1 The activation of various P 2 -receptor subtypes in rat renal vasculature by P 1 , P 5 -diadenosine pentaphosphate (Ap 5 A) and P 1 , P 6 -diadenosine hexaphosphate (Ap 6 A) were studied by measuring their eects on perfusion pressure during continuous perfusion in a rat isolated perfused kidney. 2 Permanent perfusion with Ap 5 A and Ap 6 A elicited both a transient and sustained vasoconstriction with both vasoconstrictions to be dierent: the transient vasoconstriction can be elicited with concentrations 510 nM, whereas the sustained vasoconstriction is observed with concentrations 51 nM. 3 Ap 5 A and Ap 6 A act via the same receptors as a,b-methylene ATP (a,b-meATP). 4 The rank order of potency for transient vasconstriction was a,b-meATP=Ap 5 A4Ap 6 A4b,gmeATP, and for sustained vasoconstriction a,b-meATP=Ap 5 A4b,g-meATP 5Ap 6 A. 5 Suramin, a non-selective P 2 -receptor antagonist, and pyridoxal-phosphate-6-azophenyl-2;4-disulphonic acid (PPADS) a highly selective P 2X -receptor antagonist antagonized both the transient and the sustained vasoconstriction. 6 Taken together the results of the agonist pro®le of Ap 5 A and Ap 6 A and comparing its ®ndings to literature it can be demonstrated that the transient but not the sustained vasoconstriction is mediated via the P 2X1 -receptor which is present in rat renal vasculature. 7 It is demonstrated that the agonist pro®le of the sustained vasoconstriction induced by Ap 5 A and Ap 6 A does not ®t to any currently known P 2X -or P 2Y -receptor subtype. 8 We conclude a yet unidenti®ed P 2X -receptor or chimeric P 2X -receptor may contribute to the eects on rat renal vasculature produced by Ap 5 A and Ap 6 A and which may play an important role in glomerular perfusion pressure and blood pressure control.
K, et al. Reduced binding and neutralization of infection-and vaccine-induced antibodies to the B.1.351 (South African) SARS-CoV-2 variant [preprint]. bioRxiv.
Introduction
In the general population, hyperuricemia is associated with increased morbidity and mortality. Data on this association in hemodialysis patients is controversial. Moreover, it remains elusive whether serum uric acid (SUA) lowering therapy is associated with mortality.
Methods
Retrospective analysis of 601 patients on chronic hemodialysis therapy in five outpatient centers with a maximum follow-up of 100 and a mean follow-up of 41 months. Death was defined as primary endpoint. Cumulative survival was analyzed by Kaplan–Meier analysis and Cox regressions adjusted for age.
Findings
Cumulative survival rates were higher for those subjects with a higher than median SUA concentration both based on mean annual and baseline measurements (
p
< 0.05 each). There was no survival difference anymore after adjustment for age (
p
> 0.05 each). Stratification for SUA lowering therapy (allopurinol/febuxostat) had no impact on cumulative survival, neither in Kaplan Meier nor in Cox regression analyses (
p
> 0.05 each). Furthermore, Cox regression analysis excluded an increased cardiovascular mortality in subjects with hyperuricemia.
Discussion
In contrast to the general population, hyperuricemia is not associated with increased mortality in patients undergoing hemodialysis. Moreover, xanthine oxidase inhibition was not associated with a survival benefit in this analysis. These data do not support the use of SUA lowering medication in hemodialysis patients with asymptomatic hyperuricemia.
1 The activation of P 2x -receptors in the rat renal vasculature by dinucleoside polyphosphates with variable phosphate group chain length (Xp n X; X=Adenin (A) /Guanin (G), n=4 ± 6) was studied by measuring their eects on perfusion pressure of the isolated perfused rat kidney at constant¯ow in an open circuit. 2 Like Ap 4 A, Ap 5 A and Ap 6 A the dinucleoside polyphosphates Ap 4 G, Ap 5 G and Ap 6 G exerted a vasoconstriction which could be blocked by suramin and pyridoxal-phosphate-6-azophenyl-2; 4-disulphonic acid (PPADS). 3 Gp 4 G, Gp 5 G and Gp 6 G showed only very weak vasoconstriction at high doses. 4 Ap 6 A and a, b-meATP could not be blocked by the selective P 2x1 -receptor antagonisten NF023 (30 mM), whereas Ap 4 A, Ap 4 G, Ap 5 A, Ap 5 G and Ap 6 G were partially blocked by NF023. 5 Inhibition of endothelial NO-synthase by N o -nitro-L-arginine methyl ester (L-NAME) did not aect vasoconstrictions induced by dinucleosidepolyphosphates. 6 P 2x -receptor can only be activated if at least one adenosine moiety is present in the molecule. 7 Ap n G show a weaker vasoconstrictive action than corresponding Ap n A, concluding that two adenosine moieties enhance the P 2x -receptor binding and activation. 8 Xp n X containing ®ve phosphate groups show the most pronounced vasoconstrictive eect whereas four phosphate groups show the less eect, therefore the number of phosphate groups critically changes receptor anity. 9 Additional experiments using permanent perfusion with a, b-methylene ATP (a,b-meATP) and the selective P 2x1 -receptor antagonist NF023 showed that the newly discovered human dinucleoside polyphosphates activated the vascular P 2x1 -receptor and an recently identi®ed new P 2x -receptor subtype. 10 The dierential eects of dinucleoside polyphosphates allow a ®ne tuning of local perfusion via composition of Xp n Xs.
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