Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two isolated guinea pig hearts (H1, H2) were perfused in series in order to bioassay in the recipient heart (H2) the release of vasoactive metabolites. Due to an effective reoxygenation system transit time between H1 and H2 as only 20 sec. Hypoxic perfusion (30% O2) of H1 caused relaxation of the coronary vessels of H2, and this effect could be completely abolished by adenosine deaminase. Similar results were obtained when H1 was stimulated by isoproterenol while H2 was protected by propranolol. From our findings it is concluded that adenosine is the primary vasodilating substance released by the heart into the coronary circulation.
Basic Res Cardiol
PMID:Assessment of vasoactive metabolites released from the isolated guinea pig during heart hypoxia and beta-adrenergic stimulation. 626 27

The concentrations of adenosine and other metabolic factors are known to be altered in the effluent of hypoxic hearts, but the relative contribution of these factors in elevating coronary flow has not been clarified. Langendorff prepared guinea pig hearts were perfused at constant pressure and were made mildly hypoxic so that flow increased but oxygen consumption remained unchanged. When the effluent of these hearts was reoxygenated and pH corrected and directed to perfuse similarly prepared recipient (bioassay) hearts, flow remained unchanged in recipient hearts. However, when donor hearts were made severely hypoxic so that oxygen consumption decreased, and recipient hearts were perfused at constant flow, the PO2, pH corrected effluent produced a large vasodilation in recipient hearts. This response was greatly attenuated in the presence of excess adenosine deaminase but completely abolished by theophylline. Thus the apparent loss of adenine compounds into the effluent may account for vasodilation during severe hypoxia, but not during mild hypoxia, if effluent levels of these compounds truly reflect perivascular levels.
Basic Res Cardiol
PMID:Heart bioassay of effluent of isolated, perfused guinea pig hearts to examine the role of metabolites regulating coronary flow during hypoxia. 728 37

Eighteen anesthetized, instrumented beagles (both genders, 10.4 +/- 0.5 kg) were used to investigate the effects of administered adenosine (n = 6), erythro-9-(2-hydroxy, 3-nonyl)adenine (EHNA), a potent inhibitor of endogenous adenosine deaminase (n = 6), and saline (n = 6), on the incidence of ventricular arrhythmias caused by systemic hypoxia (5% O2, 95% N2, PaO2 = 21 +/- 3 mmHg). After dogs were instrumented and monitored variables were in the steady-state, the above compounds were infused continuously into the cannulated left anterior descending (LAD) coronary artery for three minutes before, and throughout a four-minute period of hypoxia. After approximately 4 min of hypoxia the rates of ventricular ectopy [(total beats-normal beats)/total beats x 100 = % ectopy] were 73 +/- 9%, 73 +/- 11%, and 35 +/- 8% for the three groups, respectively. The percent ectopy of the adenosine- and EHNA-treated dogs was significantly greater (p < 0.05) than that for the saline-treated controls. These findings suggest that adenosine contributes to the ventricular arrhythmias of experimental systemic hypoxia.
Basic Res Cardiol
PMID:Inhibition of adenosine deaminase and administration of adenosine increase hypoxia induced ventricular ectopy. 757 76

Recently, an inhibitor of adenosine deaminase, erythro-9-(2-hydroxyl-3-nonyl)adenine (EHNA), was shown to selectively block the activity of purified cGMP-stimulated phosphodiesterase (PDE) (cGS-PDE, or PDE2) in human and porcine heart [J. Mol. Cell. Cardiol. 24 (Suppl. V):102 (1992)]. Because cGS-PDE was found to mediate the cGMP-induced inhibition of L-type Ca2+ current (Ica) in frog ventricular cells, we tested the effects of EHNA in this preparation. Ica was measured using the whole-cell patch-clamp technique and a perfusing pipette. EHNA (0.3-30 microM) had no significant effect on either basal Ica or isoprenaline (1 nM)- or cAMP (10 microM)-elevated Ica. However, EHNA dose-dependently (IC50 approximately 3 microM) reversed the inhibitory effect of cGMP on cAMP-stimulated Ica. EHNA (30 microM) also blocked the inhibitory effect of NO donors, such as sodium nitroprusside (1 mM) and 3-morpholinosydnonimine (30 microM), on isoprenaline-stimulated Ica. In addition, EHNA dose-dependently (IC50 approximately 4-5 microM) inhibited the cGMP-induced stimulation of PDE activity in frog ventricle particulate fraction, as well as purified soluble cGS-PDE. However, EHNA (up to 30 microM) did not modify the activities of three other purified soluble PDE isoforms. Moreover, EHNA did not change the Ka (40 nM) for cGMP activation of cGS-PDE, which suggests that EHNA does not inhibit cGS-PDE by displacing cGMP from the allosteric regulator site. Because adenosine did not mimic the effects of EHNA on Ica or PDE activity, it is unlikely that the effects of EHNA are due to adenosine deaminase inhibition. We conclude that EHNA acts primarily to inhibit cGS-PDE in intact cardiac myocytes. This compound should be useful in evaluating the physiological role of cGS-PDE in various tissues.
 ...
PMID:Erythro-9-(2-hydroxy-3-nonyl)adenine inhibits cyclic GMP-stimulated phosphodiesterase in isolated cardiac myocytes. 762 66

Pentostatin (2-deoxycoformycin) is a potent inhibitor of adenosine deaminase and has been demonstrated to augment endogenous adenosine levels during regional and global myocardial ischemia. Based on the rationale that increasing endogenous adenosine during ischemia may be cardioprotective, the objective of this study was to determine if adenosine deaminase inhibition with pentostatin could improve postischemic contractile dysfunction (stunning) in open-chest anesthetized dogs. All animals underwent 15 min of coronary occlusion followed by 3 h of reperfusion preceded by an intravenous bolus of either 0.2 mg/kg of pentostatin (n = 8) or saline (n = 7). Sonomicrometers were placed in the ischemic area and were used to measure systolic wall thickening before, during, and after occlusion of the left anterior descending artery. Myocardial blood flow was measured with tracer labeled microspheres at baseline, 10 min of occlusion and at 1 h of reperfusion. Both groups were equally dyskinetic during occlusion (-21 +/- 5% of baseline thickening in the controls and -28 +/- 8% in the pentostatin group). The pentostatin group, however, demonstrated better contractile function at all time points during reperfusion, which was significantly different from the control group at 3 h of reperfusion. The improvement in regional function in the pentostatin group was not due to significant disparities in hemodynamic variables, size of the region at risk, or in collateral blood flow. These results indicate that pentostatin can ameliorate the severity of myocardial stunning, an effect we propose is due to increasing endogenous levels of adenosine during the ischemic interval. Although significant improvement was detected with pentostatin, the improvement was modest compared to controls, suggesting that the utility of inhibiting adenosine deaminase to modify regional mechanical stunning is limited.
Basic Res Cardiol
PMID:Effect of adenosine deaminase inhibition with pentostatin on myocardial stunning in dogs. 764 20

Conventional inhibitors of cyclic AMP-dependent protein kinase lack membrane-permeability or selectivity, or both. The Rp diastereomer of adenosine cyclic 3',5'-phosphorothioate, Rp-cAMPS, is a novel membrane-permeable antagonist of cyclic AMP. We have assessed the ability of this compound to distinguish between cyclic AMP-dependent and cyclic AMP-independent contractile responses elicited in ventricular cardiomyocytes isolated from the hearts of adult rats. Cardiomyocytes were stimulated to contract at 0.5 Hz in the presence of calcium ion (2 mM) and adenosine deaminase (5 units/ml). Contractile shortening was expressed as maximum shortening relative to prestimulus cell length (delta L%). In the presence of a maximally-effective concentration of isoprenaline (100 nM), which acts by a cyclic AMP-dependent mechanism, Rp-cAMPS inhibited the contractile response in a concentration-dependent and time-dependent manner. Following preincubation for 30 min with Rp-cAMPS (100 microM), the contractile response to isoprenaline (100 nM) was 14% of that elicited in the absence of this inhibitor. An incubation time of 30 min was chosen for all subsequent studies. Rp-cAMPS (< or = 200 microM) inhibited the contractile response to isoprenaline (100 nM) significantly and in a concentration-dependent manner, but failed to inhibit the contractile responses elicited by phenylephrine (2 microM) and calcium ion (7 mM) which act by cyclic AMP-independent mechanisms. In the presence of Rp-cAMPs (200 microM), the contractile response to isoprenaline (100 nM) was 24% of that in the absence of inhibitor. Rp-cAMPS was used subsequently to investigate the contractile-coupling mechanisms associated with some novel inotropic agents. Rp-cAMPS (< or = 200 microM) also inhibited the contractile responses to secretin (20 nM) and VIP (20 nM) significantly. In the presence of Rp-cAMPS (200 microM), the contractile response elicited by secretin (20 nM) was 19% of that in the absence of inhibitor, while that elicited by VIP (20 nM) was abolished completely. Rp-cAMPS (< or = 200 microM) failed to inhibit the contractile response elicited by CGRP (1 nM). In summary, Rp-cAMPS is a membrane-permeable, selective antagonist of cyclic AMP in ventricular cardiomyocytes and can be used, in conjunction with the bioassay of the intracellular accumulation of cyclic AMP, to distinguish between cyclic AMP-dependent and cyclic AMP-independent contractile coupling mechanisms in these cells.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Cardiol 1994 Nov
PMID:Use of the cyclic AMP antagonist, Rp-cAMPS, to distinguish between cyclic AMP-dependent and cyclic AMP-independent contractile responses in rat ventricular cardiomyocytes. 789 68

Evaluation of enzyme activities involved in nucleotide metabolism and adenosine production within different cell types can provide important information on their contribution to the overall metabolism of the heart. The following enzyme activities were determined: adenosine kinase (AK), adenosine deaminase (ADA), S-adenosylhomocysteine hydrolase (SAHH), purine nucleoside phosphorylase (PNP), AMP deaminase (AMPD), membrane 5'nucleotidase (M5'N), AMP specific (AC5'N) and IMP specific (IC5'N) cytosolic 5'nucleotidases in (1) rat heart (n = 5), (2) rat cardiomyocytes obtained by collagenase digestion (n = 5), (3) human heart (n = 6) obtained from explants or papillary muscles collected during heart transplantation or mitral valve replacement, and (4) human umbilical cord endothelial cells in primary culture (n = 4). In the human heart, activities (mumol/min/g wet weight) were as follows: AK (0.14 +/- 0.01), ADA (0.46 +/- 0.03), SAHH (0.001 +/- 0.0003), PNP (0.43 +/- 0.08), AMPD (0.41 +/- 0.05), M5'N (1.75 +/- 0.12), IC5'N (0.21 +/- 0.03) and AC5'N (0.11 +/- 0.02). These enzyme activities were lower than those determined in the rat heart with the exception of AC5'N and IC5'N which were equal. The most prominent difference observed was for AMPD and M5'N which were nine and five-fold more active in the rat heart. Rat cardiomyocyte enzyme activities were comparable to those measured in whole rat heart with the exception of ADA (six-fold lower) and PNP (16-fold lower). Endothelial cell activities were notably different from those in the human heart particularly in the case of SAHH (nine-fold higher) and PNP (16-fold higher).(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1994 Nov
PMID:Nucleotide and adenosine metabolism in different cell types of human and rat heart. 789 72

Tissue injury associated with myocardial ischemia is assumed to largely result from the toxic effects of active oxygen species generated by accumulated polymorphonuclear leukocytes (PMNs). Recent reports have indicated that adenosine can interfere with the PMN function in vitro. The potential of adenosine to influence PMN-mediated myocardial tissue injury was assessed using a model of ischemia-reperfusion injury developed in the isolated working guinea-pig heart perfused with homologous PMNs. After an initial work phase, hearts were subjected to 30 min low-flow ischemia (1 ml/min) in the absence and presence of PMNs. Work was resumed after 15 min reperfusion in a non-working mode (Langendorff). Adenosine in the coronary effluent reached a maximum of 0.2 microM during low-flow ischemia. Recoveries of external heart work and cardiac output were reduced from about 80% to about 40% by PMNs. Infusion of adenosine deaminase (ADA, 5 U/ml), theophylline (50 microM) or the selective A1-antagonist dipropyl-8-cyclopentylxanthine (0.1 microM) prevented this effect. Furthermore, application of adenosine (0.1 microM) in combination with PMNs also resulted in a loss of pump function, even in the absence of a direct ischemic stimulus. The data indicate that adenosine contributes to post-ischemic, PMN-mediated damage in the isolated working guinea-pig heart model by a receptor-mediated action.
J Mol Cell Cardiol 1993 Aug
PMID:Adenosine contributes to neutrophil-mediated loss of myocardial function in post-ischemic guinea-pig hearts. 826 62

Calcium tolerant rabbit cardiomyocytes, isolated by collagenase perfusion, were preincubated for varying periods of time followed by resuspension in fresh media and centrifugation into an ischaemic pellet with restricted extracellular fluid. Pellets were incubated for 240 min under oil at 37 degrees C to mimic severe ischaemia. Time to onset of ischaemic contracture (rod to square transformation) and trypan blue permeability following resuspension in 85 mOSM media were monitored at sequential times. The protocol of Series 1 was a 5-10 min pre-incubation, immediately followed by ischaemic pelleting. Preincubation with pinacidil (50 microM) protected cells from ischaemic insult, but pinacidil added only into the ischaemic pellet did not protect. Protection was abolished by the protein kinase (PKC) inhibitors chelerythrine (10 microM) added with pinacidil and calphostin C (200nM) added only into the ischaemic pellet. Neither PKC inhibitor had an effect on injury of untreated ischaemic myocytes (data not shown). Series 2-5 were preconditioning protocols with a 10 min intervention period, followed by a 30 min oxygenated drug-free period, prior to ischaemic pelleting. In series 2 pinacidil protected cells from ischaemic insult and this protection was abolished when glyburide (10 microM) was present during preincubation, or during post-incubation and ischaemia. Glyburide only partially inhibited the protection when glyburide was added only into the ischaemic pellet. In Series 3, 8-sulfophenyltheophyline (SPT)(100 microM) or adenosine deaminase during preincubation, or SPT only added into the ischaemic pellet abolished pinacidil's protection. In Series 4, cardiomyocytes were ischaemically preconditioned by pelleting for 10 min followed by 30 min reoxygenation. Glyburide during initial ischaemic blocked protection, but when added during post incubation and into the final pellet protection was not reduced. In Series 5 8-cyclopentyl-1,3,dipropylxanthine (DPCPX) (10 microM) added into the final pellet abolished protection by pinacidil, but not protection following ischaemic preconditioning. In contrast to pinacidil, ischaemically preconditioned cells maintain protection in the presence of glyburide, indicating that: (1) pinacidil does not exactly mimic preconditioning and (2) ischaemically preconditioned cells do not require opened K+ATP channels for protection, although they appear to be important during initiation of the preconditioned state. It is hypothesized that pinacidil opening of K+ channels may facilitate induction of preconditioning.
J Mol Cell Cardiol 1995 Aug
PMID:Potassium channels and preconditioning of isolated rabbit cardiomyocytes: effects of glyburide and pinacidil. 852 37

Secretin, vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) each exert potent positive contractile responses directly in rat ventricular cardiomyocytes. However, the contractile-coupling mechanisms associated with these responses have not been determined. In the present study, the involvement of L-type calcium channels in the contractile responses elicited by each peptide has been investigated using the selective antagonists at L-type calcium channels, verapamil and diltiazem. Ventricular cardiomyocytes, isolated from the hearts of adult rats, were stimulated to contract at 0.5 Hz in the presence of CaCl2 (2 mM) and adenosine deaminase (5U/ml). Cardiomyocytes were pre-incubated for 3 min prior to stimulation, in the absence of L-type calcium channel antagonist, and in the presence of verapamil (< or = 1 microM) or diltiazem (< or = 1 microM). Verapamil (< or = 1 microM) and diltiazem (< or = 1 microM) inhibited the contractile responses elicited by isoprenaline (100 nM) and forskolin (40 microM), used as positive controls, significantly, and in a concentration-dependent manner, but did not inhibit significantly the contractile response elicited by phenylephrine (2 microM), which was employed as a negative control. Verapamil (< or = 1 microM) and diltiazem (< or = 1 microM) inhibited the contractile responses to secretin (20 nM) and VIP (20 nM) significantly, and in a concentration-dependent manner, but did not inhibit the contractile response to CGRP. These data indicate that the positive contractile responses to secretin and VIP in mammalian ventricular cardiomyocytes involve the influx of calcium ion via L-type calcium channels, while the positive contractile response to CGRP does not.
J Mol Cell Cardiol 1995 Sep
PMID:Inhibition by verapamil and diltiazem of agonist-stimulated contractile responses in mammalian ventricular cardiomyocytes. 852 57


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