adenosine-5--(n-ethylcarboxamide) and Hypoxia

Hypoxia is known to be a major player during pathological angiogenesis and adenosine as a negative feedback signaling to maintain oxygen delivery in pathological ischemic condition. We mimicked hypoxic condition and studied angiogenesis by inducing adenosine receptors using forskolin, a plant compound and NECA analogue of adenosine using zebrafish model. Vascular endothelial growth factor (VEGF) is known to play a key role during pathological angiogenesis and regulated by the factors HIF1a under hypoxic condition and recently Notch is proposed to play a negative feedback loop mechanism along with VEGF signaling but the role of adenosine receptor during the process is not known. We evaluated the mRNA expression of adenosine receptors (A1, A2a.1, A2a.2, A2b), HIF1a, VEGF A, VEGF R2, NRP1a, NOTCH 1a and DLL4 and the phenotypic variations of zebrafish embryos when treated with DAPT, γ-secretase inhibitor of Notch in addition to treating the embryos with SU5416, a VEGF receptor inhibitor. Upregulation of adenosine receptors (A1, A2a.1, A2a.2, A2b), HIF1a, VEGF A, VEGF R2, NRP1a, NOTCH1a and DLL4 was observed embryos were when treated with forskolin and NECA could possibly mimic hypoxic condition. Hatching and heart rate also increased with NECA and forskolin. SU5416 showed decreases in blood vessel formation and decreased adenosine receptors, VEGF, VEGFR2, HIF1a and NRP1a expression and DAPT, exhibited decreases in blood vessels and decreased NRP1a, NOTCH1a, DLL4 expression. These embryos developed with poor vasculature, tail bending, abnormal phenotypes and developmental delay. Forskolin treated with inhibitors showed increased blood vessel formation, normal phenotype, development and adenosine receptors (A1, A2a.1, A2a.2, A2b), HIF1a, VEGF A, VEGF R2, NRP1a, NOTCH 1a and DLL4 gene expression suggesting that adenosine mediated Notch and VEGF could play an important role during development and angiogenesis. Targeting VEGF and Notch signaling with adenosine receptors inhibitors which might have a therapeutic significance during hypoxia and abnormal angiogenesis.

Topics: Adenosine-5'-(N-ethylcarboxamide); Animals; Colforsin; Embryo, Nonmammalian; Female; Gene Expression Regulation, Developmental; Hypoxia; Male; Models, Animal; Neovascularization, Physiologic; Phenotype; Receptors, Notch; Receptors, Purinergic P1; RNA, Messenger; Vascular Endothelial Growth Factor A; Zebrafish; Zebrafish Proteins

Hypoxia-induced coronary vasorelaxation is a compensatory mechanism increasing blood flow. We hypothesized that hypoxia shares pathways with adenosine and causes vasorelaxation through the adenosine A(2A) receptor and force suppression by increasing cAMP and phosphorylated heat shock protein (HSP)20. Adenosine receptors in porcine left anterior descending coronary arteries (LAD) were examined by RT-PCR and isometric tension recording in myographs. Vasorelaxation was induced by adenosine, 1% oxygen, or both in the absence or presence of ZM241385, an adenosine A(2A) receptor antagonist. cAMP was determined by ELISA and p-HSP20/HSP20 and p-MLC/MLC were determined by immunoblotting and densitometric analyses. In coronary arteries exposed to 1% oxygen, there was increased sensitivity to adenosine, the adenosine A2 selective agonist NECA, and the adenosine A(2A) selective receptor agonist CGS21680. ZM241385 shifted concentration-response curves for CGS21680 to the right, whereas the adenosine A1 antagonist DPCPX, the adenosine A2B receptor antagonist MRS1754 and the adenosine A3 receptor antagonist MRS1523 failed to reduce vasodilatation induced by CGS21680. 1% oxygen or adenosine increased cAMP accumulation and HSP20 phosphorylation without changing T850-MYPT1 and MLC phosphorylation. ZM241385 failed to change 1% oxygen-induced vasodilation, cAMP accumulation, HSP20 phosphorylation and MLC phosphorylation. The PKA inhibitor Rp-8-CPT-cAMPS significantly reduced vasorelaxation induced by 1% oxygen or CGS21680. Our findings suggest that the increased sensitivity to adenosine, NECA, and CGS21680 at 1% oxygen involves adenosine A(2A) receptors. Adenosine and 1% oxygen induce vasorelaxation in PGF2α-contracted porcine coronary arteries partly by force suppression caused by increased cAMP and phosphorylation of HSP20.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Coronary Vessels; Cyclic AMP; Dinoprost; HSP20 Heat-Shock Proteins; Hypoxia; In Vitro Techniques; Oxygen; Phenethylamines; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Receptors, Purinergic P1; Swine; Triazines; Triazoles; Vasodilation

Small ubiquitin-like modifier 1 (SUMO-1) modification of IkappaBalpha has been described to actively participate in NFkappaB regulation. Following proteosomal degradation of IkappaBalpha, an auto-regulatory loop consisting of transcriptional activation of IkappaBalpha gene and SUMO-1 modification of newly synthesized IkappaBalpha proceeds. The SUMOylated IkappaBalpha form is resistant to signal-induced degradation, consequently halting NFkappaB activation. We describe a mechanistic model by which adenosine (Ado) signaling results in significant accumulation of SUMO-1 modified IkappaBalpha with subsequent attenuation of NFkappaB activation. Using models of hypoxia followed by reoxygenation (H/R), we have documented an H/R cycle-dependent increase in extracellular Ado correlating with increases in the cytoplasmic pool of IkappaBalpha/SUMO-1. We demonstrate a dose-dependent increase in IkappaBalpha/SUMO in cells treated with the general Ado receptor agonist NECA and abolished by Ado receptor antagonists. Experiments in cells exposed to cycles of H/R followed by hypoxia demonstrated differential patterns of SUMOylation and phosphorylation of IkappaBalpha, greatly impacting its proteosomal degradation by the 26 S proteasome. Assays targeting knockdown and overexpression of SUMO-1 demonstrated significant regulation of NFkappaB activation and NFkappaB-mediated gene transcription (interleukin-6). These results were confirmed in vivo using wild type and cd73 null mouse lung tissue. In summary, we present an endogenous mechanism by which cells and tissues acquire anti-inflammatory properties by recruiting a nondegradable form of IkappaBalpha, a major control point for NFkappaB activation via Ado signaling.

Topics: 5'-Nucleotidase; Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Cell Hypoxia; Gene Knockdown Techniques; HeLa Cells; Humans; Hypoxia; I-kappa B Proteins; Inflammation; Interleukin-6; Lung; Mice; Mice, Mutant Strains; NF-kappa B; NF-KappaB Inhibitor alpha; Pneumonia; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Purinergic P1 Receptor Agonists; Receptors, Purinergic P1; SUMO-1 Protein; Transcription, Genetic; Vasodilator Agents

We have recently demonstrated that adenosine controls the release of catecholamines (CA) from carotid body (CB) acting on A(2B) receptors. Here, we have investigated the hypothesis that this control is exerted via an interaction between adenosine A(2B) and dopamine D(2) receptors present in chemoreceptor cells and if it is, the location of this interaction on the CB hypoxic transduction cascade. Experiments were performed in vitro in CB from 3 months rats. The effect of adenosine A(2B) and dopamine D(2) receptor agonists applied alone or conjunctly, was studied on the basal and evoked release (10% O(2) and ionomycin) of CA from CB. We have observed that the inhibitory action of propylnorapomorphine, a D(2) selective agonist, on the normoxic and 10%O(2)-evoked release of CA was abolished by NECA, an A(2) agonist, meaning that an interaction between the D(2) and A(2B) receptors controls the release of CA from CB. Further, propylnorapomorphine inhibits the release of CA evoked by ionomycin, being this effect totally reversed by NECA. The present results provide direct pharmacological evidence that A(2B) and D(2) receptors interact to modulate the release of CA from rat CB between the steps of Ca(2+) entry and increase in intracellular free Ca(2+), and the activation of exocytosis and neurotransmitter release, of the stimulus-secretion coupling process.

Topics: Adenosine-5'-(N-ethylcarboxamide); Animals; Apomorphine; Carotid Body; Catecholamines; Dopamine Agonists; Female; Hypoxia; In Vitro Techniques; Ionomycin; Male; Rats; Rats, Wistar; Receptor, Adenosine A2B; Receptors, Dopamine D2; Signal Transduction

Because hypoxia increases extracellular adenosine levels and stimulates angiogenesis, we evaluated the relative roles of reduced oxygen concentrations and adenosine receptor activation in the production of angiogenic factors. In vitro, we analyzed the effects of hypoxia and adenosine on the secretion of angiogenic factors from human microvascular endothelial cells (HMEC-1). To study the effects of hypoxia alone, we scavenged adenosine from the hypoxic medium with adenosine deaminase, and we used the stable adenosine analog 5'-N-ethylcarboxamidoadenosine (NECA) to study the effects of stimulation of adenosine receptors. In the absence of adenosine, hypoxia stimulated vascular endothelial growth factor (VEGF) but not interleukin-8 (IL-8) secretion from HMEC-1. In contrast, NECA stimulated both VEGF and IL-8 secretion. VEGF secretion was increased 1.9 +/- 0.04-fold with NECA (10 microM) and 1.7 +/- 0.1-fold with hypoxia (5% O(2)) but 3.8 +/- 0.1-fold when these two stimuli were combined. Thus, adenosine receptors act in a cooperative fashion with hypoxia to stimulate VEGF and induce IL-8 secretion not stimulated by hypoxia alone. In vivo, antagonism of adenosine receptors with caffeine abrogated VEGF up-regulation induced by local injection of NECA into the mouse hind limb and produced a 46% reduction of neovascularization in a mouse ischemic hind limb model. Our study suggests that adenosine actions are not redundant but rather are complementary to the direct effects of hypoxia. Stimulation of adenosine receptors not only contributes to the overall effect of hypoxia but also has additional actions in the regulation of angiogenic factors. Thus, adenosine receptors represent a potential therapeutic target for regulation of neovascularization.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Cells, Cultured; Gene Expression Regulation; Hindlimb; Humans; Hypoxia; Interleukin-8; Ischemia; Male; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Receptors, Purinergic P1; RNA, Messenger; Vascular Endothelial Growth Factor A

Xanthine oxidoreductase (XOR) activity has been previously noted to be responsive to changes in O2 tension. While prior studies have focused on the extremes (0-3% and 95-100%) of O2 tensions, we report the influence of 10% O2 on endothelial cell XOR, a concentration resembling modest arterial hypoxia commonly found in patients with chronic cardiopulmonary diseases. Exposure of bovine aortic endothelial cells to 10% O2 increased XOR mRNA and protein abundance by 50%. Concomitantly, there was a 3-fold increase in XOR activity, XOR-dependent reactive oxygen species production, and cellular export of active enzyme. Although increases in mRNA and immunoreactive protein levels were observed, inhibition of transcription, translation, or protein degradation did not significantly alter cellular XOR specific activity, suggesting only modest contributions to 10% O2-induced effects. Exposure to 10% O2 did not increase cellular HIF-1alpha protein levels and hypoxia mimics did not alter XOR activity. Treatment of control cells with adenosine resulted in increased XOR activity similar to hypoxia. Exposure to the adenosine receptor agonist NECA increased enzymatic activity 4-fold while 8SPT, an adenosine receptor antagonist, reduced hypoxic induction of XOR activity approximately 50%. Combined, these data reveal that moderate hypoxia significantly enhances endothelial XOR specific activity, release, and XOR-derived reactive oxygen species generation. These effects appear to be mediated in part via adenosine-dependent processes.

Topics: Adenine; Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Aorta; Cattle; Endothelium, Vascular; Enzyme Induction; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Oxygen; Purinergic P1 Receptor Antagonists; Reactive Oxygen Species; Xanthine Oxidase

Hypoxia or anemia is the fundamental stimulus for erythropoietin (EPO) production. Recent in vitro studies suggest that EPO secretion in response to hypoxia is regulated by adenosine in the kidney. In order to examine the in vivo effect of adenosine on EPO production, we determined the effects of adenosine receptor agonists and antagonists on serum EPO concentration in normal and anemic rats. In normal rats, intravenous injection of adenosine agonists (NECA, CHA and CGS-21680) dose-dependently stimulated EPO production. Pretreatment with KW-3902, an adenosine A1 antagonist with modest A2b antagonistic action, or KF17837, an adenosine A2a antagonist, inhibited the NECA (0.1 mg/kg, i.v.)-stimulated EPO production. Anemic hypoxia, induced by 2% (v/w body weight) blood withdrawal, increased serum EPO concentration from 38 +/- 2 to 352 +/- 76 mU/ml, with the increased serum adenosine concentration in the renal vein. KF17837 (0.1 mg/kg, i.v.), but not KW-3902 (0.1 mg/kg, i.v.), inhibited the anemic hypoxia-induced increase in EPO production. The present findings support the notion that adenosine mediates the EPO production in response to hypoxia in the kidney.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Analysis of Variance; Anemia; Animals; Erythropoietin; Hematocrit; Hypoxia; Kinetics; Male; Nephrectomy; Phenethylamines; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Rats; Rats, Wistar; Time Factors; Xanthines

1. The effects of adenosine receptor agonists were examined on isolated rings of guinea-pig pulmonary artery under normoxic and hypoxic conditions. The rings were denuded of endothelium and tissues were precontracted with phenylephrine (3 x 10(-6) M) before constructing cumulative concentration-response curves to the agonists. 2. 5'-(N-ethylcarboxamido)adenosine (NECA) caused concentration-dependent contractions of the pulmonary artery which were not different between hypoxia and normoxia. The contractions were converted to a relaxation in the presence of the cyclooxygenase inhibitor, indomethacin, and again these were unaffected by hypoxia. 3. Examination of a range of agonists under normoxic conditions in the presence of indomethacin revealed relaxations, except for the A2a receptor-selective agonist, CGS 21680. The vasorelaxation was therefore A2b receptor-mediated. 4. In hypoxia, however, in the presence of indomethacin, vasoconstriction occurred to R(-)-N(6)-(2-phenylisopropyl)adenosine (R-PIA) and, to a greater extent, to Nb-cyclopentyladenosine (CPA). In the absence of indomethacin, the constriction by CPA during hypoxia was significantly greater. 5. The indomethacin-resistant contraction by CPA was abolished by the A1 receptor antagonist, 8-cyclopentyltheophylline (CPT, 3 x 10(-6) M). 6. This study has demonstrated cyclooxygenase-dependent and-independent vasoconstrictions to adenosine agonists in guinea-pig pulmonary artery under hypoxic conditions. The cyclooxygenase-independent contraction is mediated via A1 receptors. 7. These results suggest that endogenous adenosine released in the pulmonary circulation under hypoxic conditions will cause vasoconstriction and may contribute to the pulmonary hypertension associated with acute respiratory failure.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Guinea Pigs; Hypoxia; In Vitro Techniques; Indomethacin; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Phenethylamines; Phenylisopropyladenosine; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Receptors, Purinergic P1; Theophylline; Vasoconstriction; Vasodilation

Adenosine mediates vascular smooth muscle relaxation in the pulmonary circulation. The A2 receptor has been suggested to mediate adenosine-induced vasodilation (AIV). In this study, the effect(s) of selective adenosine agonist and antagonist on the hypoxic pressor response (HPR) was assessed in the isolated blood-perfused rat lung. Adenosine (0.075-7.5 mM) infusion (0.125 ml/min) into the pulmonary artery dose dependently attenuated the HPR. AIV was mimicked by 10 microM 5'-(N-ethylcarboxamido)adenosine (NECA), a nonselective adenosine agonist. Adenosine- and NECA-induced vasodilation were attenuated by 67 microM 8-(p-sulfophenyl)theophylline. In contrast, NECA-induced vasodilation was not attenuated by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (1 microM). At 10 microM, a minimal vasodilatory effect was seen with the nonselective adenosine agonists CV-1808 and N6-(2-phenylisopropyl)adenosine (R-PIA) compared with NECA. The highly selective A2a agonist 2-[p-(2-carboxyethyl)phenyl amino]-5'-N-ethyl carboxamido adenosine (CGS-21680C, 10 microM) and A1 agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 10 microM) had no vasodilatory effect. Neither the K+ channel blockers tetraethylammonium chloride (10 mM) and glibenclamide (100 microM) nor the NO synthase inhibitor N omega-nitro-L-arginine methyl ester attenuated NECA-induced vasodilation. These findings suggest that AIV is mediated via the A2b receptor and that AIV occurs via an NO-independent mechanism.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Arginine; Blood Pressure; Hypoxia; In Vitro Techniques; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Potassium Channels; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Vasodilation; Vasodilator Agents; Xanthines

The present studies were undertaken to assess the effects of 5'-N-ethylcarboxamideadenosine (NECA), an adenosine analogue, on erythropoietin (Epo) production. NECA (0.05 and 0.1 mumol/kg i.v.) produced significant increases in serum Epo levels (368.8 +/- 56.1 and 384.6 +/- 45.9 mU/ml, respectively) in exhypoxic polycythemic mice after a four hour exposure to hypoxia when compared with hypoxia controls (133.2 +/- 18.2 mU/ml). The hypoxic kidney Epo levels were 46.4 +/- 13.4 mU/kg kidney which were significantly higher than normoxic kidney Ep levels (< 1.24 mU/kg kidney). Theophylline (20 mg/kg i.p.), an adenosine receptor antagonist, significantly inhibited the stimulatory effects of NECA on serum Epo levels. In vitro cultures of an Epo producing hepatocellular carcinoma (Hep3B) cell line with NECA (> or = 10(-6) M) for 20 hours under hypoxic conditions (1% O2) produced significant increases in medium levels of Epo when compared with hypoxia controls. Hepatocellular carcinoma cells treated with NECA at a concentration range of 10(-7) M to 5 x 10(-5) M for one hour in a hypoxic atmosphere also had significantly higher cAMP levels than that of hypoxia controls. Scatchard analyses of [3H]NECA binding to membrane preparations of hepatocellular carcinoma cells showed low affinity binding sites with a dissociation-constant (Kd) of 0.44 microM and a binding capacity of 863 fmol/mg protein. These findings suggest that the increase in Epo production in response to NECA under hypoxic conditions can be attributed, at least in part, to stimulation of adenosine A2 receptors which is coupled to adenylyl cyclase activation.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Carcinoma, Hepatocellular; Dose-Response Relationship, Drug; Erythropoietin; Female; Hypoxia; Liver Neoplasms; Mice; Mice, Inbred Strains; Osmolar Concentration; Polycythemia; Theophylline; Tumor Cells, Cultured

This study characterized in rhesus monkeys the effects of selected adenosine agonists on ventilation during normal atmospheric conditions and during conditions of hypercapnia, hypoxia and hyperoxia. In seated, unanesthetized monkeys prepared with a head plethysmograph, ventilation during exposure to air, CO2 (3, 4 and 5%) mixed in air (hypercapnia), 10% O2 mixed in N2 (hypoxia) and 100% O2 (hyperoxia) was measured during cumulative dosing with each drug. The nonselective (A1/A2) agonist, 5'-N-ethylcarboxamidadenosine (NECA), the peripherally active, A2-selective agonist, CGS 21680 [2-(carboxyethylphenylamino)adenosine-5'-carboxamide], and the A1-selective agonists, N6-cyclohexyladenosine and N6-cyclopentyladenosine, increased respiratory frequency (f), but had no significant effect on minute volume (VE) during exposure to air. The relative potencies for increasing f corresponded closely with their potencies for binding at A2 receptors. NECA and CGS 21680 increased f in a dose-dependent manner during exposure to 3% CO2, but proportional increases in f were less pronounced as the concentration of CO2 increased. NECA and CGS 21680 also increased f during hypoxia, but neither had a significant effect on f during subsequent hyperoxia. The highest dose of CHA and CPA decreased f below control values during exposure to 5% CO2 and decreased f and VE during hyperoxia. In contrast, the adenosine antagonist, caffeine, and the selective phosphodiesterase inhibitor, rolipram, increased f and VE under all conditions. During hypercapnia, the magnitude of the increases in f was similar at each concentration of CO2 studied. Caffeine and rolipram increased f and VE during hypoxia, and f and VE remained elevated during hyperoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Caffeine; Carbon Dioxide; Female; Hypercapnia; Hypoxia; Macaca mulatta; Male; Oxygen; Phenethylamines; Plethysmography; Pyrrolidinones; Receptors, Purinergic; Respiration; Respiratory Function Tests; Rolipram

Erythropoietin (EPO) is mainly produced in the kidneys and is regulated by blood oxygen availability. Studies with isolated perfused kidneys have established that an oxygen-sensing system exists intrarenally but the mechanisms involved are poorly understood. Using a quantitative RNase protection assay, we have demonstrated oxygen-dependent EPO mRNA production in isolated perfused rat kidneys, with EPO mRNA levels increasing 30-fold when perfusate pO2 was reduced from 474 to 25 mm Hg. To determine if the high amplitude changes in EPO mRNA levels in response to hypoxia are mediated by cyclic AMP, four agents, which activate the cyclic AMP system in different ways, were administered to isolated kidneys perfused over a range of perfusate pO2. Salbutamol and N6-ethyl carboxamidoadenosine, which activate adenylate cyclase, dibutyryl cyclic AMP (a cyclic AMP analogue) and forskolin did not augment EPO mRNA production, and no significant differences in the regression of log (EPO mRNA) on perfusate pO2, were found between experimental groups exposed to each of these compounds and controls. We conclude that the rapid increase in EPO mRNA levels in response to hypoxia is not mediated or substantially modulated by a cyclic AMP-dependent mechanism.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Albuterol; Animals; Bucladesine; Colforsin; Cyclic AMP; Erythropoietin; Hypoxia; In Vitro Techniques; Kidney; Male; Oxygen; Perfusion; Rats; Rats, Inbred Strains; RNA, Messenger

The high pressure muscular pulmonary circulation of chronically hypoxic (CH) rats was compared with the low pressure circuit in control (C) rats; differences were found in the effects of lung inflation, in pressure/flow relations during lung inflation, in reactivity to autocoids, and in responses to pulmonary dilator drugs. Isolated blood-perfused lungs of CH rats (2 to 3 wk in 10% O2) were compared with those of C rats kept in air. High inflation (alveolar) pressure (Palv) caused a rise in pulmonary artery pressure (Ppa) close to delta Palv in both groups; in CH rats, Ppa continued to rise, whereas it adapted to a lower level in C rats. Pressure-flow (P/Q) lines were measured at high and low Palv, all in Zone 2 state. In normoxia, high Palv caused a parallel shift in the P/Q line close to delta Palv in both C and CH rats. However, during hypoxic pulmonary vasoconstriction (HPV), high Palv caused a shift in the P/Q line less than delta Palv in C rats and greater than delta Palv in CH rats. Similar differences between C and CH rats were seen during constriction caused by almitrine, a drug that simulates HPV. Thus, these stimuli affect vessels that are functionally "extra-alveolar" in C rats but functionally "alveolar" in CH rats. We consider whether vasoconstriction by hypoxia and almitrine moves peripherally to the newly muscularized alveolar arterioles that are found in CH rats. Reactivity of lung vessels to bradykinin, angiotensin-1, and platelet-activating factor was greater in CH than in C rats, possibly also associated with muscularization of arterioles in the former.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Almitrine; Angiotensin I; Animals; Bradykinin; Chronic Disease; Hypoxia; Male; Platelet Activating Factor; Pulmonary Circulation; Pyrazines; Rats; Rats, Inbred Strains; Reference Values; Respiration; Vasoconstriction; Vasodilator Agents; Vasomotor System

The effects of adenosine (ADE) and ADE agonists on erythropoietin (Ep) production were determined using percent (%) 59Fe incorporation in red cells of exhypoxic polycythemic mice. The hemisulfate salt of ADE produced a significant increase in % 59Fe incorporation in response to hypoxia in concentrations of 400 to 1600 nmol/kg/day (i.v.). 5'-N-ethyl-carboxamideadenosine (NECA), a selective A2 receptor agonist, increased radioiron incorporation in a dose-dependent manner (10-100 nmol/kg/day, i.v.). In contrast, N6-cyclohexyladenosine (CHA), a selective A1 receptor agonist, did not affect radioiron incorporation in concentrations up to 1600 nmol/kg/day (i.v.). Albuterol, a beta 2-adrenergic agonist, enhanced % 59Fe incorporation in polycythemic mice and low doses of CHA (50 and 100 nmol/kg/day), which were not effective alone on % 59Fe incorporation in polycythemic mice exposed to hypoxia, inhibited the enhancement in radioiron induced by albuterol (25 and 100 micrograms/kg/day, i.p.) plus hypoxia. Theophylline (20 and 80 mg/kg/day, i.p.), a well-known antagonist of ADE receptors, blocked the ADE and NECA enhancement in radioiron incorporation at a dose of theophylline alone which produced only a slight enhancement of % 59Fe incorporation. These results suggest that ADE may both inhibit through A1 receptor activation and increase via A2 receptor stimulation the production of Ep.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Albuterol; Animals; Erythrocytes; Erythropoietin; Female; Hypoxia; Iron Radioisotopes; Mice; Mice, Inbred ICR; Polycythemia; Receptors, Purinergic; Theophylline