pentostatin and Hypoxia

Pseudohypoxemia has been reported in leukemic patients with extreme leukocytosis, and it is characterized by a low oxygen saturation on arterial blood gas analysis despite normal saturation on pulse oximetry. We report the case of a 51-year-old man with chronic lymphocytic leukemia and an elevated white blood cell (WBC) count after splenectomy, his progressive postoperative pseudohypoxemia gradually improved as the leukocytosis was lowered by chemotherapy. We believe this is the first report to show a statistically significant correlation between the WBC count and the degree of pseudohypoxemia in a patient with leukemia.

Topics: Antibiotics, Antineoplastic; Blood Gas Analysis; Humans; Hypoxia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytosis; Male; Middle Aged; Oximetry; Pentostatin; Postoperative Complications; Pulmonary Embolism; Splenectomy

Both ischemia and hypoxia increase adenosine production in the heart. This study tested whether hypoxia increases adenosine production in the coronary artery via ecto-5'-nucleotidase and the role of protein kinase C in this condition. Canine left circumflex coronary artery was rapidly removed and incubated in 10 mL Krebs-Henseleit solution for 30 minutes. The Krebs-Henseleit solution contained 5'-iodotubercidin and 2'-deoxycoformycin, which inhibit adenosine kinase and adenosine deaminase, respectively. Adenosine production was measured in intact coronary arteries under normoxic conditions (16.2 +/- 1.2 pmol/mg protein). Adenosine production was reduced by 27% after removal of endothelium. Ecto-5'-nucleotidase activity of coronary arteries with and without endothelium was 51 +/- 6 and 41 +/- 4 nmol/mg protein per minute under normoxic conditions. Hypoxia increased adenosine production to 27.0 +/- 2.3 and 20.0 +/- 0.8 pmol/mg protein with and without endothelium. Hypoxia also increased ecto-5'-nucleotidase activity of coronary arteries with and without endothelium (74 +/- 8 and 53 +/- 5 nmol/mg protein per minute; P < .05). Increases in adenosine production under hypoxic conditions were blunted by both an inhibitor of ecto-5'-nucleotidase and inhibitors of protein kinase C. Activation of ecto-5'-nucleotidase was blunted by an inhibitor of protein kinase C. These results indicate that hypoxia increased extracellular adenosine production and activated ecto-5'-nucleotidase via activation of protein kinase C in coronary arterial smooth muscle and endothelial cells. Increased adenosine production in coronary arteries during hypoxia may contribute to coronary vasodilation and cardioprotection against ischemic injury.

Topics: 5'-Nucleotidase; Adenosine; Adenosine Deaminase Inhibitors; Adenosine Kinase; Animals; Arteries; Coronary Vessels; Dogs; Enzyme Activation; Hypoxia; In Vitro Techniques; Pentostatin; Protein Kinase C; Tubercidin

Field and intracellular potentials were recorded from CA1 pyramidal stratum in submerged slices (at 33 degrees). During "normal" oxygenation (95% O2 + 5% CO2), tonic depression of population spikes and field excitatory postsynaptic potentials by endogenous adenosine was demonstrated by (i) the marked enhancement by the adenosine antagonists 8-(p-sulfophenyl)theophylline (10 microM) and caffeine (0.2 mM), (ii) depression by the transport blocker dipyridamole (5 microM), and (iii) enhancement by exogenous adenosine deaminase (all tested by bath application). Thus, adenosine deaminase (0.5 units/ml) reduced by 10.7 +/- 3.0% (S.E.) the half-maximal stimulus intensity (for population spikes). The effects of adenosine deaminase were prevented by the specific inhibitor, deoxycoformycin (30 microM). In intracellular recordings, excitatory postsynaptic potentials were enhanced in a comparable manner by adenosine deaminase. By contrast, neither deoxycoformycin (5 and 30 microM) nor erythro-9-(2-hydroxy-3-nonyl)adenine (another adenosine deaminase inhibitor; 10 and 50 microM) had significant effects on population spikes. Superfusion with anoxic medium (saturated with 95% N2 + 5% CO2) for 2-3 min suppressed population spikes reversibly, by a mechanism involving adenosine, because 8-(p-sulfophenyl)theophylline (10 microM) and caffeine (0.2 mM) delayed the onset of anoxic block and accelerated the subsequent recovery, and the recovery was much slower or incomplete in the presence of dipyramidole (0.5 microM). However, the anoxic suppression of population spikes was not affected by deoxycoformycin (30 microM) or erythro-9-(2-hydroxy-3-nonyl)adenine (10 microM); the corresponding 50% postanoxic recovery times were also unchanged (e.g. 4.0 +/- 0.2 min for controls and 4.1 +/- 0.3 min in deoxycoformycin).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenine; Adenosine Deaminase; Adenosine Deaminase Inhibitors; Animals; Electrophysiology; Hippocampus; Hypoxia; Pentostatin; Rats; Rats, Sprague-Dawley; Reference Values; Synaptic Transmission; Theophylline

The effects of the adenosine deaminase inhibitor, deoxycoformycin, on purine release from the rat cerebral cortex were studied with the cortical cup technique. Deoxycoformycin (5 and 500 micrograms/kg i.v.) enhanced the hypoxia/ischemia-evoked release of adenosine from the cerebral cortex, indicating a marked rise in the adenosine content of interstitial fluid in the cerebral cortex. Inosine and hypoxanthine release were attenuated at the higher dose of deoxycoformycin. Uric acid release into the cortical perfusates was enhanced at the higher dose level. These results demonstrate that low doses of deoxycoformycin can be used to elevate interstitial levels of adenosine in the brain during hypoxia, and to depress the formation of some of its metabolites. The elevation of hypoxia/ischemia-evoked adenosine levels can account for the previously reported potentiation of hypoxia-evoked increases in rat cerebral blood flow after deoxycoformycin administration. The potential therapeutic utility of these findings is discussed.

Topics: Adenosine; Animals; Cerebral Cortex; Coformycin; Hypoxanthine; Hypoxanthines; Hypoxia; Inosine; Male; Pentostatin; Rats; Rats, Inbred Strains; Ribonucleosides; Uric Acid; Xanthine; Xanthines

Topics: Adenine; Adenosine Deaminase Inhibitors; Animals; Cerebrovascular Circulation; Coformycin; Dogs; Hypoxia; Nucleoside Deaminases; Pentostatin; Rats; Ribonucleosides; Vasodilation