Visualisation of the Effects of Dilazep on Rat Afferent and Efferent Arterioles In Vivo

Nakamoto, Hiroshi; Ogasawara, Yasuo; Kajiya, Fumihiko

doi:10.1291/hypres.31.315

Cited by 16 publications

(9 citation statements)

References 35 publications

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“…Thus, adenosine is a renal constrictor only when it can interact with afferent arteriolar Adora1a without affecting the bulk of renal Adora2a at the same time (61). Other studies have shown that ENT inhibition with dipyridamole is associated with an initial constriction of the afferent and efferent arterioles at an early phase and subsequent dilation at a later phase, with the same degree of vasoconstrictive and vasodilatory effect on both arterioles in rats (62). In contrast to these studies, previous studies report vasoconstrictive properties of dipyridamole during the initiation phase of postischemic acute renal failure in rats (63) or in patients with liver cirrhosis (64).…”

Section: Discussionmentioning

confidence: 95%

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

Grenz¹,

Bauerle²,

Dalton³

et al. 2012

J. Clin. Invest.

114

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A complex biologic network regulates kidney perfusion under physiologic conditions. This system is profoundly perturbed following renal ischemia, a leading cause of acute kidney injury (AKI) -a life-threatening condition that frequently complicates the care of hospitalized patients. Therapeutic approaches to prevent and treat AKI are extremely limited. Better understanding of the molecular pathways promoting postischemic reflow could provide new candidate targets for AKI therapeutics. Due to its role in adapting tissues to hypoxia, we hypothesized that extracellular adenosine has a regulatory function in the postischemic control of renal perfusion. Consistent with the notion that equilibrative nucleoside transporters (ENTs) terminate adenosine signaling, we observed that pharmacologic ENT inhibition in mice elevated renal adenosine levels and dampened AKI. Deletion of the ENTs resulted in selective protection in Ent1 -/-mice. Comprehensive examination of adenosine receptor-knockout mice exposed to AKI demonstrated that renal protection by ENT inhibitors involves the A2B adenosine receptor. Indeed, crosstalk between renal Ent1 and Adora2b expressed on vascular endothelia effectively prevented a postischemic no-reflow phenomenon. These studies identify ENT1 and adenosine receptors as key to the process of reestablishing renal perfusion following ischemic AKI. If translatable from mice to humans, these data have important therapeutic implications. IntroductionAcute kidney injury (AKI) is clinically defined by an abrupt reduction in kidney function (e.g., a decrease in glomerular filtration rate [GFR]), occurring over a period of minutes to days. AKI is frequently caused by an obstruction of renal blood flow (renal ischemia) and represents an important cause of morbidity and mortality of patients (1-3). Indeed, a recent study revealed that only a mild increase (0.3 mg/dl) in the serum creatinine level is associated with a 70% greater risk of death than in patients without this increase (2, 3). Particularly for surgical patients, AKI represents a significant threat. For example, surgical procedures requiring cross-clamping of the aorta and renal vessels are associated with a rate of AKI of up to 30% (4). Similarly, AKI after cardiac surgery occurs in up to 10% of patients under normal circumstances and is associated with dramatic increases in mortality (5). In addition, patients with sepsis frequently go on to develop AKI, and the combination of moder-

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Section: Discussionmentioning

confidence: 95%

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

Grenz¹,

Bauerle²,

Dalton³

et al. 2012

J. Clin. Invest.

114

View full text Add to dashboard Cite

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“…We visualized glomerular filtration under in vivo conditions by two‐photon confocal microscopy. In our method, it is not necessary to use any special rat species to observe renal microcirculation under in vivo conditions as we visualized renal microcirculation with our intravital videomicroscope in our previous study . Our observation of glomerular filtration was performed at depths of up to 50 μm, as that was the greatest depth at which reasonable visibility could be acquired.…”

Section: Discussionmentioning

confidence: 99%

“…These studies were based on either isolated preparations or pathological animal models, and therefore, their results may differ from those of studies performed under in vivo conditions. A few visualization studies have been performed under in vivo conditions, including a study by our group, which used a CCD intravital videomicroscope . In addition, a few studies have examined glomerular filtration function quantitatively by using visualization under in vivo conditions .…”

Section: Introductionmentioning

confidence: 99%

In Vivo Quantitative Visualization Analysis of the Effect of C‐Peptide on Glomerular Hyperfiltration in Diabetic Rats by Using Multiphoton Microscopy

Nakamoto

Kajiya

2013

Microcirculation

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“…The clear increase in circulating adenosine and inosine levels in ENT1-deficient mice indicates that the bulk of extracellular adenosine is derived from breakdown of released adenine nucleotides. An increase of plasma adenosine levels has previously been observed in ENT1 Ϫ/Ϫ mice (28) as well as (18,33). The important question of whether an increase of extracellular adenosine through nucleotide metabolism also occurs in the JGA interstitium cannot be answered directly.…”

Section: F385 Type 1 Equilibrative Nucleoside Transporter and Tgfmentioning

confidence: 97%

“…While direct evidence for a reduced renal vascular resistance in the ENT1-deficient mice is lacking, it is conceivable that the increased adenosine levels exert a dilatory influence that might reduce TGF efficiency nonspecifically. Administration of dilazep has been noted to cause a lasting increase of renal blood flow accompanied by vasodilatation of both afferent and efferent arterioles, and these changes were prevented by inhibition of adenosine receptors (18,39). Vasodilatation is also the net effect of prolonged elevations of circulating adenosine levels although it is not clear whether the distal afferent arteriolar TGF effector site participates in this relaxation (12).…”

Section: F385 Type 1 Equilibrative Nucleoside Transporter and Tgfmentioning

confidence: 99%

Tubuloglomerular feedback and renal function in mice with targeted deletion of the type 1 equilibrative nucleoside transporter

Mizel

Huang

et al. 2013

American Journal of Physiology-Renal Physiology

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mann J. Tubuloglomerular feedback and renal function in mice with targeted deletion of the type 1 equilibrative nucleoside transporter. Am J Physiol Renal Physiol 304: F382-F389, 2013. First published December 26, 2012 doi:10.1152/ajprenal.00581.2012.-A1 adenosine receptors (A1AR) are required for the modulation of afferent arteriolar tone by changes in luminal NaCl concentration implying that extracellular adenosine concentrations need to change in synchrony with NaCl. The present experiments were performed in mice with a null mutation in the gene for the major equilibrative nucleoside transporter ENT1 to test whether interference with adenosine disposition by cellular uptake of adenosine may modify TGF characteristics. Responses of stop flow pressure (PSF) to maximum flow stimulation were measured in mice with either C57Bl/6 or SWR/J genetic backgrounds. Maximum flow stimulation reduced PSF in ENT1 Ϫ/Ϫ compared with wild-type (WT) mice by 1.6 Ϯ 0.4 mmHg (n ϭ 28) and 5.8 Ϯ 1.1 mmHg (n ϭ 17; P Ͻ 0.001) in C57Bl/6 and by 1.4 Ϯ 0.4 mmHg (n ϭ 15) and 9 Ϯ 1.5 mmHg (n ϭ 9; P Ͻ 0.001) in SWR/J. Plasma concentrations of adenosine and inosine were markedly higher in ENT1 Ϫ/Ϫ than WT mice (ado: 1,179 Ϯ 78 and 225 Ϯ 48 pmol/ml; ino: 179 Ϯ 24 and 47.5 Ϯ 9 pmol/ml). Renal mRNA expressions of the four adenosine receptors, ENT2, and adenosine deaminase were not significantly different between WT and ENT1 Ϫ/Ϫ mice. No significant differences of glomerular filtration rate or mean arterial blood pressure were found while plasma renin concentration, and heart rates were significantly lower in ENT1 Ϫ/Ϫ animals. In conclusion, TGF responsiveness is significantly attenuated in the absence of ENT1, pointing to a role of nucleoside transport in the NaCl-synchronous changes of extracellular adenosine levels in the juxtaglomerular apparatus interstitium. stop flow pressure; micropuncture; adenosine; plasma renin; blood pressure SUBSTANTIAL EXPERIMENTAL EVIDENCE supports a critical role of purine nucleotides and nucleosides in the mediation of the tubuloglomerular feedback (TGF) response of afferent arterioles to changes of NaCl concentration at the macula densa cells of the juxtaglomerular apparatus. Release of nucleotides, specifically of ATP, by macula densa cells appears to provide the substrate for extracellular ATPases to generate AMP, which is subsequently dephosphorylated by 5=-ecto-nucleotidase to form the nucleoside adenosine. Activation of A 1 adenosine receptors (A1AR) on afferent arterioles seems to be the endpoint responsible for TGF-mediated vasoconstriction. An underlying assumption of this scenario is that both ATP and adenosine levels within the juxtaglomerular apparatus (JGA) interstitium fluctuate dependent on the composition of the tubular fluid at the macula densa and that these fluctuations are required for afferent arteriolar resistance to adjust to luminal NaCl concentration changes. It is conceivable therefore that interference with the pathways for the appearance and disappearance of the purinergic mediator co...

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Visualisation of the Effects of Dilazep on Rat Afferent and Efferent Arterioles In Vivo

Cited by 16 publications

References 35 publications

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

In Vivo Quantitative Visualization Analysis of the Effect of C‐Peptide on Glomerular Hyperfiltration in Diabetic Rats by Using Multiphoton Microscopy

Tubuloglomerular feedback and renal function in mice with targeted deletion of the type 1 equilibrative nucleoside transporter

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