Protection of the heart by ischaemic preconditioning: mechanisms and possibilities for pharmacological exploitation

Parratt, J. R.

doi:10.1016/0165-6147(94)90129-5

Cited by 207 publications

(112 citation statements)

References 38 publications

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“…2,3 Indeed large quantities of adenosine are released within seconds from the beginning of myocardial ischemia and, by interacting with adenosine receptors, mediate myocardiocyte protection. 2,3,21 Adenosine receptors have been divided into 4 major subclasses: A 1 , A 2A , A 2B , and A 3 , 15 and stimulation of A 1 adenosine receptors is mainly responsible for heart preconditioning. 15,21 Adenosine has also been implicated in liver preconditioning.…”

Section: Discussionmentioning

confidence: 99%

Signal pathway involved in the development of hypoxic preconditioning in rat hepatocytes

Carini¹,

Cesaris²,

Splendore³

et al. 2001

Hepatology

102

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Ischemic preconditioning improves liver resistance to hypoxia and reduces reperfusion injury following transplantation. However, the intracellular signals that mediate the development of liver hypoxic preconditioning are largely unknown. We have investigated the signal pathway leading to preconditioning in freshly isolated rat hepatocytes. Hepatocytes were preconditioned by 10-minute incubation under hypoxic conditions followed by 10 minutes of reoxygenation and subsequently exposed to 90 minutes of hypoxia. Preconditioning reduced hepatocyte killing by hypoxia by about 35%. A similar protection was also obtained by preincubation with chloro-adenosine or with A 2A -adenosine receptor agonist CGS21680, whereas A 1 -adenosine receptor agonist N-phenyl-isopropyladenosine (R-PIA) was inactive. Conversely, the development of preconditioning was blocked by A 2 -receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX), but not by A 1 -receptor antagonist 8-cyclopenthyl-1,3-dipropylxanthine (DPCPX). In either preconditioned or CGS21680-treated hepatocytes a selective activation of ␦ and protein kinase C (PKC) isoforms was also evident. Inhibition of heterotrimeric G i protein or of phospholypase C by, respectively, pertussis toxin or U73122, prevented PKC activation as well as the development of preconditioning. MEK inhibitor PD98509 did not interfere with preconditioning that was instead blocked by p38 MAP kinase inhibitor SB203580. The direct activation of p38 MAPK by anisomycin A mimicked the protection against hypoxic injury given by preconditioning. Consistently, an increased phosphorylation of p38 MAPK was observed in preconditioned or CGS21680-treated hepatocytes, and this effect was abolished by PKC-blocker, chelerythrine. We propose that a signal pathway involving A 2A -adenosine receptors, G i -proteins, phospholypase C, ␦-and -PKCs, and p38 MAPK, is responsible for the deve- The term ischemic preconditioning refers to the resistance to ischemic injury acquired by tissue following one or more brief periods of ischemia followed by reperfusion. 1,2 Ischemic preconditioning was first described in the myocardium, 1 but has been shown in several other organs, including the brain, the skeletal muscles, and the small intestine. 3 In the heart, ischemic preconditioning occurs in 2 phases: an early phase (early preconditioning) that immediately follows the transient hypoxia and lasts 2 to 3 hours and a late phase (late preconditioning), which begins 12 to 24 hours from the transient ischemia and lasts for about 3 to 4 days. 3 Recent studies have shown that the same phenomenon could also be observed in the liver. [4][5][6][7][8][9][10] In particular, 10-minute interruption of liver blood supply in anesthetized rats followed by 10 minutes of reperfusion reduces transaminases released during a subsequent 90-minute period of ischemia and 90-minute reoxygenation. 5 A similar effect has also been observed in steatosic livers following heat shock preconditioning. 7 Furthermore, ischemic preconditioning before cold preserva...

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Section: Discussionmentioning

confidence: 99%

Signal pathway involved in the development of hypoxic preconditioning in rat hepatocytes

Carini¹,

Cesaris²,

Splendore³

et al. 2001

Hepatology

102

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“…It has been observed that adenosine accumulates in ischemic tissue, 14 that the protective effect of preconditioning could be mimethized by adenosine agonists, 5 and that the administration of adenosine receptor antagonists blocks the beneficial effect of preconditioning. 9 Consequently, it has been hypothesized that accumulation of adenosine plays a key role in the mechanism of preconditioning.…”

Section: Discussionmentioning

confidence: 99%

Hepatic preconditioning in rats is defined by a balance of adenosine and xanthine

et al. 1998

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The present work investigates the relationship between adenosine, nitric oxide (NO), and free radicals during ischemic preconditioning in rat liver. For this purpose, we evaluated: 1) the efficacy of different periods of preconditioning; 2) the changes in the concentration of adenine nucleotides during preconditioning; 3) the importance of adenosine and xanthine concentrations in the induction of preconditioning; and 4) the possible effect of xanthine oxidase-derived superoxide anion on NO during preconditioning. Results show that just a 10-to 15-minute period of ischemia followed by 10-minute reperfusion prevents the ischemic damage that would be induced by a subsequent 90 minutes of ischemia followed by 90 minutes of reperfusion. Administration of xanthine or metabolization of endogenous adenosine abolishes the protective effect of preconditioning. When rats have been subjected to a period of preconditioning not within the effective time window (10-15 minutes), and thus offering no protection, the administration of a NO donor was found to restore the protection. The dose needed to restore protection appears to be proportional to the endogenous xanthine concentration. In addition, when xanthine oxidase was inhibited, preconditioning effectively offered protection in front of ischemia and reperfusion, independently of the xanthine concentration. Altogether, this indicates that the time window of ischemia capable to induce preconditioning in liver is defined by the relative tissue concentrations of adenosine and xanthine. The lower limit of this window (10 minutes) is defined by the amount of adenosine able to induce NO generation. Its upper limit (15 minutes) is defined by the concentration of xanthine able to remove the generated NO. (HEPATOLOGY 1998;28:768-773.)In 1986, Murry et al. discovered that short periods of ischemia and reperfusion render the myocardium resistant to a subsequent more-sustained ischemic insult. 1 This phenomenon, called ischemic preconditioning, has been commonly studied in the heart, but few studies have been performed on intestine 2 or liver. 3 The mechanism underlying preconditioning remains unknown and is currently under intense investigation. It has been suggested that protection depends on the release of substances by the organ helping to protect it against injury. Along this line, potential mediators include nitric oxide (NO) 2,4 and adenosine. 5 Vegh et al. 6 reported that the protection conferred by preconditioning in dog heart in vivo disappeared after NO inhibition. Nevertheless, other authors 7 found that endogenous NO is not a mediator in the ischemic preconditioning in the isolated rat heart. Recent work by our group, using a model of hepatic preconditioning in rat, demonstrated that inhibition of NO abolishes the effect of preconditioning. 8 In the same study, we suggested that NO production was stimulated by endogenous adenosine. It is known that pretreatment with adenosine or selective adenosine A 1 receptor agonists mimics the effect of preconditioning in heart. 10 Bot...

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“…Second, elevation of cyclic GMP inhibits calcium influx through L-type channels in the sarcolemma (Tohse & Sperelakis, 1991). Third, stimulation of a cyclic-GMP dependent cyclic-AMP phosphodiesterase should lead to a decrease in myocardial cyclic AMP levels, which would also result following direct stimulation of bradykinin B2 receptors (Parratt, 1994a).…”

Section: Discussionmentioning

confidence: 99%

“…Particularly impressive in the canine model is the complete abolition of ventricular fibrillation and a marked reduction in the incidence and number of episodes of ventricular tachycardia (Vegh et al, 1992a). The most likely mechanisms of this protection, recently reviewed by Lawson & Downey (1993) and by Parratt (1994a) would appear to be a reduction in the severity of ischaemia and its metabolic consequences, a reduction in the release of substances such as noradrenaline which induce arrhythmias under ischaemic conditions, and the production of some endogenous myocardial protective substance.…”

Section: Introductionmentioning

confidence: 99%

Attenuation of the antiarrhythmic effects of ischaemic preconditioning by blockade of bradykinin B₂ receptors

Végh

Papp

Parratt

1994

British J Pharmacology

101

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1 The possibility that bradykinin is involved in the pronounced antiarrhythmic effects of ischaemic preconditioning in anaesthetized mongrel dogs was examined with the use of the selective B2 antagonist, icatibant . 2 Preconditioning, achieved by two 5 min occlusions of the left anterior descending coronary artery, followed 20 min later by a 25 min occlusion of the same artery resulted, during this prolonged occlusion, in less severe arrhythmias (VF 0% versus 47% in control non-preconditioned dogs), reductions in the incidence and number of episodes of ventricular tachycardia (VT) and in the number of ventricular premature beats and increased survival following reperfusion (50% versus 0% in the controls). 3 Hoe-140 was given in a dose of 300 Ag kg-' either before the preconditioning procedure or after preconditioning but before the prolonged occlusion. This dose of Hoe-140 had insignificant haemodynamic effects and failed to modify the increase in coronary blood flow that occurred in the circumflex coronary artery when the anterior descending branch was occluded. 4 It was difficult to precondition dogs in the presence of Hoe-140. There were more ventricular arrhythmias during the initial 5 min occlusion (44 ± 12 versus 10 ± 3) and a higher incidence of ventricular fibrillation (50% versus 21%) during the preconditioning procedure. There was also a more pronounced ST-elevation (recorded from epicardial electrodes) during the preconditioning occlusions in those dogs given Hoe-140. 5 In those dogs that survived to the long (25 min) occlusion, Hoe-140 prevented the antiarrhythmic effects of preconditioning (reduction in ventricular premature beats and in VT) although all the dogs survived the occlusion period. However on reperfusion, survival in the preconditioned dogs given Hoe-140 was less than in those dogs preconditioned without the B2 antagonist. 6 Changes in the degree of inhomogeneity of conduction within the ischaemic area, which were markedly suppressed by preconditioning, were attenuated in those dogs preconditioned in the presence of Hoe-140. 7 These results suggest that bradykinin acts as both a 'trigger' for preconditioning and as one of the mediator protective (antiarrhythmic) substances generated by the myocardium under these conditions. Since the protection afforded both by preconditioning and by local intracoronary infusions of bradykinin is markedly attenuated by an inhibitor of the L-arginine nitric oxide pathway, we suggest that much of the protection afforded by ischaemic preconditioning results from the generation of nitric oxide, and that bradykinin, released early during ischaemia, acts as a stimulant for this generation.

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Protection of the heart by ischaemic preconditioning: mechanisms and possibilities for pharmacological exploitation

Cited by 207 publications

References 38 publications

Signal pathway involved in the development of hypoxic preconditioning in rat hepatocytes

Signal pathway involved in the development of hypoxic preconditioning in rat hepatocytes

Hepatic preconditioning in rats is defined by a balance of adenosine and xanthine

Attenuation of the antiarrhythmic effects of ischaemic preconditioning by blockade of bradykinin B₂ receptors

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Protection of the heart by ischaemic preconditioning: mechanisms and possibilities for pharmacological exploitation

Cited by 207 publications

References 38 publications

Signal pathway involved in the development of hypoxic preconditioning in rat hepatocytes

Signal pathway involved in the development of hypoxic preconditioning in rat hepatocytes

Hepatic preconditioning in rats is defined by a balance of adenosine and xanthine

Attenuation of the antiarrhythmic effects of ischaemic preconditioning by blockade of bradykinin B2 receptors

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Attenuation of the antiarrhythmic effects of ischaemic preconditioning by blockade of bradykinin B₂ receptors