Plasma Adenosine during Investigation of Hypoxic Ventilatory Response

Abstract

Adenosine, an endogenous nucleoside, is released by hypoxic tissue, causes vasodilation, and influences ventilation. Its effects are mediated by P1-purinoceptors. We examined to what extent the plasma adenosine concentration in the peripheral venous blood correlates with hypoxic ventilatory response (HVR) and ventilatory drive P0.1 to find out whether endogenously formed adenosine has an influence on the individual ventilatory drive under hypoxic conditions. While investigating the HVR of 14 healthy subjects, the ventilatory drive P0.1 was measured with the shutter of a spirometer. Determination of the ventilatory drive P0.1(RA) started under room air conditions (21% O (2)) and then inspiratory gas was changed to a hypoxic mixture of 10% O (2) in N (2) to determine P0.1(Hyp). At the time of the P0.1 measurements, two blood samples were taken to determine the adenosine concentrations. After removal of cellular components and proteins, samples were analyzed by high-pressure liquid chromatography (HPLC). Both adenosine concentrations in plasma under room air (r = 0.59, p < 0.05) and adenosine concentrations under hypoxia (r = 0.75, p < 0.01) correlated significantly with the ventilatory drive P0.1. In addition, plasma adenosine concentrations during hypoxic conditions showed a significant correlation with HVR on the 0.01 level (r = 0.71, p < 0.01). The results indicate a possible role of endogenous adenosine in the regulation of breathing in humans. We assume that endogenous adenosine influences the HVR and the ventilatory drive, probably by modulating the carotid body chemoreceptor response to hypoxia.

Equilibrative Nucleoside Transporter 1 Expression Is Downregulated by Hypoxia in Human Umbilical Vein Endothelium

“…4 Our results show that exposure of HUVEC to 2% O 2 increases extracellular adenosine compared with 5% O 2 (considered as normoxia because oxygen content in human umbilical vein blood is 3% to 5%), 20 -22 confirming previous reports in HUVEC 27 and complementing the hypoxiaincreased adenosine plasma concentration detected in humans. 15 Because ecto-nucleosidases are not expressed in HUVEC, 4,11,24 hypoxia-increased extracellular adenosine concentration may become an alternative mechanism to the proposed endothelial adenosine release detected in hypoxia. 2,27,28 Adenosine transport is primarily mediated by Na ϩ -independent hENT1 8 and hENT2 12 in HUVEC.…”

“…4,5,11 Adenosine transport via hENT1 is reduced by nitric oxide (NO) in HUVEC, 4,8,9 thus endothelial NO synthase (eNOS) may play a critical role under conditions where its expression and activity are altered such as gestational diabetes 4,8 or intrauterine growth restriction (IUGR), 13 a disease associated with low oxygen (hypoxia) levels. 13 Hypoxia downregulates mouse ENT1 activity and mRNA level in the cardiomyocyte cell line, HL-1, 14 and increases extracellular adenosine in humans, 15 animals, 16 and in oxygen-sensitive pheochromocytoma (PC-12) cells. 17 Hypoxia also leads to limb vasodilation in humans 7 and animal models, 16,18 and induces endotheliumindependent vasodilation in human heart arteriole.…”

Insulin restores glucose inhibition of adenosine transport by increasing the expression and activity of the equilibrative nucleoside transporter 2 in human umbilical vein endothelium

“…Since the extracellular concentration of adenosine was reduced by insulin in cultures of HUVEC, and because ecto-nucleosidases are not expressed in this cell type (Sobrevia et al, 1994;Yegutkin et al, 2001;da Silva et al, 2006), a change in extracellular adenosine level is likely to result from altered adenosine removal by the umbilical vein endothelium. Thus, insulin modulation of adenosine transport becomes a crucial mechanism maintaining adenosine extracellular concentrations in the physiological range in the umbilical vein (Ontyd and Schrader, 1984;Maguire et al, 1998;Drumm et al, 2004). This phenomenon seems determinant in the pathophysiology inherent to the abnormally elevated plasma adenosine to which HUVEC are exposed since this nucleoside increases the expression and activity of cationic amino acid transporters 1 (hCAT-1) and eNOS in this cell type (Sobrevia et al, 1997;Wyatt et al, 2002;Vá squez et al, 2004;Farías et al, 2006).…”

Equilibrative Nucleoside (ENTs) and Cationic Amino Acid (CATs) Transporters: Implications in Foetal Endothelial Dysfunction in Human Pregnancy Diseases

“…Hypoxia downregulates mouse ENT1 activity and mRNA level in the cardiomyocyte cell line HL-1 [98], and increases extracellular adenosine in humans [89], animals [99], and in oxygen-sensitive pheochromocytoma (PC-12) cells [100]. It has been reported that Fig.…”

“…In HUVEC from normal pregnancies insulin also seems to increase the number of nucleoside membrane transporters (2.31 x10 6 transporters per cell) vs. cells incubated in the absence of insulin (1.34 x10 6 transporters per cell) [84]. Because ecto-nucleosidases are not expressed in this cell type [69,86], insulin-modulation of adenosine transport in HUVEC becomes a crucial mechanism maintaining the extracellular concentrations of adenosine within its physiological range [87][88][89].…”