5′-Nucleotidase Inhibitors and the Myocardial Reactive Hyperemia and Adenosine Content

Imai, Shoichi; Nakazawa, Makoto; Imai, Hirotatsu; Jin, Hiromasa

doi:10.1007/978-3-642-45619-0_34

Cited by 22 publications

(10 citation statements)

References 10 publications

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“…This interpretation is supported by the finding that the adenosine transport inhibitor 4-nitrobenzylthioinosine (NMBPR, 5 ,uM)18 increased basal adenosine release from the isolated perfused guinea pig heart from 0.07+0.01 to 0.23+±0.04 nmol/min (n=9; unpublished data from our laboratory). Similar effects of NMBPR were also reported by Imai et al 27 Thus, the isolated heart normally releases significant quantities of adenine nucleotides that are partially degraded during passage through the heart, thereby permitting the adenosine formed to be salvaged by efficient transport processes. 5 Conversely, measuring adenosine release in the absence and presence of NMBPR permits estimation of the salvage of adenosine derived from extracellular adenine nucleotide metabolism.…”

Section: Control Releasesupporting

confidence: 66%

“…Interestingly, Imai and coworkers observed a diminution of the reactive hyperemic flow responses when AOPCP was infused in isolated guinea pig hearts. 27 In the light of the above findings it needs to be explored to what extent AOPCP, an ADP derivative, can interact with purine receptors, thus possibly interfering with vascular actions of adenine nucleotides.…”

Section: Ischemiamentioning

confidence: 99%

See 1 more Smart Citation

Adenine nucleotide release from isolated perfused guinea pig hearts and extracellular formation of adenosine.

Borst

Schrader

1991

Circulation Research

158

101

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The quantification of adenine nucleotides released from the heart is hampered by their rapid dephosphorylation to adenosine in the extracellular space catalyzed by highly active ectonucleotidases. To determine the total release of adenine nucleotides from isolated Langendorffperfused guinea pig hearts, ecto 5'-nucleotidase was effectively blocked by infusion of a4.-methylene-ADP (AOPCP, 50 ,M). Adenine nucleotides were measured in the coronary venous effluent by the luciferin-luciferase method after enzymatic rephosphorylation to ATP. In hearts perfused at a constant flow rate (10 ml/min) with normoxic buffer (95% 02,5% C02) the release+SEM of adenine nucleotides and adenosine was 0.06±0.01 (n=11) and 0.04+±0.01 (n=13) nmol/min. In the presence of AOPCP, the release of adenine nucleotides increased to 0.43 +0.04 nmol/min (n=9; p<0.05), whereas adenosine remained unchanged. Hypoxic perfusion (10% 02, 85% N2, 5% C02) caused a threefold increase in adenine nucleotide release but a 40-fold increase in adenosine. In contrast, global ischemia (30 seconds) caused adenine nucleotide and adenosine release to rise to similar values of 1.06±0.10 and 0.80+0.14 nmol/min (n=9). Stimulation of hearts with isoproterenol (4 nM) likewise increased the release of adenine nucleotides (0.50±0.04 nmol/min) and adenosine (0.87±0.21 nmol/min) (n=6). To determine the cellular source of adenine nucleotides released from the heart, the coronary endothelial adenine nucleotide pool was selectively prelabeled by [3H]adenosine. Global ischemia increased the specific radioactivity of released adenine nucleotides by 57%. The findings indicate that 1) adenine nucleotides and adenosine are released at the same order of magnitude from the well-oxygenated heart; 2) P-adrenergic stimulation and ischemia stimulate the release of adenine nucleotides and adenosine, both purines reaching vasoactive concentrations in the effluent perfusate; 3) during hypoxic perfusion only the release of adenosine is greatly enhanced; and 4) the coronary endothelium preferentially contributes to the ischemiainduced adenine nucleotide release. (Circulation Research 1991;68:797-806) In hearts adenosine is generally assumed to be formed intracellularly by dephosphorylation of adenine nucleotides' and by hydrolysis of S-adenosyl-L-homocysteine.2 Adenosine production is accelerated when the breakdown of energy-rich adenine nucleotides is increased, for example, by an imbalance in the myocardial supply-to-demand ratio for oxygen.34 After being formed, adenosine is thought to reach the extracellular space by facilitated diffusion5 to finally cause the adaptive changes in coronary blood flow.

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Section: Control Releasesupporting

confidence: 66%

Section: Ischemiamentioning

confidence: 99%

Adenine nucleotide release from isolated perfused guinea pig hearts and extracellular formation of adenosine.

Borst

Schrader

1991

Circulation Research

158

101

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“…While we have not studied this aspect directly, recent work has defined a role for CRE and CRE-binding protein (CREB) in hypoxia-elicited induction of a number of proteins (31,32), and this pathway may be particularly relevant to a number of cardiovascular diseases in vivo. For instance, adenosine production in the ischemic myocardium is attributable to activity of CD73 (33), and both CD73 activity and adenosine metabolism have been implicated in cardiac preconditioning by brief periods of ischemia (34,35). Importantly in this regard, it was recently shown that adenosine (via activation of A 1 receptors) can directly regulate extracellular adenosine levels in rat cardiac fibroblasts (36), providing a potential feed-forward loop in this metabolic process.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Endothelial CD73 by Adenosine: Paracrine Pathway for Enhanced Endothelial Barrier Function

Narravula

Lennon

Mueller

et al. 2000

The Journal of Immunology

109

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During episodes of inflammation, multiple cell types release adenine nucleotides in the form of ATP, ADP, 5′-AMP, and adenosine. In particular, following activation, polymorphonuclear leukocytes release larger quantities of 5′-AMP. Extracellular 5′-AMP is metabolized to adenosine by surface-expressed 5′-ectonucleotidase (CD73). Adenosine liberated by this process activates surface adenosine A2B receptors, results in endothelial junctional reorganization, and promotes barrier function. We hypothesized that adenosine signaling to endothelia provides a paracrine loop for regulated expression of CD73 and enhanced endothelial barrier function. Using an in vitro microvascular endothelial model, we investigated the influence of 5′-AMP; adenosine; and adenosine analogues on CD73 transcription, surface expression, and function. Initial experiments revealed that adenosine and adenosine analogues induce CD73 mRNA (RT-PCR), surface expression (immunoprecipitation of surface biotinylated CD73), and function (HPLC analysis of etheno-AMP conversion to ethenoadenosine) in a time- and concentration-dependent fashion. Subsequent studies revealed that similar exposure conditions increase surface protein through transcriptional induction of CD73. Analysis of DNA-binding activity by EMSA identified a functional role for CD73 cAMP response element and, moreover, indicated that multiple cAMP agonists induce transcriptional activation of functional CD73. Induced CD73 functioned to enhance 5′-AMP-mediated promotion of endothelial barrier (measured as a paracellular flux of 70-kDa FITC-labeled tracer). These results provide an example of transcriptional induction of enzyme (CD73) by enzymatic product (adenosine) and define a paracrine pathway for the regulated expression of vascular endothelial CD73 and barrier function.

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“…9 -12 We have previously reported that IP increases ecto-5Ј-nucleotidase activity, 13,14 which seems to be consistent with the results of Liu et al, 6 because adenosine production in the ischemic myocardium is attributable to ecto-5Ј-nucleotidase. 15,16 The adenosine production via ecto-5Ј-nucleotidase may enhance the triggering mechanisms of IP or may contribute as an intermediate mediator to activate the final mediators such as the opening of ATP-sensitive K ϩ (K ATP ) channels. Interestingly, protein tyrosine kinase is reported to be located downstream of activation of protein kinase C in the rat and rabbit hearts.…”

mentioning

confidence: 99%

Protein Tyrosine Kinase Is Not Involved in the Infarct Size–Limiting Effect of Ischemic Preconditioning in Canine Hearts

Kitakaze

Node

Asanuma

et al. 2000

Circulation Research

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Protein kinase C (PKC) plays an important role in ischemic preconditioning (IP). Because (1) tyrosine kinase is located at the downstream of PKC for IP in the rabbit hearts and (2) we have reported that ecto-5'-nucleotidase is the substrate for PKC and plays a crucial role for the infarct size-limiting effect, we tested whether tyrosine kinase activation contributes to either activation of ecto-5'-nucleotidase or the infarct size-limiting effect of the early phase of IP in the canine heart. In dogs, the IP procedure (4 cycles of 5-minute occlusion of coronary artery) and exposure to 12, 13-phorbol myristate acetate (PMA) each activated myocardial ecto-5'-nucleotidase and Lck tyrosine kinase. Genistein (10, 30, and 100 microg. kg(-)(1). min(-)(1) IC), an inhibitor of tyrosine kinase, attenuated the activation of Lck tyrosine kinase but did not attenuate the activation of ecto-5'-nucleotidase due to either IP or PMA. In the other canine hearts, IP attenuated infarct size (49+/-5 versus 11+/-3 or 16+/-3%, P<0.01) due to 90 minutes of coronary occlusion followed by 6 hours of reperfusion, which was not blunted by 3 or 2 (30 and 100 microg. kg(-)(1). min(-)(1)) doses of genistein (infarct sizes, 15+/-4, 13+/-4, and 13+/-3%, respectively, and 17+/-3 and 15+/-4%, respectively) or lavendustin A. Tyrosine kinase does not activate ecto-5'-nucleotidase or trigger the infarct size-limiting effect of the early phase of IP in canine hearts.

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5′-Nucleotidase Inhibitors and the Myocardial Reactive Hyperemia and Adenosine Content

Cited by 22 publications

References 10 publications

Adenine nucleotide release from isolated perfused guinea pig hearts and extracellular formation of adenosine.

Adenine nucleotide release from isolated perfused guinea pig hearts and extracellular formation of adenosine.

Regulation of Endothelial CD73 by Adenosine: Paracrine Pathway for Enhanced Endothelial Barrier Function

Protein Tyrosine Kinase Is Not Involved in the Infarct Size–Limiting Effect of Ischemic Preconditioning in Canine Hearts

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