Theophylline Improves Early Allograft Function in Rat Kidney Transplantation

Grenz, Almut; Baier, Detlef; Petroktistis, Fotios; Wehrmann, Manfred; Köhle, Christoph; Schenk, Martin; Sessler, Michael J.; Gleiter, Christoph H.; Fändrich, F.; Oßwald, Hartmut

doi:10.1124/jpet.105.096917

Cited by 11 publications

(8 citation statements)

References 38 publications

(39 reference statements)

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“…Thus the dose of DPCPX showed a protective effect in glycerol-induced acute renal failure (20,44), the dose of DMPX had a maximal effect on NECA-induced hypothermia and locomotor activity depression (42), and the dose of MRS 1119 was protective in ischemia-reperfusion and myoglobinuria-mediated renal injury (25). Furthermore, we could show that the dose of theophylline was protective following renal transplantation (14) and that the dose of APCP or PSB 1115 abolished the renal or cardioprotective effects of ischemic preconditioning, respectively (7,15). To provide confidence that the results of this study do not reflect in our hands a lack of sensitivity and/or specificity for the detection of EPO, we refer to our previous investigations showing an increase or decrease of the EPO secretory response in rats following renal denervation or in rats on a high-salt diet, respectively, following 4 h of exposure to 600 ppm CO compared with controls.…”

Section: Discussionmentioning

confidence: 88%

“…The doses of all substances that we have tested were based on earlier reports in which clear antagonistic effects were demonstrated on different organ function in experimental animals. We used 8-phenyltheophylline (8-PT) as a nonspecific AR antagonist (10 mg/kg ip) (14) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 1 mg/kg ip) (20,44), 3,7-dimethyl-1-propargylxanthine (DMPX; 1 mg/kg ip) (42), PSB 1115 (10 mg/kg ip) (7), and MRS 1119 (1 mg/kg ip) (25) as specific AR subtype inhibitors. CD73 was inhibited using adenosine 5Ј-(␣,␤-methylene) diphosphate (APCP; 2 mg ip) (7,15).…”

Section: Methodsmentioning

confidence: 99%

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Lack of effect of extracellular adenosine generation and signaling on renal erythropoietin secretion during hypoxia

Grenz¹,

Zhang²,

Weingart³

et al. 2007

American Journal of Physiology-Renal Physiology

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Previous studies have yielded conflicting results as to whether extracellular adenosine generation and signaling contributes to hypoxia-induced increases in renal erythropoietin (EPO) secretion. In this study, we combined pharmacological and genetic approaches to elucidate a potential contribution of extracellular adenosine to renal EPO release in mice. To stimulate EPO secretion, we used murine carbon monoxide exposure (400 and 750 parts per million CO, 4 h), ambient hypoxia (8% oxygen, 4 h), or arterial hemodilution. Because the ecto-5-nucleotidase (CD73, conversion of AMP to adenosine) is considered the pacemaker of extracellular adenosine generation, we first tested the effect of blocking extracellular adenosine generation with the specific CD73-inhibitor adenosine 5'-(alpha,beta-methylene) diphosphate (APCP) or by gene-targeted deletion of cd73. These studies showed that neither APCP-treatment nor targeted deletion of cd73 resulted in changes of stimulated EPO mRNA or serum levels, although the increases of adenosine levels in the kidney following CO exposure were attenuated in mice with APCP treatment or in cd73(-/-) mice. Moreover, pharmacological studies using specific inhibitors of individual adenosine receptors (A1 AR, DPCPX; A 2A AR, DMPX; A 2B AR, PSB 1115; A3AR, MRS 1191) showed no effect on stimulated increases of EPO mRNA or serum levels. Finally, stimulated EPO secretion was not attenuated in gene-targeted mice lacking A1A(-/-, A2A AR-/-, A2BAR(-/-), or A3AR-/-. Together, these studies combine genetic and pharmacological in vivo evidence that increases of EPO secretion during limited oxygen availability are not affected by extracellular adenosine generation or signaling.

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Section: Discussionmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Lack of effect of extracellular adenosine generation and signaling on renal erythropoietin secretion during hypoxia

Grenz¹,

Zhang²,

Weingart³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…The efficacy of aminophylline for renal protection has been reported in cisplatin- (3), tacrolimus- (4), and contrast-induced (5, 6) AKI, in animal models of kidney transplantation (20), and in the vasomotor nephropathy of very pre-term newborns (21). However, its use in critically ill infants and children is not well described.…”

Section: Discussionmentioning

confidence: 99%

A Prospective Assessment of the Effect of Aminophylline Therapy on Urine Output and Inflammation in Critically Ill Children

et al. 2014

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Background: Aminophylline, an established bronchodilator, is also purported to be an effective diuretic and anti-inflammatory agent. However, the data to support these contentions are scant. We conducted a prospective, open-label, single arm, single center study to assess the hypothesis that aminophylline increases urine output and decreases inflammation in critically ill children.Methods: Children less than 18 years of age admitted to the pediatric intensive care unit who were prescribed aminophylline over a 24-h period were eligible for study. The use and dosing of aminophylline was independent of the study and was at the discretion of the clinical team. Data analyzed consisted of demographics, diagnoses, medications, and markers of pulmonary function, renal function, and inflammation. Data were collected at baseline and at 24-h after aminophylline initiation with primary outcomes of change in urine output and inflammatory cytokine concentrations.Results: Thirty-five patients were studied. Urine output increased significantly with aminophylline use [median increase 0.5 mL/kg/h (IQR: −0.3, 1.3), p = 0.05] while blood urea nitrogen and creatinine concentrations remained unchanged. Among patients with elevated C-reactive protein concentrations, levels of both interleukin-6 (IL-6) and IL-10 decreased at 24 h of aminophylline therapy. There were no significant differences in pulmonary compliance or resistance among patients invasively ventilated at both time points. Side effects of aminophylline were detected in 7 of 35 patients.Conclusion: Although no definitive conclusions can be drawn from this study, aminophylline may be a useful diuretic and effective anti-inflammatory medication in critically ill children. Given the incidence of side effects, the small sample size and the uncontrolled study design, further study is needed to inform the appropriate use of aminophylline in these children.

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“…Furthermore, theophylline administered 5 days after ischemia acutely increased renal blood flow and GFR in previously untreated rats (Lin et al 1988). Theophylline also caused an increase of GFR measured 5 days after experimental renal transplantation in rats without affecting the inflammatory response (Grenz et al 2006). On the other hand, in a small study with limited statistical power theophylline was not found to afford protection against acute renal failure during cardiac surgery (Kramer et al 2002).…”

Section: Disease and Therapeutic Aspectsmentioning

confidence: 99%