Adenosine uptake, transport, and metabolism in human erythrocytes

Plagemann, Peter G.W.; Wohlhueter, Robert M.; Kraupp, Martin

doi:10.1002/jcp.1041250223

Cited by 69 publications

(41 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In hyperhomocysteinemia, erythrocytes are relevant in the regulation of circulating endogenous adenosine because adenosine is efficiently taken up by erythrocytes through the dipyridamole-sensitive transporter and because homocysteine and AdoHcy are increased in erythrocytes of patients with hyperhomocysteinemia. [11][12][13] Freshly isolated erythrocytes were resuspended in MOPS buffer to obtain a 2% solution. Fifty-L portions were incubated at 37°C with L-homocysteine (100 mol/L) in DTT and with DTT alone for 10 minutes (paired experiments).…”

Section: Adenosine Uptake In Isolated Erythrocytesmentioning

confidence: 99%

Enhanced Cellular Adenosine Uptake Limits Adenosine Receptor Stimulation in Patients With Hyperhomocysteinemia

Riksen

Rongen

Boers

et al. 2005

ATVB

View full text Add to dashboard Cite

Objective-Endogenous adenosine has several cardioprotective effects. We postulate that in patients with hyperhomocysteinemia increased intracellular formation of S-adenosylhomocysteine decreases free intracellular adenosine. Subsequently, facilitated diffusion of extracellular adenosine into cells through dipyridamole-sensitive transporters is enhanced, limiting adenosine receptor stimulation. We tested this hypothesis in patients with classical homocystinuria (nϭ9, plasma homocysteine 93.1Ϯ24.7 mol/L) and matched controls (nϭ8, homocysteine 9.1Ϯ1.0). Methods and Results-Infusion of adenosine (0.5, 1.5, 5.0, and 15.0 g/min/dL forearm) into the brachial artery increased forearm blood flow, as measured with venous occlusion plethysmography, to 2.9Ϯ0.4, 4.3Ϯ0.5, 5.6Ϯ1.1, and 9.6Ϯ2.1 in the patients and to 2.8Ϯ0.6, 4.4Ϯ1.0, 9.0Ϯ1.7, and 17.0Ϯ3.1 mL/min/dL in controls (PϽ0.05). However, adenosine-induced vasodilation in the presence of dipyridamole (100 g/min/dL) was similar in both groups (Pϭ0.9). Additionally, in isolated erythrocytes, adenosine uptake was accelerated by incubation with homocysteine (half-time 6.4Ϯ0.3 versus 8.1Ϯ0.5 minutes, PϽ0.001) associated with increased intracellular formation of S-adenosylhomocysteine (PϽ0.0001). Conclusions-In hyperhomocysteinemia, adenosine-induced vasodilation is impaired but is restored by dipyridamole.Accelerated cellular adenosine uptake probably accounts for these observations. These impaired actions of adenosine could well contribute to the cardiovascular complications of hyperhomocysteinemia. Key Words: adenosine Ⅲ hyperhomocysteinemia Ⅲ dipyridamole Ⅲ forearm Ⅲ nucleoside transport H yperhomocysteinemia is an independent risk factor for atherosclerosis and thromboembolism. It is poorly understood which mechanism is responsible for these cardiovascular complications.Recently, we and others have drawn attention to a new hypothesis, focusing on the influence of homocysteine on the metabolism of the endogenous nucleoside adenosine. 1,2 According to this hypothesis, a homocysteine-induced fall in extracellular adenosine contributes to the cardiovascular sequelae of hyperhomocysteinemia. Fundamental to this is the reversibility of the reaction in which S-adenosylhomocysteine (AdoHcy) is hydrolyzed to form homocysteine and adenosine. 3 Although the equilibrium constant of this reaction favors AdoHcy synthesis, under physiological conditions AdoHcy is hydrolyzed to homocysteine and adenosine, because both reaction products are rapidly metabolized. In hyperhomocysteinemia, the reaction shifts toward AdoHcy synthesis at the expense of free intracellular adenosine. Subsequently, facilitated diffusion of extracellular adenosine into the cells through the dipyridamole-sensitive equilibrative nucleoside transporter is enhanced, limiting stimulation of membrane-bound adenosine receptors (Figure 1).By stimulation of these receptors, extracellular adenosine induces several effects, which could protect against the development of atherosclerosis and thrombosis and against ischemia-re...

show abstract

Section: Adenosine Uptake In Isolated Erythrocytesmentioning

confidence: 99%

Enhanced Cellular Adenosine Uptake Limits Adenosine Receptor Stimulation in Patients With Hyperhomocysteinemia

Riksen

Rongen

Boers

et al. 2005

ATVB

View full text Add to dashboard Cite

show abstract

“…21 In addition, the plasma half-life of adenosine is short (seconds-minutes), 25 due in large part to its rapid degradation by adenosine deaminase contained within red blood cells. 26 Thus, while a possible synergistic contribution cannot be excluded, 27 these two factors essentially preclude the blood-borne transport of this nucleotide in appreciable quantities from a remote, ischemic ''trigger'' organ [7][8][9][10][11][12] to the heart. If adenosine is not the primary humoral trigger for preconditioning at a distance, what are the other possibilities?…”

Section: Identity Of the Protective Humoral Trigger?mentioning

confidence: 99%

“Preconditioning at a Distance” in the Isolated Rabbit Heart

Dickson

Porcaro

Fenton

et al. 2000

Academic Emergency Medicine

View full text Add to dashboard Cite

Abstract. Objective: Brief myocardial ischemia evokes a cardioprotective response, referred to as ''ischemic preconditioning'' (IP), that limits injury caused by a subsequent prolonged ischemic insult. The myocardial IP effect can be induced by ischemia of ''distant'' cardiac and noncardiac tissue, implicating the involvement of an as-yet-unidentified humoral trigger. If a preconditioning hormone exists, the authors hypothesize that the IP effect should be transferable, via administration of coronary effluent, from a preconditioned donor heart to a virgin nonpreconditioned acceptor heart. Methods: Isolated buffer-perfused rabbit hearts were assigned to one of four treatment groups in a donor/acceptor sequence. Donor hearts underwent either three IP cycles or a matched period of uninterrupted perfusion (control donors). Coronary perfusate collected from IP and control donor hearts was reoxygenated and transfused to virgin acceptor hearts. All hearts then underwent 30 minutes of global ischemia followed by 30 minutes of reperfusion. Left ventricular developed pressure (LVDP) (the authors' index of cardioprotection) was monitored throughout the protocol by a left ventricular (LV) balloon. Results: In donor controls, LVDP assessed at 30 minutes post-reflow was restored to only 49 Ϯ 5% of baseline values. Recovery of LV function was significantly enhanced in both IP donor hearts (69 Ϯ 4%*) and IP acceptor hearts (70 Ϯ 6%*) vs donor controls (*p < 0.05), while, in acceptor controls, intermediate values of LVDP (62 Ϯ 7%) were obtained. Conclusion: The IP effect can be transferred between rabbit hearts, suggesting the presence of a humoral trigger signal for distant preconditioning. Isolating this hormone may have therapeutic and diagnostic implications in the management of acute myocardial ischemia.

show abstract

“…In our earlier study, we showed that LY2033298 also displayed positive cooperativity with ACh in binding affinity (16-fold) indicating that there is no efficacy modulation by LY2033298 with the parent agonist (Valant et al, 2012). Similarly to ACh, adenosine is also rapidly metabolized (by adenosine deaminase) to inosine (Plagemann et al, 1985) ( Supplemental Fig. 1B); inosine displayed greater than 1000-fold lower potency at the A 1 -AR in ERK1/2 phosphorylation compared with its parent ligand, adenosine.…”

mentioning

confidence: 93%

Allosteric Modulation of Endogenous Metabolites as an Avenue for Drug Discovery

et al. 2012

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and a key drug target class. Recently, allosteric drugs that can cobind with and modulate the activity of the endogenous ligand(s) for the receptor have become a major focus of the pharmaceutical and biotechnology industry for the development of novel GPCR therapeutic agents. This class of drugs has distinct properties compared with drugs targeting the endogenous (orthosteric) ligand-binding site that include the ability to sculpt cellular signaling and to respond differently in the presence of discrete orthosteric ligands, a behavior termed "probe dependence." Here, using cell signaling assays combined with ex vivo and in vivo studies of insulin secretion, we demonstrate that allosteric ligands can cause marked potentiation of previously "inert" metabolic products of neurotransmitters and peptide hormones, a novel consequence of the phenomenon of probe dependence. Indeed, at the muscarinic M 2 receptor and glucagon-like peptide 1 (GLP-1) receptor, allosteric potentiation of the metabolites, choline and GLP-1(9 -36)NH 2 , respectively, was ϳ100-fold and up to 200-fold greater than that seen with the physiological signaling molecules acetylcholine and GLP-1(7-36)NH 2 . Modulation of GLP-1(9 -36)NH 2 was also demonstrated in ex vivo and in vivo assays of insulin secretion.This work opens up new avenues for allosteric drug discovery by directly targeting modulation of metabolites, but it also identifies a behavior that could contribute to unexpected clinical outcomes if interaction of allosteric drugs with metabolites is not part of their preclinical assessment.

show abstract

Adenosine uptake, transport, and metabolism in human erythrocytes

Cited by 69 publications

References 37 publications

Enhanced Cellular Adenosine Uptake Limits Adenosine Receptor Stimulation in Patients With Hyperhomocysteinemia

Enhanced Cellular Adenosine Uptake Limits Adenosine Receptor Stimulation in Patients With Hyperhomocysteinemia

“Preconditioning at a Distance” in the Isolated Rabbit Heart

Allosteric Modulation of Endogenous Metabolites as an Avenue for Drug Discovery

Contact Info

Product

Resources

About