M J Miller1. 1. University of Calgary, Calgary, Canada.
Abstract
BACKGROUND: In recent years, extensive studies have expanded the knowledge of the role of preconditioning (PC) for cardiac protection against ischemia reperfusion (I/R) injury. These studies are reviewed, and their relevance to the early and late phases of cardiac protection is discussed. CONCLUSIONS: First, there is strong evidence that the L-arginine-nitric oxide pathway plays a major role in PC. Second, early and late phase protection are probably distinct phenomena with similar effects induced by different mechanisms. Third, nitric oxide appears to be causally involved in both mechanisms. Fourth, nitric oxide produced by endothelial nitric oxide synthase (eNOS) in the early seconds of ischemia induces reactive hyperemia. It is proposed that reactive hyperemia provides the short-lived protection of early phase PC. It is unlikely that heat shock protein 72 (HSP72) or antioxidants have a role in early phase protection--both have a time lag of 12 to 24 h after PC before gene expression occurs. Fifth, late phase PC appears to depend on HSP72 gene expression mediated by the L-arginine-nitric-oxide pathway; during late phase PC, the inducible nitric oxide synthase (iNOS) content is increased while the eNOS content is unchanged. There is good evidence for an obligatory role of iNOS in cardiac protection afforded by the late phase of I/R protection in vivo. Sixth, the results of studies on the role of endogenous antioxidants in late phase protection are contradictory and further study is required. Seventh, studies on the signalling and transduction processes associated with preconditioning provide important information that may be helpful in the development of drugs protective against I/R injury. Finally, until such drugs are developed, PC by heat shock may be an effective alternative. A recent study in a human subject reported that HSP72 is upregulated by induction of hyperthermia within a range of moderate fever levels--oral temperatures between 38.6 degrees C and 39.5 degrees C. If this is confirmed, it seems plausible that inducing hyperthermia 24 h before major cardiac surgery may be an effective therapeutic strategy for protection against I/R.
BACKGROUND: In recent years, extensive studies have expanded the knowledge of the role of preconditioning (PC) for cardiac protection against ischemia reperfusion (I/R) injury. These studies are reviewed, and their relevance to the early and late phases of cardiac protection is discussed. CONCLUSIONS: First, there is strong evidence that the L-arginine-nitric oxide pathway plays a major role in PC. Second, early and late phase protection are probably distinct phenomena with similar effects induced by different mechanisms. Third, nitric oxide appears to be causally involved in both mechanisms. Fourth, nitric oxide produced by endothelial nitric oxide synthase (eNOS) in the early seconds of ischemia induces reactive hyperemia. It is proposed that reactive hyperemia provides the short-lived protection of early phase PC. It is unlikely that heat shock protein 72 (HSP72) or antioxidants have a role in early phase protection--both have a time lag of 12 to 24 h after PC before gene expression occurs. Fifth, late phase PC appears to depend on HSP72 gene expression mediated by the L-arginine-nitric-oxide pathway; during late phase PC, the inducible nitric oxide synthase (iNOS) content is increased while the eNOS content is unchanged. There is good evidence for an obligatory role of iNOS in cardiac protection afforded by the late phase of I/R protection in vivo. Sixth, the results of studies on the role of endogenous antioxidants in late phase protection are contradictory and further study is required. Seventh, studies on the signalling and transduction processes associated with preconditioning provide important information that may be helpful in the development of drugs protective against I/R injury. Finally, until such drugs are developed, PC by heat shock may be an effective alternative. A recent study in a human subject reported that HSP72 is upregulated by induction of hyperthermia within a range of moderate fever levels--oral temperatures between 38.6 degrees C and 39.5 degrees C. If this is confirmed, it seems plausible that inducing hyperthermia 24 h before major cardiac surgery may be an effective therapeutic strategy for protection against I/R.