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

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K %-j-p activation is already enhanced, eg. reduced intracellular ATP caused by ischaemia/hypoxia, and thereby appear to have useful property of targeting ischernic tissues. The consequences of the interaction of K,. %-I, p channel openers, the ATP concentration and other metabolic regulators, is that K. \.,.,, channel openers are much more potent dufing periods of ischerma or hypoxia. It is not yet known whether the drug receptor that K., -I-p channel openers act upon is the K%. I-p channel itself or a separate protein. The first generation of these compounds lacked selectivity [13], but the newer compounds being developed are more likely to be tissue selective, and therefore have greater therapeutic potential. The profound vasodilatory effect induced by the early K, %ri, channel openers may be due to their almost exclusive action on vascular smooth muscle, thereby limiting their use in patients. Newer agents have been proposed, eg BMS 180884, which appear to be cardioselective but have been shown to cause profound side effects and thus their clinical application has not succeeded. At present in the UK, the only licensed KATP channel opener for patient use is nicorandil. Nicorandil is commercially available for the treatment of angina pectons, but has not been shown to be superior to placebo when used as monotherapy [292]. At present, there is an on-going multi-center clinical tnal investigating nicorandil as a treatment for angina pectons as a second line drug (IONA Study) and this is expected to yield its interim analysis in the next year. The K.. %-I-p channel opener activity of nicorandil causes an indirect blockade of calcium channels, and dilatation of arterial resistance vessels. In addition, the nitrate group activates guanylate cyclase, which causes an increase in intracellular cyclic guanosine monophosphate (cGMP) leading to dilatation of 25
venous capacitance vessels. At therapeutic doses nicorandil has little efTect on blood pressure, with minimal increase in heart rate. Headache is the most frequently reported side-effect, with the majority reported in the early stages of treatment [91 ]. Nicorandil not only has beneficial vascular effects for patients with coronary artery disease, but since various animal experiments have shown it to be directly card ioprotect i ve [106,178,220- 22 1], it may well protect cardiornyocytes from the detrimental effects of ischacmia. 1.7.5 Pharmacological KATPchannel Blockers In common with the structural diversity of drugs that open potassium channels, the blockers are also chemically different. KATP channel blockers fall into three clinical categones: 1. Oral hypoglycaemic agents e. g. glibenclamide, tolbutamide 2. Antiarrhythmic agents e. g. sernatilide 3. Bradycardic agents e. g. tedisamil K vrp channels are blocked by anti-diabetic sulphonylurea drugs [9] with glibenclamide, the most widely used for this purpose [84]. GlIbenclamide has been reported to be effective in blocking KATP channels in the heart at a concentration of 0.1 - 10 [tM (901. Glibenclamide has not been reported to block other types of K+ channels in cardiovascular tissues, suggesting that it is selective for K.. %-I-p channels in these tissues at concerntrations up to about 10 ýLM. Other sulphonylureas can also block K,, %. I. p channels, but tolbutamide is much less potent than glibenclamide. Chemically different blockers that are site selective for KATP channels are 5-hydroxydecanoate for mitochondrial sites [2321 and HMR 1883 for sarcolernmal channels [ 1021. Glibenclamide , 5-HD and HMR 26
Page 1 and 2: ISCHAEMIC PRECONDITIONING OF THE HU
Page 3 and 4: ABSTRACT Ischaemic preconditioning
Page 5 and 6: andomised clinical study with the f
Page 7 and 8: CHAPTERI Introduction 35 Matefials
Page 9 and 10: Discussion 151 CHAPTER Vill Conclus
Page 11 and 12: 44 CK leakage and MTT reduction on
Page 13 and 14: The Wellcome Trust and The British
Page 15 and 16: Presentations International "The Ef
Page 17 and 18: Abbreviations An attempt has been m
Page 19 and 20: 1.1 Introduction Ischaernic heart d
Page 21 and 22: 1.2 Myocardial Ischaemia Myocardial
Page 23 and 24: hours up to several days to complet
Page 25 and 26: phosphates and its influence on hyd
Page 27 and 28: 1.4 Myocardial Protection This refe
Page 29 and 30: performed. This process is repeated
Page 31 and 32: 1.6 Possible Mechanisms of Ischaemi
Page 33 and 34: kilodalton stress proteins. These p
Page 35 and 36: and these proteins have been sugges
Page 37 and 38: K vi-1, channels were initially fou
Page 39 and 40: tissues the K.. %,.,, channels are
Page 41: Subsequently, Jaburek et al 1145] i
Page 45 and 46: preconditioning to be investigated
Page 47 and 48: In the angioplasty model, Tomai et
Page 49 and 50: patients were randomized into two g
Page 51 and 52: CHAPTER 11 THE HUMAN RIGHT ATRIAL T
Page 53 and 54: inexpensive. Briefly in this model,
Page 55 and 56: of each ischemic period, slices wer
Page 57 and 58: 30 nini FO linlin L 60 min 120 inin
Page 59 and 60: In Study 3 (see Figure 2.4), slices
Page 61 and 62: D. Metabolite analysis Samples were
Page 63 and 64: leakage is calculated as the net LD
Page 65 and 66: B. Effect of the severity of ischae
Page 67 and 68: 2.11 DISCUSSION: The present studie
Page 69 and 70: clearly insufficient to induce myoc
Page 71 and 72: The present model may facilitate th
Page 73 and 74: 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
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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 and 126:
Furthermore, Van den Hoek et al [3
Page 127 and 128:
mechanism by which the opening of m
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
Page 177 and 178:
(0 -I 3 CD CD CD 1 3 0 :3 0 0 =r w
Page 179 and 180:
0 co t X 3 co 0 0 Cumulative Releas
Page 181 and 182:
-& a) c) UT 0 =r w CD 3 CD 0 1ý (a
Page 183 and 184:
When ischaernic preconditioning was
Page 185 and 186:
evidence tbr the involvement ot'PKC
Page 187 and 188:
institution o fcardiopu Imo nary by
Page 189 and 190:
Biblioqraphv 1. Abete P, Ferrara N,
Page 191 and 192:
14. Auchampach J, Cavero, I and Gro
Page 193 and 194:
27. Becker LB, Van den Hoek TLV, Sh
Page 195 and 196:
41. Bums PG, Krunkenkamp IB, Calder
Page 197 and 198:
55. Cohen G, Shirai T, Weisel RD, e
Page 199 and 200:
69. Currie RW and White FP (1983).
Page 201 and 202:
83. Downey JM, Liu GS and Thornton
Page 203 and 204:
97. Ganote C, Armstrong S and Downe
Page 205 and 206:
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 and 258:
938 S. Ghosh et al. / Cardiovascula
Page 259 and 260:
940 S. Ghosh et al. [41 Goto M, Liu
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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