Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular smooth muscle has been reported to contain the A1 subtype of adenosine receptors, but the existence of such receptor(s) in coronary smooth muscle has not been established. In the present study, the 3H-labeled A1-selective antagonist [3H]8-cyclopentyl-1,3-dipropylxanthine ([3H]DPCPX) was used to demonstrate the specific binding in porcine coronary artery smooth muscle membranes. The binding was saturable with a Bmax of 6.43 +/- 1.02 fmol/mg protein. Scatchard analysis of the binding data provided a single binding site with a Kd of 0.21 +/- 0.025 nmol/L. In the competition experiments, adenosine receptor agonists and antagonists showed the following order of potency (nmol/L): S-N6-(2-endonorbornyl)adenosine (S-ENBA) 0.11 = R(-)-N6-phenylisopropyladenosine 0.32 > DPCPX 3.2 = xanthine amine congener 2.4 = N6-cyclopentyladenosine 2.67 > 5'-(N-ethylcarboxamido)-adenosine 7.35 >> 2-[p-(2-carboxyethyl)-phenethyl-amino]-5'-(N-ethylcarboxamido)- adenosine 1000 > theophylline 83,000. This order of potency fits the criteria for the A1 adenosine receptor. S-ENBA, a highly selective A1 receptor agonist, was used to investigate the effect on isoproterenol-mediated vasorelaxation and cAMP accumulation. S-ENBA (0.1 to 10 nmol/L) dose-dependently shifted the isoproterenol-mediated (10(-8) to 10(-5) mol/L) vasorelaxation to the right in vascular rings. S-ENBA (10 nmol/L) inhibited the basal cAMP levels by 36% and attenuated the isoproterenol (10(-5) mol/L)-stimulated cAMP by 25% in the coronary rings. These inhibitory effects of S-ENBA on isoproterenol-mediated cAMP-accumulation and vasorelaxation were abolished by pertussis toxin (100 ng/mL, overnight) treatment of the arteries.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Binding of A1 adenosine receptor ligand [3H]8-cyclopentyl-1,3-dipropylxanthine in coronary smooth muscle. 778 77

Adenosine exerts pronounced biological effects in the heart cell. The role of multiple adenosine receptor subtypes in regulating the heart cell function is not known. Ventricular cells cultured from chick embryos 14 days in ovo were used to study a novel feature of heart cell regulation by the stimulatory adenosine receptors. The inhibitory adenosine A1 receptor pathway was first inactivated by pertussis toxin treatment of the cultures, and the effects of adenosine agonists and antagonists on the heart cell contractile amplitude, measured via an opticovideo motion detection system, and on the modulation of cAMP level were determined. Adenosine and N-ethyladenosine-5'-uronic acid (NECA), capable of activating both the adenosine A2a and A2b receptors, caused a greater increase in the contractile amplitude than did the A2a-selective agonist 2-[4-(2-carboxythyl)phenylethylamino]-5'-N-ethylcarboxamidoa denosine (CGS21680). NECA caused a biphasic increase in cAMP, which became monophasic in the presence of the A2a receptor-selective antagonist 8-(3-chlorostyryl)caffeine, whereas the CGS21680-induced cAMP response was monophasic. Blocking with 8-(3-chlorostyryl)caffeine abolished most of the CGS21680-elicited contractile or cAMP response while attenuating only part of the adenosine- or NECA-stimulated responses. Blocking with the A2b-selective antagonists 1,3-diethyl-8-phenylxanthine or alloxazine caused a more pronounced inhibititon of the contractile or cAMP response by adenosine or NECA than by CGS21680. Affinity of the A2a receptor was 60-fold higher than that of the A2b receptor. These data demonstrate that a functional A2b receptor is expressed on the heart cell and is capable of mediating augmentation of cardiac myocyte contractility and that adenosine A2a and A2b receptors, with greatly different affinity, coexist and are coupled to the same functional responses. Taken together, the data suggest a novel feature of heart cell regulation, where the high-affinity A2a receptor can play an important modulatory role in the presence of a low level of adenosine, whereas the low-affinity A2b receptor becomes functionally important when the adenosine level is high.
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PMID:Adenosine A2a and A2b receptors in cultured fetal chick heart cells. High- and low-affinity coupling to stimulation of myocyte contractility and cAMP accumulation. 783 35

Left atria were isolated from rats made hypothyroid by adding propylthiouracil to their drinking water, such rats after saturating doses of thyroid hormones, and from control rats. Isoproterenol (ISO; 1 microM) increased the values of developed tension (DT), maximal rate of tension development (+dt/dt) and tension fall (-dT/dt). The effect was largest in hypothyroid and lowest in hyperthyroid atria. The adenosine A1-receptor agonist N6-(phenylisopropyl)-adenosine (PIA) had a powerful negative inotropic effect in ISO-stimulated atria. The effects of PIA on +dT/dt, -dT/dt and DT were enhanced in hypothyroidism. Adenosine receptor number was not decreased. The amount of total Gi-like proteins was estimated by pertussis toxin labeling. The amounts of Gi2 and Gi3 were estimated in Western blots using such antisera raised in rabbits against peptides corresponding to parts of their sequences, using purified recombinant alpha subunits as standards. The amounts of low and high molecular weight forms of Gs were estimated by cholera toxin labeling Gi2, Gi3 and pertussis toxin substrate concentrations were slightly lower in the hypothyroid animals, while the amounts of both forms of Gs per mg of protein were only half of those in euthyroid rat atria. The levels of Gi2 and Gi3 were greatly elevated as compared to Gs as membrane marker. These changes were reversed by treatment of the hypothyroid rats with thyroid hormones. In conclusion, the present results show an enhanced negative inotropic effect of an adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enhanced negative inotropic effect of an adenosine A1-receptor agonist in rat left atria in hypothyroidism. 791 34

1. The effects of adenosine on adenosine 5'-triphosphate (ATP)-evoked dopamine release from rat phaeochromocytoma PC12 cells was investigated to determine whether adenosine exerts a regulatory effect on the ATP-evoked response. Adenosine potentiated ATP (30 microM)-evoked dopamine release in a concentration-dependent manner over a concentration-range of 1 to 100 microM. Adenosine (100 microM) shifted the concentration-dependence of the ATP-evoked response to the left without affecting the maximal response. 2. Aminophylline, a non-selective adenosine receptor antagonist, and CP66713, a selective antagonist at the A2 subclass of adenosine receptors, abolished the adenosine-induced potentiation. Furthermore, 8-cyclopentyltheophylline, a selective antagonist at the adenosine A1 receptor partially inhibited the adenosine-evoked potentiation. CGS22492, a selective A2 receptor agonist, potentiated ATP-evoked dopamine release whereas N6-cyclohexyladenosine (CHA), a selective A1 receptor agonist, had no effect. 3. Pertussis toxin (PTX), a bacterial exotoxin which catalyzes the ADP-ribosylation of guanosine 5'-triphosphate (GTP)-binding proteins (G-proteins), inhibited the adenosine-induced potentiation of dopamine release. Dibutyryl cyclic AMP (db cyclic AMP), an analogue of cyclic AMP, had no effect on the release on the ATP-evoked response. 4. Adenosine potentiated the ATP-evoked rise in intracellular Ca2+ concentration ([Ca]i) in PC12 cells. This potentiation was also observed with CGS 22492 but not with CHA. PTX completely inhibited the adenosine-induced potentiation of the rise in [Ca]i. 5. On the basis of these findings, we suggest that the adenosine-induced potentiation of ATP-evoked dopamine release was due to an increase in [Ca]i in the cells. Although the potentiation is most likely mediated by a subclass of A2 receptors, the subclass may be different from those previously reported since the potentiation was sensitive to PTX and was not reproduced by db cyclic AMP.
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PMID:Potentiation by adenosine of ATP-evoked dopamine release via a pertussis toxin-sensitive mechanism in rat phaeochromocytoma PC12 cells. 792 29

A1 adenosine receptors are in general coupled to inhibition of adenylyl cyclase, but have more recently been reported to be capable of also activating phospholipase C. The present study was done in order to investigate whether these different effects can be elicited by a single A1 receptor, or whether A1 receptor subtypes have to be invoked. The cDNA of a rat brain A1 adenosine receptor was stably expressed in CHO-cells, resulting in clones with varying receptor densities; a clone expressing 1.9 pmol receptors/mg membrane protein was used for further characterization. The ligand binding properties of the expressed receptors were typical for the rat A1 adenosine receptor. A1 receptor agonists caused a concentration-dependent inhibition of adenylyl cyclase activity in the membranes, with maximal inhibition by 70%. A1 receptor stimulation also caused concentration-dependent stimulation of inositol phosphate generation in these cells, with maximal effects of 300%. Both adenylyl cyclase inhibition and enhancement of inositol phosphate generation were essentially abolished after pretreatment of the cells with pertussis toxin. These results indicate that a single A1 adenosine receptor can couple to two effector pathways, and that both effectors are activated via pertussis toxin sensitive G proteins.
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PMID:A1 adenosine receptors expressed in CHO-cells couple to adenylyl cyclase and to phospholipase C. 793 54

Adenosine, an important regulator of many cardiac functions, is produced by ectosolic and cytosolic 5'-nucleotidase. The activity of these enzymes is influenced by several ischemia-sensitive metabolic factors, e.g., ATP, ADP, H+, and inorganic phosphate. However, there is no clear evidence that adenosine itself affects 5'-nucleotidase activity. This study tested whether adenosine decreases the activity of ectosolic and cytosolic 5'-nucleotidase. Cardiomyocytes were isolated from adult male Wistar rats and suspended in the modified Hepes-Tyrode buffer solution. After stabilization, isolated cardiomyocytes were incubated with and without adenosine (10(-9) - 10(-4) M). Ectosolic and cytosolic 5'-nucleotidase activity was decreased by exogenous adenosine (ectosolic 5'-nucleotidase activity, 20.6 +/- 2.3 vs. 8.6 +/- 1.6 mumol/min per 10(6) cells [P < 0.05]; cytosolic 5'-nucleotidase activity, 2.47 +/- 0.58 vs. 1.61 +/- 0.54 mumol/min per 10(6) cells [P < 0.05] at 10(-6) M adenosine) after 30 min. The decrease in ectosolic and cytosolic 5'-nucleotidase activity was inhibited by 8-phenyltheophylline and pertussis toxin, and was mimicked by N6-cyclohexyladenosine, an adenosine A1 receptor agonist. Neither CGS21680C, and A2 receptor agonist, nor cycloheximide deactivated ectosolic and cytosolic 5'-nucleotidase. Thus, we conclude that activation of adenosine A1 receptors is coupled to Gi proteins and attenuates ectosolic and cytosolic 5'-nucleotidase activity in rat cardiomyocytes.
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PMID:Evidence for deactivation of both ectosolic and cytosolic 5'-nucleotidase by adenosine A1 receptor activation in the rat cardiomyocytes. 798 2

Adenosine A1 receptors and alpha 2-adrenoceptors are both potent inhibitors of adipocyte lipolysis when activated by their agonists. The aim of this work was to compare the coupling of these receptors to the Gi-proteins in hamster adipocytes. The adenosine A1 receptor was characterized with the antagonist [3H]dipropyl-cyclopentyl-xanthine ([3H]DPCPX) and the agonist [3H](-)-phenylisopropyladenosine ([3H]PIA). It was demonstrated by [32P]ADP-ribosylation with pertussis toxin and immunoblotting that Gi1, Gi2 and Gi3 are expressed in hamster adipocytes. Partial ADP-ribosylation of Gi-proteins by pertussis toxin, acting on the intact cells or on the adipocyte membranes, demonstrated that the adenosine A1 receptor was less sensitive to the disappearance of functional Gi-proteins than the alpha 2-adrenoceptor. These results are in accordance with the weak sensitivity of the binding of the agonist [3H]PIA to guanine nucleotides and seem to confirm that the adenosine A1 receptor is strongly and differently coupled than the alpha 2-adrenoceptor to the Gi-proteins in hamster adipocyte membranes.
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PMID:Coupling of inhibitory receptors with Gi-proteins in hamster adipocytes: comparison between adenosine A1 receptor and alpha 2-adrenoceptor. 805 Apr 82

1. The whole-cell configuration of the gigaohm seal voltage clamp and an internal perfusion technique were used to study the effects of adenosine on the basal L-type Ca2+ current (ICa) in enzymatically isolated right ventricular myocytes of ferrets. Basal L-type ICa was isolated by using a Na(+)- and K(+)-free saline (replacement by N-methyl-D-glucamine+, Cs+ and TEA+, respectively). All experiments were conducted at room temperature (22-24 degrees C). 2. Basal ICa was markedly reduced during exposure to adenosine in a concentration-dependent manner with a half-inhibitory concentration (IC50) of 0.3 microM and maximum inhibition of 35%. This effect was completely abolished by 50 nM 8-cyclopentyl-1,3-dipropylxanthine (CPDPX), a specific A1 adenosine receptor antagonist with an inhibition constant, Ki = 0.48 nM. Inhibition was also observed in the presence of 1 microM atropine. 3. Adenosine decreased basal ICa by decreasing the peak amplitude of ICa without significantly altering (i) the voltage dependence of the current-voltage relationship, (ii) the apparent reversal potential, (iii) the voltage dependence of steady-state activation and inactivation, (iv) the kinetics of inactivation at 0 mV, and (v) the kinetics of recovery from inactivation at -70 mV. 4. Pretreatment of cells with 0.4 microns/ml pertussis toxin (PTX) for 4 h at 37 degrees C produced greater than 90% ADP ribosylation of PTX-sensitive G proteins. PTX pretreatment significantly attenuated the adenosine-mediated decrease in ICa (35% in control; 4.6% after PTX pretreatment). 5. The peptide inhibitor (PKI) of cyclic AMP-dependent protein kinase A at a concentration of 2 microM neither inhibited basal ICa nor attenuated the effects of adenosine on basal ICa. However, PKI decreased the stimulatory effects of 100 microM cAMP on ICa. 6. Increasing intracellular cAMP to a supra-saturable level by using 10 mM cAMP and 100 microM papaverine did not prevent adenosine from inhibiting ICa. 7. Consistent with the reduction of basal ICa, adenosine produced an inhibitory effect on the action potential under basal conditions, i.e. hyperpolarization of the plateau phase and marked shortening of action potential duration. These effects were concentration dependent. 8. These results demonstrate a reduction of the basal L-type ICa by adenosine in ferret ventricular myocardium. This reduction is not mediated by modification of voltage-dependent properties of macroscopic ICa. The shortening of action potentials may be explained in part by the reduction in ICa.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Modulation of basal L-type Ca2+ current by adenosine in ferret isolated right ventricular myocytes. 812 Aug 7

1. The effects of extracellular adenosine triphosphate (ATP) on the basal L-type Ca2+ current (ICa) were investigated in ferret isolated right ventricular myocytes using the gigaohm seal voltage clamp in the whole-cell and cell-attached configurations. 2. Micromolar levels of extracellular ATP reversibly inhibited ICa in a concentration-dependent manner, without any significant changes in the voltage dependence of either the peak ICa I-V relationship or steady-state activation curve. 3. In contrast, micromolar levels of extracellular ATP did significantly alter the inactivation characteristics of ICa. Ten micromolar ATP: (i) increased the degree of steady-state inactivation of ICa; (ii) altered the time constants of ICa inactivation at 0 mV; and (iii) decreased the time constant of ICa recovery from inactivation at -70 mV. 4. The inhibitory effect of ATP on ICa was not blocked by atropine, a muscarinic cholinergic receptor antagonist, or CPDPX (8-cyclopentyl-3,4-dipropylxanthine), an A1 adenosine receptor antagonist. In contrast, the inhibitory effect of 10 microM ATP could be nearly completely antagonized by 100 microM suramin, a purinergic P2 receptor antagonist. 5. The potency order of ATP analogues in inhibiting ICa was 2-methyl-thio-ATP > ATP > alpha,beta-methylene-ATP, indicating involvement of a P2Y-type ATP receptor. 6. Pretreatment of cells with pertussis toxin (PTX) did not prevent the ATP-induced decrease in ICa. However, (i) ATP produced an irreversible decrease of ICa in the presence of intracellular GTP gamma S, and (ii) the inhibitory effect was significantly attenuated in the presence of intracellular GDP beta S, indicating the involvement of a PTX-insensitive G protein in the P2Y receptor-coupling process. 7. Neither (i) replacing extracellular Ca2+ with 1 mM Ba2+, nor (ii) intracellular perfusion of 10 mM BAPTA for at least 30 min attenuated the inhibitory effect of ATP on the current through Ca2+ channels, suggesting that the inhibitory effect was not obligatorily dependent upon influx of Ca2+ or changes in [Ca2+]i. 8. Ensemble-average current behaviour constructed from cell-attached patch recordings of single L-type Ca2+ channels (110 mM BaCl2) demonstrated that when 10 microM ATP was added to the superfusate on the outside of the patch electrode the inhibition of ICa was still observed, providing evidence for the involvement of intracellular diffusible second messenger(s).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Modulation of L-type Ca2+ current by extracellular ATP in ferret isolated right ventricular myocytes. 812 Aug 8

Chinese hamster ovary cells were transfected with both A1 adenosine receptor and muscarinic type 3 acetylcholine receptor cDNAs. The muscarinic receptor agonist carbachol stimulated phospholipase C activity, resulting in Ca2+ mobilization and arachidonate release. N6-Cyclopentyladenosine (CPA), an A1 receptor agonist, did not activate Ca(2+)-related signal transduction systems by itself but instead inhibited cAMP accumulation. In the presence of carbachol, however, the A1 receptor agonist enhanced muscarinic receptor agonist-induced phospholipase C/Ca2+ responses. In addition, the arachidonate release caused by Ca2+ ionophores or thapsigargin was also amplified by CPA, without a change in phospholipase C activity. Thus, CPA augments Ca(2+)-mediated phospholipase A2 activation in addition to and separate from its ability to amplify phospholipase C-mediated Ca2+ mobilization. Because the permissive actions of CPA on phospholipase C and phospholipase A2 activation were each reversed by pertussis toxin treatment, in a manner similar to that of the CPA-induced inhibition of cAMP accumulation, we conclude that a single species of A1 receptor expressed in Chinese hamster ovary cells can couple to multiple signal transduction systems stemming from phospholipase C stimulation, phospholipase A2-mediated and Ca(2+)-dependent arachidonate release, and inhibition of cAMP accumulation. A pertussis toxin-sensitive G protein (or proteins) mediates the permissive actions of the A1 receptor in the stimulation of phospholipase C- and phospholipase A2-mediated arachidonate release.
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PMID:A single species of A1 adenosine receptor expressed in Chinese hamster ovary cells not only inhibits cAMP accumulation but also stimulates phospholipase C and arachidonate release. 819 94


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