic period, slices wer
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30 nini FO linlin L 60 min 120 inin
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In Study 3 (see Figure 2.4), slices
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D. Metabolite analysis Samples were
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leakage is calculated as the net LD
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B. Effect of the severity of ischae
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2.11 DISCUSSION: The present studie
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clearly insufficient to induce myoc
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The present model may facilitate th
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2.12 Conclusiow I have characterise
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3.5 3 V 2.5 3: m Je m Z0 z 2 1.5 0.
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(3 3 2.5 a 1.5 - -r T 0 2 0.5 0 I P
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Q oro . 21 . 0 'a IP 10 '. R -C3 A
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=3 0 h X CD 0 x CD :3 0 , 7, CD 0 0
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CHAPTER III PRECONDITIONING THE HUM
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3.2 MATERIALS AND METHODS-. 3.2.1 E
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A117'reduction- At the end of the e
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-4 ýi r. () .1 a 0 1 tli n F5* - C
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v M. %; n C) .0 ý U ý ý - - - -2
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leakage resulting from precondition
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3.5 DISCUSSION: The present studies
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during cardiac surgery totalling 10
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different. The cellular mechanisms
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cn Je 8 7 6 5 4 1 0 0.8 0.7 0.6 0.5
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8 6 C) 2 0.7 0.6 Q) 0.5 0) E 25 0.4
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6 5 CY) ,u3 CF) m -ýe m 2 1 0 -0.8
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CHAPTERIV THE ROLE OF THE KATPCHANN
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It has been reported that K.. %-I-p
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0 a- I a 3 I cr =r Cl. 2 qQ 0'-ý 0
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Figure 4.7 shows that ischaemia alo
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Figure 4.2 Dosc-responsc experiment
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Figure 4.4 Dose-response experiment
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Figure 4.6 Dosc-response experiment
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1 0.9 -ý 0.8 0.7 E 0.6 0.5 0.4 0.2
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activity, and showed that diazoxide
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Furthermore, Van den Hoek et al [3
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mechanism by which the opening of m
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5.1 INTRODUCTION: Within the enormo
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5.2 MATERIALS AND METHODS: 5.2.1 Ex
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M77'rechiction: At the end of the e
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oc 0 0 cr F; * 10 eb I ý; o I 5 0
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Pages missing original in the
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esulted in a decrease of CK leakage
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are on long-term hypoglycaernics or
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absence of uniformity of expeniment
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5.7 Conclusion Preconditioning is a
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0.9 0.8 07 m 0.6 E -0 0t 4 0.3 02 0
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-0 1.2 1 &8 0.6 04 0.2 o Aerobic Is
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6.1 INTRODUCIFION' Life expectancv
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(MI-T) to blue t'()rmazan product C
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The demonstration that ischaemic in
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Table 61 Patients' demographic and
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Nure 6,1: Creatine Kinase (CK) leak
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CHAPTER VII IN VIVO STUDIES ON T"E
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The apparent discrepancy bet,.,,, e
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In the off-pump group, coronary byp
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eduction as described in section 3.
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7.4.2 In vitro studies Figures 7.3A
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preconditioning stimulus in man is
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myocardium. Several investigators [
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Table 7.2 - Patients haemod-v-namic
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(0 -I 3 CD CD CD 1 3 0 :3 0 0 =r w
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0 co t X 3 co 0 0 Cumulative Releas
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-& a) c) UT 0 =r w CD 3 CD 0 1ý (a
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When ischaernic preconditioning was
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evidence tbr the involvement ot'PKC
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institution o fcardiopu Imo nary by
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Biblioqraphv 1. Abete P, Ferrara N,
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14. Auchampach J, Cavero, I and Gro
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27. Becker LB, Van den Hoek TLV, Sh
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41. Bums PG, Krunkenkamp IB, Calder
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55. Cohen G, Shirai T, Weisel RD, e
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69. Currie RW and White FP (1983).
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83. Downey JM, Liu GS and Thornton
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97. Ganote C, Armstrong S and Downe
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110. Grover GJ, D'Alonzo A, Hess T,
Page 207 and 208: 122. Hamilton T and Weston A (1989)
Page 209 and 210: 137. Hu H, Sato T, Seharaseyon J, L
Page 211 and 212: 151. Jennings R, Steenbergen C, Kin
Page 213 and 214: 164. Kelpzig H, Kobert G, Mafter C,
Page 215 and 216: 178. Lamping K, Christensen C, Pelc
Page 217 and 218: 192. Liu GS, Thornton J, Van Winkle
Page 219 and 220: 206. Maulik N, Yoshida T, Das DK. (
Page 221 and 222: 219. Miyawaki H, Zhou X, Ashraf, M.
Page 223 and 224: 233. Okazaki Y, Kodama K, Sato H, K
Page 225 and 226: 248. Pryzlenk K, Li G, Whittaker P
Page 227 and 228: 260. Saito S, Tamura Y, Moriuchi M,
Page 229 and 230: 274. Schulz R, Post H, Valhaus C, e
Page 231 and 232: 288. Stewart JR, Blackwell WH, Crut
Page 233 and 234: 300. Tani M, Suganuma Y, Hasegawa H
Page 235 and 236: 312. Tosaki A, Engelman DT, Engelma
Page 237 and 238: 324. Walker D, Marber M, Walker J a
Page 239 and 240: 337. Yamashita N, Nishida M, Hoshid
Page 241 and 242: 351. Zhang JG, Lindup WE. (1993). R
Page 243 and 244: 444 J. -G. Zhang and others are dif
Page 245 and 246: 446 J. -G. Zhang and others Assessm
Page 247 and 248: 448 J. -G. Zhang and others 0.9 0.8
Page 249 and 250: 450 J. -G. Zhang and others C E 07
Page 251 and 252: 4S2 J. -G. Zhang and othen effects
Page 253 and 254: ELSEVIER Abstract Cardiovascular Re
Page 255 and 256: 936 S. Ghosh et al. / Cardiovascula
Page 257: 938 S. Ghosh et al. / Cardiovascula
Page 261 and 262: 712 0" et &L h wcomMe geg in Obwa»
Page 263 and 264: 714 Gbosb ot aL hmoo dmoWmbDbsnedH
Page 265 and 266: 716 chmä et aL Pi unamOso äu In O
Page 267: 718 ehe* et &L ditioning in the hum
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