Interstitial Adenosine Levels Research Articles

Pentostatin-augmented interstitial adenosine prevents postcardioplegia injury in damaged hearts

This study tests the hypothesis that the adenosine deaminase inhibitor pentostatin (2-deoxycoformycin), when given before ischemia or during infusions of blood cardioplegia, augments interstitial adenosine levels and prevents postcardioplegia dysfunction in hearts with antecedent ischemia. Twenty-one anesthetized dogs were placed on cardiopulmonary bypass, and the hearts were made globally ischemic for 30 minutes. Dogs received blood cardioplegia with no pentostatin (BCP group, n = 6), pretreatment pentostatin (0.2 mg/kg) infused 5 minutes before global ischemia (PS-PTx group, n = 7), or pentostatin included only in the blood cardioplegia without pretreatment (PS-BCP group, n = 8). Microdialysate myocardial adenosine levels (an index of interstitial fluid levels) increased only modestly in the BCP group (from 0.55 ± 0.13 μM to 2.64 ± 0.50 μM) and the PS-BCP group (from 0.55 ± 0.18 μM to 1.08 ± 0.48 μM) during normothermic ischemia, but interstitial adenosine levels were not augmented further during cardioplegic arrest in either group. In contrast, the adenosine level in the PS-PTx group was significantly ( p < 0.05) augmented during global ischemia (from 0.50 ± 0.13 μM to 63.16 ± 28.08 μM) and cardioplegia infusion (to 15.26 μM ± 5.61 μM). Relative to baseline, postischemic left ventricular performance (end-systolic pressure-volume relation) was depressed in both the BCP (from 5.5 ± 1.2 mm Hg/mL to 3.8 ± 0.4 mm Hg/mL) and PS-BCP groups (from 7.1 ± 0.9 mm Hg/mL to 3.8 ± 0.7 mm Hg/mL). In contrast, PS-PTx restored postischemic performance (from 6.2 ± 0.5 mm Hg/mL to 7.5 ± 0.9 mm Hg/mL). Similar preservation of postischemic function in the PS-PTx group was observed with preload recruitable stroke work. There were no group differences in postischemic diastolic stiffness. Myocardial myeloperoxidase activity (an index of neulrophil accumulation) was significantly less in the PS-PTx group (0.39 ± 0.07 U/g of tissue) than in the BCP (0.65 ± 0.09 U/g of tissue) and PS-BCP groups (0.67 ± 0.12 U/g of tissue). We conclude that pentostatin used as a pretreatment before cardioplegia augments endogenous adenosine levels, reduces postischemic dysfunction, and inhibits neutrophil accumulation in ischemically injured canine hearts.

The role of adenosine in extended myocardial preservation with the University of Wisconsin solution

The purpose of this study was to determine the role that adenosine plays in enhanced myocardial preservation during cold storage with the University of Wisconsin solution. Hearts from adult rabbits were flushed with University of Wisconsin solution with or without adenosine and stored at 4 degrees C for 24 hours. Interstitial fluid purine levels during the period of cold storage were estimated with cardiac microdialysis probes. In a second series of experiments hearts were flushed with University of Wisconsin solution with or without adenosine or St. Thomas' Hospital cardioplegic solution and stored for 18 hours (4 degrees C). Functional recovery was assessed by reperfusing the hearts on a Langendorff apparatus (100 cm H2O) for 45 minutes with Krebs-Henseleit buffer. During cold storage dialysate adenosine concentrations in hearts flushed with University of Wisconsin solution were 20- to 40-fold greater than adenosine levels in hearts flushed without adenosine. After 45 minutes of reperfusion hearts preserved with University of Wisconsin solution exhibited a rate-pressure product of 11,098 +/- 576 mm Hg/min, significantly greater than that for hearts flushed with University of Wisconsin solution minus adenosine (8106 +/- 780 mm Hg/min) and St. Thomas' Hospital solution (7317 +/- 768 mm Hg/min). These results suggest that adenosine plays a major role in enhanced myocardial preservation with the University of Wisconsin solution, possibly by maintaining elevated interstitial fluid adenosine levels during the period of cold storage.

3-Isobutyl-1-Methylxanthine decreases renal cortical interstitial levels of adenosine and inosine

The purpose of this study was to test the hypothesis that endogenous cyclic AMP, via metabolism by phosphodiesterase, contributes to interstitial levels of adenosine in the renal cortex in vivo. This hypothesis was tested by determining the effects of 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, on renal cortical interstitial levels of adenosine and inosine. Changes in renal cortical interstitial adenosine and inosine levels were assessed in rats by implanting microdialysis probes into the renal cortex and measuring adenosine and inosine levels in the dialysate exiting the kidney using high performance liquid chromatography. When added to the dialysate entering the kidney at concentrations of 0.5, 1 and 2.5 mM, 3-isobutyl-1-methylxanthine significantly and dose-dependently decreased interstitial levels of both adenosine and inosine. The percentage changes from baseline of interstitial levels of adenosine and inosine were: −39 ± 6% and −19 ± 6%, respectively, with 0.5 mM 3-isobutyl-1-methylxanthine; −45 ± 7 % and −24 ± 8 %, respectively, with 1 mM 3-isobutyl-1-methylxanthine; and −56 ± 12 % and −38 ± 8 %, respectively, with 2.5 mM 3-isobutyl-1-methylxanthine. These data suggest that in the renal cortex, cyclic AMP metabolism via phosphodiesterase is an important source of renal interstitial adenosine.

Myocardial adenosine formation during hypoxia: Effects of ecto-5′-nucleotidase inhibition

Release of adenosine and AMP into epicardial fluid and coronary venous effluent of isovolumic guinea-pig hearts was examined during normoxic (95% O 2) and hypoxic (30% O 2) perfusion with and without the ecto-5′-nucleotidase inhibitor α,β-methylene adenosine diphosphate (AOPCP) ∗ ∗ Abbreviations: AOPCP is α,β-methylene-adenosine diphosphate. . Normoxic epicardial and venous adenosine levels were 221 ± 27 and 67 ± 11 n m, respectively, in untreated hearts. During 15 min of hypoxia, epicardial and venous adenosine levels increased in a phasic manner, reaching maximal values of 498 ± 32 and 441 ± 43 n m, respectively, during the initial 5 min of hypoxia. Epicardial and venous adenosine levels then declined slightly during the subsequent 10 min to 332 ± 33 and 224 ± 34 n m, respectively. Infusion of 50 μ m AOPCP significantly reduced venous adenosine levels during normoxia (< 50% of control), but was without effect on normoxic epicardial adenosine. Epicardial and venous adenosine levels increased during hypoxia with AOPCP but the increases were lower than those for untreated hypoxic hearts. Epicardial and venous adenosine levels recovered to baseline levels following 30 min of reoxygenation in both groups. Epicardial and venous AMP levels were elevated by AOPCP treatment during normoxia and hypoxia. Coronary vascular resistance decreased during hypoxia but the decline in resistance was less in AOPCP treated hearts. It is concluded that whereas basal interstitial adenosine levels appear to be independent of ecto-5′-nucleotidase activity, the hypoxic increase in interstitial adenosine is partially derived from an AOPCP sensitive ecto-5′-nucleotidase. Venous adenosine appears to be significantly dependent on ecto-5′-nucleotidase activity during normoxia and hypoxia. The data are also consistent with a role for endogenous adenosine in regulating coronary vascular resistance during hypoxia.

Adenosine receptor blockade enhances isoproterenol-induced increases in cardiac interstitial adenosine

The failure of adenosine receptor antagonists to consistently attenuate metabolic coronary vasodilation suggests that adenosine is not a primary regulator of functional hyperemia. An alternative hypothesis, however, is that metabolic stimulation of the heart in the presence of an adenosine receptor antagonist results in enhanced interstitial levels of adenosine which then might overcome the blockade. To test this hypothesis, interstitial levels of adenosine and inosine were estimated by HPLC analysis of fluid which exudes from the epicardial surface of isolated rat hearts perfused with crystalloid solution at constant flow. Isoproterenol infusion (10 n m) produced increases in heart rate, left ventricular systolic pressure, rate of pressure development, myocardial oxygen consumption and adenosine and inosine concentrations of venous effluent and surface exudate and produced decreases in coronary vascular resistance. The presence of the adenosine receptor antagonist, 8-(4-sulfophenyl) theophylline (spT) (100μ m), in the perfusate had little or no effect upon most of the responses to isoproterenol except that it significantly enhanced the isoproterenol-induced increases in adenosine release and adenosine concentrations in the venous effluent and surface exudate. The isoproterenol-induced change in adenosine concentration per unit change in oxygen consumption was approximately 3-fold greater in the presence of spT than in its absence. This extra adenosine production may tend to overcome the competitive blocking effect of spT and help explain why agents such as spT are not always effective in blocking metabolic vasodilation.

Cardiovascular purinoceptors

Cardiovascular purinoceptors

Myocardial interstitial and coronary venous effluent adenosine levels during severe expoxia in the developing rabbit

Myocardial interstitial and coronary venous effluent adenosine levels during severe expoxia in the developing rabbit

Effects of deoxycoformycin on adenosine, inosine, hypoxanthine, xanthine, and uric acid release from the hypoxemic rat cerebral cortex.

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.

Ethanol-induced increase in portal blood flow: role of adenosine.

The mechanism by which ethanol induces an increase in portal vein blood flow was studied in rats using radiolabeled microspheres. Ethanol (2 g/kg) by gavage resulted in an increase of 50-70% in portal vein blood flow. The ethanol-induced increase in portal blood flow was suppressed by the adenosine receptor blocker 8-phenyltheophylline [ethanol, 61.8 +/- 4.1 ml.kg-1.min-1; ethanol + 8-phenyltheophylline (0.2 mg.kg-1.min-1), 44.2 +/- 2.0 ml.kg-1.min-1; P less than 0.05]. By itself, 8-phenyltheophylline (0.2 mg.kg-1.min-1) was without effect on cardiac output or portal blood flow. Adenosine infusion resulted in a dose-dependent increase in portal blood flow with a maximal effect at a dose of 0.17 mg.kg-1.min-1 (control, 41.3 +/- 2.3; adenosine, 81.7 +/- 8.0 ml.kg-1.min-1; P less than 0.05). This adenosine-induced increase in portal blood flow was inhibited by 8-phenyltheophylline in a dose-dependent manner [adenosine, 81.7 +/- 8.0 ml.kg-1.min-1; adenosine + 8-phenyltheophylline (0.2 mg.kg-1.min-1), 49.8 +/- 6.6 ml.kg-1.min; P less than 0.05]. Both alcohol and adenosine significantly reduced preportal vascular resistance by 40% (P less than 0.02) and 60% (P less than 0.01), respectively. These effects were fully suppressed by 8-phenyltheophylline. It is concluded that adenosine is a likely candidate to mediate the ethanol-induced increase in portal vein blood flow. It is suggested that an increase in circulating acetate and liver hypoxia may mediate the effects of alcohol by increasing tissue and interstitial adenosine levels.

Effects of dipyridamole on myocardial adenosine and active hyperemia.

Dipyridamole, a vasodilator that potentiates the actions of exogenous adenosine, is known to inhibit cellular uptake of adenosine, but its effects on cellular adenosine release, and thus interstitial adenosine levels, are disputed. We used the accumulation of adenosine in pericardial infusates (PCI) as an index of interstitial adenosine concentration and observed the effects of dipyridamole on relationships among coronary blood flow (CBF), myocardial oxygen consumption (MVO2), and PCI adenosine concentrations during steady-state alterations of cardiac work. Dipyridamole increased CBF and PCI adenosine concentration without altering MVO2. The relationship between PCI adenosine and CBF was unaltered, supporting a cause and effect relationship between interstitial adenosine concentration and CBF. In addition, we determined that unlike previous studies in isolated perfused hearts the washout of adenosine by coronary plasma was unaffected by dipyridamole. The results support previous suggestions that, whereas dipyridamole inhibits adenosine uptake, it does not alter cellular adenosine release, and therefore interstitial adenosine levels are increased. The constant relationship between PCI adenosine and CBF supports hypotheses that attribute the hyperemias associated with increased cardiac work or with dipyridamole to increased interstitial adenosine.

Effect of aminophylline on adenosine and exercise dilation of rat cremaster arterioles.

The present study was undertaken to evaluate the role that adenosine may play in exercise vasodilation. Responses of rat cremaster muscle arterioles to either topically applied adenosine or muscle exercise were recorded via video-microscopy before and after topical administration of aminophylline (10(-4) M). In all experiments, alpha-adrenergic receptors were blocked by pretreatment with phentolamine. Under control conditions the average concentration of adenosine required to produce a 50% dilation response (ED50) was 1.9 X 10(-6) M, and the full dose-response curve spanned 2 log units from threshold to near maximum responses. Topical aminophylline increased the ED50 for adenosine dilation to 9.1 X 10(-6) M. Stepwise increases in muscle twitch rate produced a progressive arteriolar dilation, and the dilation associated with 2-Hz exercise approached the maximal dilation observed with adenosine. Topical aminophylline, however, had no effect on the arteriolar dilation response to cremaster muscle exercise. It is unlikely that our results can be explained by any influence that exercise might have on the arteriolar sensitivity to adenosine or on the efficacy of aminophylline blockade because aminophylline had no effect on the arteriolar response to even the lowest rates of exercise tested. We conclude either that adenosine does not mediate exercise dilation in rat cremaster muscle or that interstitial adenosine levels during exercise in the presence of 10(-4) M aminophylline are significantly higher (5X) than during exercise without aminophylline.

Reduction by adenosine of the isoproterenol-induced increase in cyclic adenosine 3',5'-monophosphate formation and glycogen phosphorylase activity in rat heart muscle.

HomeCirculation ResearchVol. 43, No. 5Reduction by adenosine of the isoproterenol-induced increase in cyclic adenosine 3',5'-monophosphate formation and glycogen phosphorylase activity in rat heart muscle. Free AccessAbstractPDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessAbstractPDF/EPUBReduction by adenosine of the isoproterenol-induced increase in cyclic adenosine 3',5'-monophosphate formation and glycogen phosphorylase activity in rat heart muscle. J G DobsonJr J G DobsonJrJ G DobsonJr Search for more papers by this author Originally published1 Nov 1978https://doi.org/10.1161/01.RES.43.5.785Circulation Research. 1978;43:785–792 Previous Back to top Next FiguresReferencesRelatedDetailsCited ByGupta R, Neumann J, Durant P and Watanabe A (1993) A1-adenosine receptor-mediated inhibition of isoproterenol-stimulated protein phosphorylation in ventricular myocytes. Evidence against a cAMP-dependent effect., Circulation Research, 72:1, (65-74), Online publication date: 1-Jan-1993.Fenton R and Dobson J (1993) Hypoxia enhances isoproterenol-induced increase in heart interstitial adenosine, depressing beta-adrenergic contractile responses., Circulation Research, 72:3, (571-578), Online publication date: 1-Mar-1993.Xu D, Kong H and Liang B (1992) Expression and pharmacological characterization of a stimulatory subtype of adenosine receptor in fetal chick ventricular myocytes., Circulation Research, 70:1, (56-65), Online publication date: 1-Jan-1992.Liang B and Donovan L (1990) Differential desensitization of A1 adenosine receptor-mediated inhibition of cardiac myocyte contractility and adenylate cyclase activity. Relation to the regulation of receptor affinity and density., Circulation Research, 67:2, (406-414), Online publication date: 1-Aug-1990.Fenton R, Tsimikas S and Dobson J (1990) Influence of beta-adrenergic stimulation and contraction frequency on rat heart interstitial adenosine., Circulation Research, 66:2, (457-468), Online publication date: 1-Feb-1990.Dobson J, Fenton R and Romano F (1990) Increased myocardial adenosine production and reduction of beta-adrenergic contractile response in aged hearts., Circulation Research, 66:5, (1381-1390), Online publication date: 1-May-1990.Scamps F, Legssyer A, Mayoux E and Vassort G (1990) The mechanism of positive inotropy induced by adenosine triphosphate in rat heart., Circulation Research, 67:4, (1007-1016), Online publication date: 1-Oct-1990.Kato M, Yamaguchi H and Ochi R (1990) Mechanism of adenosine-induced inhibition of calcium current in guinea pig ventricular cells., Circulation Research, 67:5, (1134-1141), Online publication date: 1-Nov-1990.Böhm M, Pieske B, Ungerer M and Erdmann E (1989) Characterization of A1 adenosine receptors in atrial and ventricular myocardium from diseased human hearts., Circulation Research, 65:5, (1201-1211), Online publication date: 1-Nov-1989.Deussen A, Borst M and Schrader J (1988) Formation of S-adenosylhomocysteine in the heart. I: An index of free intracellular adenosine., Circulation Research, 63:1, (240-249), Online publication date: 1-Jul-1988.Fenton R and Dobson J (1987) Measurement by fluorescence of interstitial adenosine levels in normoxic, hypoxic, and ischemic perfused rat hearts., Circulation Research, 60:2, (177-184), Online publication date: 1-Feb-1987.Clemo H and Belardinelli L (1986) Effect of adenosine on atrioventricular conduction. I: Site and characterization of adenosine action in the guinea pig atrioventricular node., Circulation Research, 59:4, (427-436), Online publication date: 1-Oct-1986.Linden J, Hollen C and Patel A (1985) The mechanism by which adenosine and cholinergic agents reduce contractility in rat myocardium. Correlation with cyclic adenosine monophosphate and receptor densities., Circulation Research, 56:5, (728-735), Online publication date: 1-May-1985.Linden J, Patel A and Sadek S (1985) [125I]Aminobenzyladenosine, a new radioligand with improved specific binding to adenosine receptors in heart., Circulation Research, 56:2, (279-284), Online publication date: 1-Feb-1985.Isenberg G and Belardinelli L (1984) Ionic basis for the antagonism between adenosine and isoproterenol on isolated mammalian ventricular myocytes., Circulation Research, 55:3, (309-325), Online publication date: 1-Sep-1984.Dobson J (1983) Mechanism of adenosine inhibition of catecholamine-induced responses in heart., Circulation Research, 52:2, (151-160), Online publication date: 1-Feb-1983.Belardinelli L and Isenberg G (1983) Actions of adenosine and isoproterenol on isolated mammalian ventricular myocytes., Circulation Research, 53:3, (287-297), Online publication date: 1-Sep-1983.Fiscus R and Mayer S (1982) Neural regulation of cyclic AMP, cyclic AMP-dependent protein kinase, and phosphorylase in bullfrog ventricular myocardium., Circulation Research, 51:5, (551-559), Online publication date: 1-Nov-1982.Baumann G, Schrader J and Gerlach E (1981) Inhibitory action of adenosine on histamine- and dopamine-stimulated cardiac contractility and adenylate cyclase in guinea pigs., Circulation Research, 48:2, (259-266), Online publication date: 1-Feb-1981. November 1, 1978Vol 43, Issue 5Article InformationMetrics Download: 56 Copyright © 1978 by American Heart Associationhttps://doi.org/10.1161/01.RES.43.5.785 Originally publishedNovember 1, 1978 PDF download

Effects of catecholamines, histamine, and nitroglycerin on flow, oxygen utilization, and adenosine production in the perfused guinea pig heart.

Effects of catecholamines, histamine, and nitroglycerin on flow, oxygen utilization, and adenosine production in the perfused guinea pig heart.