Renal interstitial adenosine metabolism during ischemia in dogs

Abstract

The present study was conducted to determine the metabolism of renal interstitial adenosine under resting conditions and during ischemia. By using a microdialysis method with HPLC-fluorometric analysis, renal interstitial concentrations of adenosine, inosine, and hypoxanthine were assessed in pentobarbital-anesthetized dogs. Average basal renal interstitial concentrations of adenosine, inosine, and hypoxanthine were 0.18 +/- 0.04, 0.31 +/- 0.05, and 0.35 +/- 0.05 micromol/l, respectively. Local inhibition of adenosine kinase with iodotubercidin (10 micromol/l in perfusate) or inhibition of adenosine deaminase with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; 100 micromol/l in perfusate) did not change adenosine concentrations in the nonischemic kidneys (0.18 +/- 0.04 and 0.24 +/- 0.05 micromol/l, respectively). On the other hand, treatment with iodotubercidin+EHNA significantly increased adenosine concentration (0.52 +/- 0.07 micromol/l) with significant decreases in inosine and hypoxanthine levels (0.13 +/- 0.03 and 0.19 +/- 0.04 micromol/l, respectively). During 30 min of ischemia, adenosine, inosine, and hypoxanthine were significantly increased to 0.76 +/- 0.29, 2.14 +/- 0.45, and 21.8 +/- 4.7 micromol/l, respectively. The treatment with iodotubercidin did not alter ischemia-induced increase in adenosine (0.84 +/- 0.18 micromol/l); however, EHNA alone markedly enhanced adenosine accumulation (13.54 +/- 2.16 micromol/l), the value of which was not augmented by an addition of iodotubercidin (15.80 +/- 1.24 micromol/l). In contrast, ischemia-induced increases in inosine and hypoxanthine were inversely diminished by the treatment with iodotubercidin+EHNA (0.90 +/- 0.20 and 9.86 +/- 1.96 micromol/l, respectively). These results suggest that both adenosine kinase and adenosine deaminase contribute to the metabolism of renal interstitial adenosine under resting conditions, whereas adenosine produced during ischemia is mainly metabolized by adenosine deaminase and the rephosphorylation of adenosine by adenosine kinase is small.sent

Role of Adenosine A1Receptor in Angiotensin II- and Norepinephrine-Induced Renal Vasoconstriction

“…They were maintained on a standard laboratory diet for 1 week. The surgical preparation of the animals and basic experimental techniques are identical to those previously described (Aki et al, 1990(Aki et al, , 1997Nishiyama et al, 1999Nishiyama et al, , 2000Nishiyama et al, , 2001b. Briefly, dogs were fasted for 24 h before the experiments.…”

“…For the determination of renal interstitial concentrations of adenosine, we used a microdialysis method as previously reported (Siragy and Linden, 1996;Nishiyama et al, 1999Nishiyama et al, , 2000Nishiyama et al, , 2001bZou et al, 1999). The dialysis membrane is made from cuprophan fiber, measuring 15 mm in length, with a 5500-Da transmembrane diffusion cut-off (Toyobo Co. Ltd., Otsu, Japan).…”

“…Furthermore, recent studies have documented that renal interstitial fluid adenosine concentrations are significantly increased during ischemia (Nishiyama et al, 1999(Nishiyama et al, , 2001b. Therefore, the possibility exists that accumulation of renal interstitial adenosine by angiotensin II-induced ischemia amplifies the vasoconstrictor responses to angiotensin II.…”

“…Accordingly, responses of angiotensin II to renal blood flow were examined during treatments with 1) exogenous adenosine; 2) dipyridamole, which blocks the cellular uptake of adenosine resulting in an increase in endogenous adenosine level (Heistad et al, 1981;Ballarin et al, 1991;Wang et al, 1992); and 3) a selective adenosine A 1 receptor antagonist, 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902) (Nonaka et al, 1996;Aki et al, 1997;Nishiyama et al, 2001a). Using a renal microdialysis method (Siragy and Linden, 1996;Nishiyama et al, 1999;2000, 2001bZou et al, 1999), renal interstitial concentrations of adenosine were monitored during angiotensin II administration. To determine whether synergistic interactions between adenosine and angiotensin II are specific for the renal vascular beds, these interactions were also investigated in the cerebral vascular bed.…”

Regulation of Renal Hemodyamics by Purinergic Receptors in Angiotensin II -Induced Hypertension

“…Several conditions that induce the elevation of Ang II concentrations also enhance the vasoconstrictor response of the kidney to adenosine Hansen et al, 2003;Weihprecht et al, 1994;Nishiyama et al, 2001). Furthermore, various studies suggest that Ang II-induced ischemia results in the novo formation of adenosine.…”