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

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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 Ovo situation. It should also be emphasized, that in common with previous studies in non-human hearts [99,196,2661, my evidence for the involvement of mitoK.. %.,,, rather than sarcolernmal Kx-, ý,, channels depends strongly on the selectivity of the K\11, channel openers and blockers used, in particular diazoxide, 5-1-113, and HMR1883 In this context, the concentration of diazoxide that I used (100 [M) has been reported to activate mitoK. but N-1-1, not sarcolemmal K., %-I-p in rabbit ventricular myocytes [ 1961. HMR 1883 should be an effective blocker of sarcolemmal K.. \., 1, channels at 10 pM, since its reported K, for these channels is 0.8 4M [1021, though its effects on mitoK.. xll, have not been tested directly. 5-HD is an effective blocker of mitoK. %j-p provided that the channel is opened by a physiological or pharmacological opener [145,1961, but its selectivity for mitoK., \, I-p over sarcolemmal K.. %. I-p merits further study. Notsu et a] [2321 reported block of sarcolemmal K. x-j-p channels in guinea pig myocytes by 5-HD, though more recently Hu et al [137] have argued that 5-HD at a concentration of 0.5 mM selectively blocks mItoK.. ý-j-j, without affecting sarcolernmal KATP channels of rabbit ventricular cells. Certainly, 5-HD at a concentration of I mM was an effective blocker of card ioprotect ion in this human model. In conclusion, the present study provides strong evidence that mitochondrial rather than sarcolemmal K,. %. I-p channels are effectors of Ischaernic preconditioning in the human myocardium. The finding has obvious important clinical implications, however, the 109
mechanism by which the opening of mito K%-11. channels is protective is not fully understood and merits further investigation. With the establishment of the role of K, \,.,, channels in human myocardial preconditioning, I turned my attention to exploring the responses of these channels in human myocardium effected by diabetes mellitus and chronic ischaerma causing heart failure and this is the subject of the experiments discussed in the next chapter. 110
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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
Page 75 and 76: 3.5 3 V 2.5 3: m Je m Z0 z 2 1.5 0.
Page 77 and 78: (3 3 2.5 a 1.5 - -r T 0 2 0.5 0 I P
Page 79 and 80: Q oro . 21 . 0 'a IP 10 '. R -C3 A
Page 81 and 82: =3 0 h X CD 0 x CD :3 0 , 7, CD 0 0
Page 83 and 84: CHAPTER III PRECONDITIONING THE HUM
Page 85 and 86: 3.2 MATERIALS AND METHODS-. 3.2.1 E
Page 87 and 88: A117'reduction- At the end of the e
Page 89 and 90: -4 ýi r. () .1 a 0 1 tli n F5* - C
Page 91 and 92: v M. %; n C) .0 ý U ý ý - - - -2
Page 93 and 94: leakage resulting from precondition
Page 95 and 96: 3.5 DISCUSSION: The present studies
Page 97 and 98: during cardiac surgery totalling 10
Page 99 and 100: different. The cellular mechanisms
Page 101 and 102: cn Je 8 7 6 5 4 1 0 0.8 0.7 0.6 0.5
Page 103 and 104: 8 6 C) 2 0.7 0.6 Q) 0.5 0) E 25 0.4
Page 105 and 106: 6 5 CY) ,u3 CF) m -ýe m 2 1 0 -0.8
Page 107 and 108: CHAPTERIV THE ROLE OF THE KATPCHANN
Page 109 and 110: It has been reported that K.. %-I-p
Page 111 and 112: 0 a- I a 3 I cr =r Cl. 2 qQ 0'-ý 0
Page 113 and 114: Figure 4.7 shows that ischaemia alo
Page 115 and 116: Figure 4.2 Dosc-responsc experiment
Page 117 and 118: Figure 4.4 Dose-response experiment
Page 119 and 120: Figure 4.6 Dosc-response experiment
Page 121 and 122: 1 0.9 -ý 0.8 0.7 E 0.6 0.5 0.4 0.2
Page 123 and 124: activity, and showed that diazoxide
Page 125: Furthermore, Van den Hoek et al [3
Page 129 and 130: 5.1 INTRODUCTION: Within the enormo
Page 131 and 132: 5.2 MATERIALS AND METHODS: 5.2.1 Ex
Page 133 and 134: M77'rechiction: At the end of the e
Page 135 and 136: oc 0 0 cr F; * 10 eb I ý; o I 5 0
Page 137 and 138: Pages missing original in the
Page 139 and 140: esulted in a decrease of CK leakage
Page 141 and 142: are on long-term hypoglycaernics or
Page 143 and 144: absence of uniformity of expeniment
Page 145 and 146: 5.7 Conclusion Preconditioning is a
Page 147 and 148: 0.9 0.8 07 m 0.6 E -0 0t 4 0.3 02 0
Page 149 and 150: -0 1.2 1 &8 0.6 04 0.2 o Aerobic Is
Page 151 and 152: 6.1 INTRODUCIFION' Life expectancv
Page 153 and 154: (MI-T) to blue t'()rmazan product C
Page 155 and 156: The demonstration that ischaemic in
Page 157 and 158: Table 61 Patients' demographic and
Page 159 and 160: Nure 6,1: Creatine Kinase (CK) leak
Page 161 and 162: CHAPTER VII IN VIVO STUDIES ON T"E
Page 163 and 164: The apparent discrepancy bet,.,,, e
Page 165 and 166: In the off-pump group, coronary byp
Page 167 and 168: eduction as described in section 3.
Page 169 and 170: 7.4.2 In vitro studies Figures 7.3A
Page 171 and 172: preconditioning stimulus in man is
Page 173 and 174: myocardium. Several investigators [
Page 175 and 176: 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,
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122. Hamilton T and Weston A (1989)
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137. Hu H, Sato T, Seharaseyon J, L
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151. Jennings R, Steenbergen C, Kin
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164. Kelpzig H, Kobert G, Mafter C,
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178. Lamping K, Christensen C, Pelc
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192. Liu GS, Thornton J, Van Winkle
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206. Maulik N, Yoshida T, Das DK. (
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219. Miyawaki H, Zhou X, Ashraf, M.
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233. Okazaki Y, Kodama K, Sato H, K
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248. Pryzlenk K, Li G, Whittaker P
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260. Saito S, Tamura Y, Moriuchi M,
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274. Schulz R, Post H, Valhaus C, e
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288. Stewart JR, Blackwell WH, Crut
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300. Tani M, Suganuma Y, Hasegawa H
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312. Tosaki A, Engelman DT, Engelma
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324. Walker D, Marber M, Walker J a
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337. Yamashita N, Nishida M, Hoshid
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351. Zhang JG, Lindup WE. (1993). R
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444 J. -G. Zhang and others are dif
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446 J. -G. Zhang and others Assessm
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448 J. -G. Zhang and others 0.9 0.8
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450 J. -G. Zhang and others C E 07
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4S2 J. -G. Zhang and othen effects
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ELSEVIER Abstract Cardiovascular Re
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936 S. Ghosh et al. / Cardiovascula
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938 S. Ghosh et al. / Cardiovascula
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940 S. Ghosh et al. [41 Goto M, Liu
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712 0" et &L h wcomMe geg in Obwa»
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714 Gbosb ot aL hmoo dmoWmbDbsnedH
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716 chmä et aL Pi unamOso äu In O
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718 ehe* et &L ditioning in the hum
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