Adenosine and the anti-infarct effects of preconditioning

Downey, James M.; Liu, Guang S.; Thornton, J D

doi:10.1093/cvr/27.1.3

Cited by 148 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%

“…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. 4,6 However, recent studies have shown that, different from the heart, the stimulation of liver adenosine A 2 receptors is responsible for the hepatoprotec- tive action.…”

Section: Discussionmentioning

confidence: 99%

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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%

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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“…This endogenous protection mechanism occurred in all animal species studied 9 , and some authors also suggested its existence in man 10,11 . In 1986, Murry et al 8 were the first to report this phenomenon in a canine model.…”

Section: Groupmentioning

confidence: 79%

Influence of ischemic preconditioning in myocardial protection in patients undergoing myocardial revascularization with intermittent crossclamping of the aorta. Analysis of ions and blood gases

Pêgo-Fernandes¹,

Jatene²,

Gentil³

et al. 2001

Arq. Bras. Cardiol.

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Objective -To test the hypothesis that short periods of ischemia may increase the myocardial protection obtained with intermittent crossclamping of the aorta. Methods -In the control group (18 patients)Despite theoretical criticism of the technique of intermittent crossclamping of the aorta with hypothermia at 32ºC, the simplicity of the procedure and its good clinical results have led several surgeons to use it, particularly in myocardial revascularization surgery 1,2 .In Brazil, Jatene et al 3 have been using it since 1969, with good clinical results. A few randomized studies 4,5 comparing the efficacy of intermittent crossclamping of the aorta with the use of cardioplegic solutions exist, but none of them conclude that one method is superior to the others.One question about the technique is that the repetition of ischemic episodes, which are individually reversible, may cause cumulative damage resulting in necrosis. Reimer et al 6 disproved this concept by showing experimentally that intermittent reperfusion avoids cumulative metabolic deficit and myocardial ischemia with cell death and that the first episode of ischemia reduces the consumption of high energy phosphates in subsequent episodes. Other studies 7 have shown that short periods of ischemia do not induce irreversible cellular damage and that they do not result in cumulative metabolic, structural, and functional deficits. It has also been reported that, paradoxically, short periods of ischemia increase the tolerance of the heart instead of making it more vulnerable to subsequent ischemic episodes. This induction of tolerance to ischemia is called ischemic preconditioning 8 .The objective of this study was to assess the influence of ischemic preconditioning on myocardial protection obtained with intermittent crossclamping of the aorta in patients undergoing myocardial revascularization.

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“…Recently, a series of studies indicated that injections of adenosine can mimic the protection against myocardial ischaemia induced by preconditioning, including reduced severity of life threatening ventricular arrhythmias that occur during prolonged occlusion and reduced myocardial infarct size (Vegh et al, 1992;Downey et al, 1993). However, the mechanism by which preconditioning protects the heart remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Antiarrhythmic effects of BN‐063, a newly synthesized adenosine A₁ agonist, on myocardial ischaemia in rats

Lee

Chern

Yen

1994

British J Pharmacology

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It has been shown that adenosine is able to reduce the severity of arrhythmias induced by myocardial ischaemia. In isolated preparations, the antiarrhythmic effect of adenosine on ventricular myocardium is known to antagonize the catecholamine‐induced stimulation of intracellular cyclic AMP production, an effect mediated via adenosine A1 receptors. The aim of this study was to evaluate the antiarrhythmic effect of BN‐063 (1‐cyclo‐propylisoguanosine), a newly synthesized selective adenosine A1 agonist, on ventricular arrhythmias in rats. Arrhythmias were induced by left coronary artery ligation or by administration of isoprenaline (7 mg kg−1) subcutaneously. Pretreatment with BN‐063 (0.25, 0.5 and 1.0 mg kg−1) 10 min prior to occlusion significantly delayed the onset of ventricular arrhythmias, reduced the total number of ventricular premature contraction (VPC) and ventricular tachycardia (VT), decreased the incidence of VT and ventricular fibrillation (VF) and mortality during the first 30 min following left coronary artery ligation. In contrast, pretreatment with 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX), an adenosine A1 antagonist, was arrhythmogenic during the ischaemic period. The rate‐pressure product, an index for indirect measurement of myocardial oxygen consumption, was also significantly reduced by BN‐063 during ligation time. The incidence of VT, VF and mortality was also significantly reduced when BN‐063 was administered after left coronary artery ligation. BN‐063 converted the VF induced by isoprenaline to normal sinus rhythm and improved the survival rate. It is concluded that, through activation of adenosine A1 receptors, BN‐063 can suppress ventricular arrhythmias induced by myocardial ischaemia and catecholamines. The antiarrhythmic actions of BN‐063 may be mediated by reducing heart rate and antagonizing the stimulatory effects of catecholamine in myocardial ischaemia.

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Adenosine and the anti-infarct effects of preconditioning

Cited by 148 publications

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

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

Influence of ischemic preconditioning in myocardial protection in patients undergoing myocardial revascularization with intermittent crossclamping of the aorta. Analysis of ions and blood gases

Antiarrhythmic effects of BN‐063, a newly synthesized adenosine A₁ agonist, on myocardial ischaemia in rats

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Adenosine and the anti-infarct effects of preconditioning

Cited by 148 publications

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

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

Influence of ischemic preconditioning in myocardial protection in patients undergoing myocardial revascularization with intermittent crossclamping of the aorta. Analysis of ions and blood gases

Antiarrhythmic effects of BN‐063, a newly synthesized adenosine A1 agonist, on myocardial ischaemia in rats

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Antiarrhythmic effects of BN‐063, a newly synthesized adenosine A₁ agonist, on myocardial ischaemia in rats