Acadesine reduces myocardial infarct size by an adenosine mediated mechanism

Zhao, Zhi‐Qing; Williams, Mark W.; Sato, Hiroki; Hudspeth, Dudley A.; McGee, D.Scott; Vinten-Johansen, J.; Wylen, D. G. L. Van

doi:10.1016/s0008-6363(96)88525-7

Cited by 27 publications

(9 citation statements)

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“…First, AICAR is an analogue of adenosine that in some studies has been reported to have physiological actions in the heart via adenosine receptor stimulation. 30 However, adenosine-induced vasodilatation in our model develops within 1 minute (E. Eringa, unpublished results) and is endothelium independent. Furthermore, the adenosine receptor blocker 8-phenyltheophylline did not inhibit AICARinduced vasodilation in isolated resistance arteries (data not shown).…”

Section: Discussionmentioning

confidence: 67%

Activation of AMP-Activated Protein Kinase by 5-Aminoimidazole-4-Carboxamide-1-β- d -Ribofuranoside in the Muscle Microcirculation Increases Nitric Oxide Synthesis and Microvascular Perfusion

Bradley

Eringa²,

Stehouwer

et al. 2010

ATVB

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Objective-To investigate the effects of activation of the AMP-activated protein kinase (AMPK) on muscle perfusion and to elucidate the mechanisms involved. Methods and Results-In a combined approach, we studied the vasoactive actions of AMPK activator by 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR) on rat cremaster muscle resistance arteries (Ϸ100 m) ex vivo and on microvascular perfusion in the rat hindlimb in vivo. In isolated resistance arteries, AICAR increased Thr172 phosphorylation of AMPK in arteriolar endothelium, which was predominantly located in microvascular endothelium. AICAR induced vasodilation (19Ϯ4% at 2 mmol/L, PϽ0.01), which was abolished by endothelium removal, inhibition of NO synthase (with N-nitro-L-arginine), or AMPK (with compound C). Smooth muscle sensitivity to NO, determined by studying the effects of the NO donor S-nitroso-N-acetylpenicillamine (SNAP), was not affected by AICAR except at the highest dose. AICAR increased endothelial nitric oxide synthase activity, as indicated by Ser1177 phosphorylation. In vivo, infusion of AICAR markedly increased muscle microvascular blood volume (Ϸ60%, PϽ0.05), as was evidenced by contrast-enhanced ultrasound, without effects on blood pressure, femoral blood flow, or hind leg glucose uptake. Conclusion-Activation

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Section: Discussionmentioning

confidence: 67%

Activation of AMP-Activated Protein Kinase by 5-Aminoimidazole-4-Carboxamide-1-β- d -Ribofuranoside in the Muscle Microcirculation Increases Nitric Oxide Synthesis and Microvascular Perfusion

Bradley

Eringa²,

Stehouwer

et al. 2010

ATVB

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“…One might therefore conclude that intravascular adenosine is critical in mediating cardioprotection. This is further supported by studies demonstrating reduced infarct size or contractile dysfunction with adenosine-regulating agents (155,314), which fail to modify interstitial adenosine. Large-molecular-weight adenosine agonists restricted to the vascular compartment also elicit cardioprotection (277).…”

Section: Importance Of Intravascular Versus Interstitial Adenosinementioning

confidence: 77%

Acute adenosinergic cardioprotection in ischemic-reperfused hearts

Headrick

Hack

Ashton

2003

American Journal of Physiology-Heart and Circulatory Physiology

150

164

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. Acute adenosinergic cardioprotection in ischemic-reperfused hearts. Am J Physiol Heart Circ Physiol 285: H1797-H1818, 2003; 10.1152/ajpheart.00407. 2003.-Cells of the cardiovascular system generate and release purine nucleoside adenosine in increasing quantities when constituent cells are "stressed" or subjected to injurious stimuli. This increased adenosine can interact with surface receptors in myocardial, vascular, fibroblast, and inflammatory cells to modulate cellular function and phenotype. Additionally, adenosine is rapidly reincorporated back into 5Ј-AMP to maintain the adenine nucleotide pool. Via these receptor-dependent and independent (metabolic) paths, adenosine can substantially modify the acute response to ischemic insult, in addition to generating a more sustained ischemia-tolerant phenotype (preconditioning). However, the molecular basis for acute adenosinergic cardioprotection remains incompletely understood and may well differ from more widely studied preconditioning. Here we review current knowledge and some controversies regarding acute cardioprotection via adenosine and adenosine receptor activation.adenosine; adenosine receptor activation; ischemia; reperfusion injury THE HEART possesses its own intrinsic protective responses, including the adenosine receptor system, which enhance resistance to ischemic insult. An understanding of the mechanisms involved in these responses not only informs us of how the heart reacts to injurious stimuli, but may provide avenues for developing novel protective strategies applicable in the setting of ischemia-reperfusion. The purine nucleoside adenosine was attributed with cardioregulatory functions almost 75 years ago (64), and since then has emerged as a crucially important control substance in essentially every tissue of the body. In the heart adenosine not only plays a role in regulating growth and differentiation, angiogenesis, coronary blood flow, cardiac conduction and heart rate, substrate metabolism, and sensitivity to adrenergic stimulation (23,67,68,73,74,260,271,283), but may play a role as an endogenous determinant of ischemic tolerance (189,225,245,259,311,312,318). From a therapeutic viewpoint, adenosine-based therapies protect against ischemic injury in a variety of animal models (72,177,208,265,288) and in human cardiac tissue (34, 36, 37,240,296). However, much remains unclear regarding the roles and mechanisms of action of adenosine in producing acute protection against ischemia and reperfusion. Generation of Endogenous Adenosine During InsultEndogenous adenosine levels increase rapidly with ischemic insult (104,109,285,286) to mediate a retaliatory response. This protective pool of adenosine can be formed via dephosphorylation of 5Ј-AMP by intra-and extracellular 5Ј-nucleotidases and from S-adenosylhomocysteine (SAH) via SAH hydrolase. Extracellular adenosine is rapidly taken into cells via a facilitative transporter (131). Within cells it is either deaminated by adenosine deaminase or rephosphorylated to 5Ј-AMP via adenosine kinase. O...

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“…It is interesting to note that a meta-analysis of clinical studies using AICAR in the setting of coronary artery bypass grafting demonstrated modest reductions in early cardiac death, myocardial infarction, and the need for LV assist device support (48). Historically, AICAR was developed as a drug (acadesine) designed to increase extracellular adenosine concentrations and adenosine receptor stimulation in ischemic tissue (49). Although not recognized at the time, it is possible that activation of AMPK may have played a role in these beneficial effects.…”

Section: Figurementioning

confidence: 99%

AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury

et al. 2004

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AMP-activated protein kinase (AMPK)is an important regulator of diverse cellular pathways in the setting of energetic stress. Whether AMPK plays a critical role in the metabolic and functional responses to myocardial ischemia and reperfusion remains uncertain. We examined the cardiac consequences of long-term inhibition of AMPK activity in transgenic mice expressing a kinase dead (KD) form of the enzyme. The KD mice had normal fractional shortening and no heart failure, cardiac hypertrophy, or fibrosis, although the in vivo left ventricular (LV) dP/dt was lower than that in WT hearts. During low-flow ischemia and postischemic reperfusion in vitro, KD hearts failed to augment glucose uptake and glycolysis, although glucose transporter content and insulin-stimulated glucose uptake were normal. KD hearts also failed to increase fatty acid oxidation during reperfusion. Furthermore, KD hearts demonstrated significantly impaired recovery of LV contractile function during postischemic reperfusion that was associated with a lower ATP content and increased injury compared with WT hearts. Caspase-3 activity and TUNEL-staining were increased in KD hearts after ischemia and reperfusion. Thus, AMPK is responsible for activation of glucose uptake and glycolysis during low-flow ischemia and plays an important protective role in limiting damage and apoptotic activity associated with ischemia and reperfusion in the heart.

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Acadesine reduces myocardial infarct size by an adenosine mediated mechanism

Abstract: Acadesine reduces infarct size by an adenosine mediated mechanism, but this cardioprotective action is not associated with significantly augmented interstitial fluid adenosine levels.

Cited by 27 publications

References 0 publications

Activation of AMP-Activated Protein Kinase by 5-Aminoimidazole-4-Carboxamide-1-β- d -Ribofuranoside in the Muscle Microcirculation Increases Nitric Oxide Synthesis and Microvascular Perfusion

Activation of AMP-Activated Protein Kinase by 5-Aminoimidazole-4-Carboxamide-1-β- d -Ribofuranoside in the Muscle Microcirculation Increases Nitric Oxide Synthesis and Microvascular Perfusion

Acute adenosinergic cardioprotection in ischemic-reperfused hearts

AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury

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