Remote Ischemic Preconditioning Provides Early and Late Protection Against Endothelial Ischemia-Reperfusion Injury in Humans
Role of the Autonomic Nervous System
Stavros P. Loukogeorgakis, BSc*,
,*,
Anna T. Panagiotidou, BSc*,,
Michael W. Broadhead, BSc, MRCP, FRCA
,,
Ann Donald, AVS*,
John E. Deanfield, BA, BChir, MB, FRCP* and
Raymond J. MacAllister, MA, MD, FRCP
* Vascular Physiology Unit, Institute of Child Health, University College London, London, United Kingdom
Portex Anesthesia, Intensive Therapy and Respiratory Medicine Unit, Institute of Child Health, University College London, London, United Kingdom
Centre for Clinical Pharmacology and Therapeutics, University College London, London, United Kingdom.
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Figure 1 Protocol of studies to determine the time course of remote ischemic preconditioning (RIPC). Flow-mediated dilation (FMD) of the brachial artery was assessed before 20 min of arm ischemia (I) and at 20 min of reperfusion (R) (a). The effect of IR on brachial artery smooth muscle function was determined by measuring dilation in response to sublingual glyceryl trinitrate (GTN) (25 µg) administered before and after IR (b). Because pilot studies had shown that GTN prevented endothelial IR injury when administered immediately but not 24 h before, the control dilator response to GTN was determined 24 h before IR. The effect of RIPC of the contralateral arm on endothelial IR injury was determined by applying the RIPC stimulus immediately before IR (c). To determine the time course of protection by RIPC, the RIPC stimulus was applied 4 h (d), 24 h (e), and 48 h (f) before IR.
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Figure 2 Protocol of studies to determine the effect of autonomic blockade on remote ischemic preconditioning (RIPC). Trimetaphan (1 to 6 mg/min) was administered by continuous intravenous infusion to cause autonomic nervous system blockade. To determine the effect of trimetaphan on early and late protection by RIPC, trimetaphan was infused during the RIPC stimulus that was applied immediately (a) and 24 h before ischemia and reperfusion (IR) (b). Protocols (c) and (d) were designed in order to determine whether trimetaphan had direct effects on flow-mediated dilation (FMD) or the endothelial response to IR, respectively.
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Figure 3 Effect of ischemia and reperfusion (IR) on endothelial and smooth muscle function. Flow-mediated dilation (FMD) was 8.7 ± 1.1% at baseline (BL) and was reduced by IR (a) (IR 4.9 ± 1.2%; *p < 0.001 vs. BL, analysis of variance; n = 13). Glyceryl trinitrate (GTN) dilation was 9.3 ± 2.0% at BL, and was unaffected by IR (b) (IR 10.0 ± 2.0%; p = NS, t test; n = 7).
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Figure 4 Time course of the protective effect of remote ischemic preconditioning (RIPC) on ischemia-reperfusion (IR)-induced endothelial dysfunction. Flow-mediated dilation (FMD) was 9.4 ± 0.7% at baseline (BL) and was unaffected by IR preceded immediately by RIPC (a) (IR+RIPC 8.0 ± 0.8%; p = NS vs. BL, analysis of variance [ANOVA]; n = 13). Ischemia-reperfusion reduced FMD when RIPC was applied 4 h before IR (b) (BL 8.6 ± 1.1% vs. IR+RIPC4 4.9 ± 1.1%; *p < 0.001, ANOVA; n = 10). However, the effect of IR to reduce FMD was prevented when RIPC was applied 24 h before IR (c) (BL 8.7 ± 1.1% vs. IR+RIPC24 8.4 ± 1.2%; p = NS, ANOVA; n = 12) and 48 h before IR (d) (BL 10.0 ± 0.9% vs. IR+RIPC48 8.8 ± 1.4%; p = NS, ANOVA; n = 8).
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Copyright © 2005 by the American College of Cardiology Foundation.
