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Humans↗
Biomedical subjects
P Strong
Publications and source records attributed to P Strong.
Release of calreticulin from neutrophils may alter C1q-mediated immune functions.
Calreticulin is an abundant intracellular protein which is involved in a number of cellular functions. During cytomegalovirus infection, as well as inflammatory episodes in autoimmune disease, calreticulin can be released from cells and detected in the circulation, where it may act as an immunodominant autoantigen in diseases such as systemic lupus erythematosus. Calreticulin is known to bind to the molecules of innate immunity, such as C1q, the first subcomponent of complement. However, the functional implications of C1q-calreticulin interactions are unknown. In the present study we sought to investigate, in greater detail, the interaction between these two proteins following the release of calreticulin from neutrophils upon stimulation. In order to pinpoint the regions of interaction, recombinant calreticulin and its discrete domains (N-, P- and C-domains) were produced in Escherichia coli. Both the N- and P-domains of calreticulin were shown to bind to the globular head regions of C1q. Calreticulin also appeared to alter C1q-mediated immune functions. Binding of calreticulin to C1q inhibited haemolysis of IgM-sensitized erythrocytes. Both the N- and P-domains of calreticulin were found to contain sites involved in the inhibition of C1q-induced haemolysis. Full-length calreticulin, and its N- and P-domains, were also able to reduce the C1q-dependent binding of immune complexes to neutrophils. We conclude that calreticulin, once released from neutrophils during inflammation, may not only induce an antigenic reaction, but, under defined conditions, may also interfere with C1q-mediated inflammatory processes.
Autoantigens↗
Lung surfactant proteins A and D can inhibit specific IgE binding to the allergens of Aspergillus fumigatus and block allergen-induced histamine release from human basophils.
Aspergillus fumigatus is an opportunistic fungal pathogen which, in the immunocompetent host, causes allergic disorders such as allergic rhinitis, allergic sinusitis, hypersensitivity pneumonitis, and allergic bronchopulmonary Aspergillosis (ABPA). In the present study, the interaction of 3-week culture filtrate (3wcf) allergens and various purified glycosylated and non-glycosylated allergens of A. fumigatus with lung surfactant proteins, SP-A and SP-D, was investigated. Purified SP-A and SP-D, isolated from human bronchoalveolar lavage fluid, bound to the 3wcf allergens and purified allergens, gp55 and gp45, in a carbohydrate-specific and calcium-dependent manner. Both SP-A and SP-D did not bind to deglycosylated allergens, suggesting that the ability of SP-A and SP-D to bind certain allergens is mediated through their carbohydrate recognition domains, interacting with the carbohydrate residues on the allergen. Both SP-A and SP-D could inhibit the ability of allergen-specific IgE from Aspergillosis patients to bind these allergens, suggesting that SP-A and SP-D may be involved in the modulation of allergic sensitization and/or development of allergic reactions. The view that SP-A and SP-D play a protective role against airborne allergens is further supported by the demonstration of their ability to inhibit A. fumigatus allergen-induced histamine release from allergic patients' basophils.
Allergens↗
Binding of pulmonary surfactant proteins A and D to Aspergillus fumigatus conidia enhances phagocytosis and killing by human neutrophils and alveolar macrophages.
To determine whether the lung surfactant proteins A (SP-A) and D (SP-D) are involved in the initial protective immunity against opportunistic pulmonary fungal infections caused by Aspergillus fumigatus, we performed a series of in vitro functional studies to see if SP-A and SP-D enhanced binding, phagocytosis, activation, and killing of A. fumigatus conidia by human alveolar macrophages and circulating neutrophils. Both SP-A and SP-D bound to carbohydrate structures on A. fumigatus conidia in a calcium-dependent manner. SP-A and SP-D were also chemoattractant and significantly enhanced agglutination and binding of conidia to alveolar macrophages and neutrophils. Furthermore, in the presence of SP-A and SP-D, the phagocytosis, oxidative burst, and killing of A. fumigatus conidia by neutrophils were significantly increased. These findings indicate that SP-A and SP-D may have an important immunological role in the early antifungal defense responses in the lung, through inhibiting infectivity of conidia by agglutination and by enhancing uptake and killing of A. fumigatus by phagocytic cells.
Agglutination↗
Interaction of human lung surfactant proteins A and D with mite (Dermatophagoides pteronyssinus) allergens.
Human lung surfactant proteins A (SP-A) and D (SP-D) are both collagenous C-type lectins which appear to mediate antimicrobial activity by binding to carbohydrates on micro-organisms and to receptors on phagocytic cells. Purified native SP-A and SP-D, isolated from human bronchoalveolar lavage fluid, were found to bind to whole mite extracts (Dermatophagoides pteronyssinus) and the purified allergen Der p I, in a carbohydrate-specific and calcium-dependent manner. Binding was inhibited by ethylenediamine tetra-acetic acid (EDTA) as well as by maltose in the case of SP-D, or mannose in the case of SP-A. A recombinant polypeptide, which trimerized to form the neck region and carbohydrate recognition domains of SP-D, also inhibited the binding of native SP-D to the whole mite extract and Der p I. Both SP-A and SP-D did not bind to deglycosylated whole mite extracts or to recombinant Der p proteins, which lacked carbohydrate residues. These results suggest that the ability of surfactant proteins to bind certain allergens is mediated through their carbohydrate-recognition domains (CRDs) interacting with carbohydrate residues on the allergens. Moreover, SP-A and SP-D were found to inhibit allergen-specific IgE binding to the mite extracts either via steric hindrance or competitive binding. It is therefore possible that SP-A and SP-D may be involved in the modulation of allergen sensitization and/or the development of allergic reactions.
Allergens↗
Comparison of the profiles of agonists as stimulants of the beta 3-adrenoceptor in vitro with their gastroprotective effects in the conscious rat.
1. This paper compares the activity of a range of agonists as stimulants of the beta 3-adrenoceptor in rat isolated oesophagus with their ability to afford protection against indomethacin-induced gastric damage in the conscious rat. 2. The beta 3-adrenoceptor agonists, CL 316243 and BRL 37344, the non-selective beta-adrenoceptor agonist, isoprenaline and the selective beta 2-adrenoceptor agonist, salmeterol, all evoked concentration-dependent relaxation of precontracted muscularis mucosa from rat oesophagus. The rank order of agonist potency was BRL 37344 > CL 316243 > isoprenaline >> salmeterol. The selective beta 1-adrenoceptor agonist, denopamine, did not relax the preparation. 3. The relaxant responses to all agonists were resistant to blockade by atenolol (10 microM), and ICI 118551 (1 microM) thus suggesting that they were not mediated by either beta 1- or beta 2-adrenoceptor stimulation. In contrast, cyanopindolol and propranolol did inhibit responses to BRL 37344, CL 316243 and isoprenaline, giving pA2 values or pKB estimates which were consistent with an interaction at beta 3-adrenoceptors (i.e. approximately 8.0 and 6.5 respectively). However, responses to salmeterol were resistant to blockade by all the antagonists tested, which suggests that the high (> 1 microM) concentrations of salmeterol used exerted non-specific relaxant effects. 4. The agonist effects of CL 316243 and BRL 37344 on beta 1- and beta 2-adrenoceptors were assessed on guinea-pig right atrium and precontracted trachea respectively. Both agonists had minimal activity as stimulants of heart rate, but did relax trachea, being 380 (CL 316243) and 21 (BRL 37344) fold less potent than isoprenaline. 5. CL 316243 and BRL 37344 were potent inhibitors of indomethacin-induced gastric antral ulceration in the conscious rat (ED50 values = 0.24 and 0.09 mumol kg-1, p.o.) Salmeterol was approximately 100 times less potent than BRL 37344 as a gastroprotective agent and denopamine was without effect. 6. The gastroprotective effects of CL 316243 and BRL 37344 were resistant to blockade by ICI 118551 (10 mg kg-1, p.o.) and propranolol (10 mg kg-1, p.o.). In contrast, both antagonists caused dose-related inhibition of the protective action of salmeterol (10 mg kg-1, p.o.). Cyanopindolol was not assessed as an antagonist in vivo because preliminary experiments revealed that it exacerbated indomethacin-induced gastric damage in its own right. 7. In conclusion, the beta 3-adrenoceptor agonists CL 316243 and BRL 37344 were potent inhibitors of indomethacin-induced gastric antral ulceration in the rat. These data suggest that an agonist which is potent and selective for the human beta 3-adrenoceptor may confer mucosal protection in man.
Adrenergic beta-Agonists↗
The late effects of poliomyelitis: nursing interventions for a unique patient population.
Over half a million Americans who had paralytic poliomyelitis as children or young adults are at risk for experiencing the unexpected late effects of post-poliomyelitis syndrome (PPS). When hospitalized or treated for a variety of conditions requiring medical or surgical interventions, these individuals present challenges which include life-threatening complications.
Adult↗
Non-steroidal anti-inflammatory drug-induced gastric damage in experimental animals: underlying pathological mechanisms.
A major impetus to experimental studies examining the pathogenesis of NSAID-induced gastric damage is the hope that key mechanisms can be identified that may lead to the design of "safer" NSAIDs or to the development of novel cytoprotectives to co-administer with current NSAIDs. Virtually every hypothesis proposed to explain the pathogenesis of NSAID-induced gastric damage has arisen from studies examining fundic lesions. Our results suggest that not only is the pathogenesis of gastric damage in the fundus and antrum of the rat potentially very different but that it is NSAID-induced damage to the rat gastric antrum (and not the fundus) that more closely resembles that of humans. Thus, hypotheses constructed from experimental studies examining fundic damage may not be predictive of the clinical setting. We would suggest, therefore, that future studies should concentrate on studying the pathogenesis of antral ulceration induced by NSAIDs. In particular, we believe that future research should assess whether NSAIDs do indeed reduce blood flow in the gastric antrum and define the mechanism(s) involved. Identification of these processes should significantly advance our understanding of antral ulceration and may suggest novel approaches in the design of cytoprotective agents. Recent work has established that two distinct forms of the enzyme cyclooxygenase (COX) can catalyse the metabolism of arachidonic acid and initiate prostaglandin synthesis. It is hypothesised (De Witt et al., 1993) that the analgesic/anti-inflammatory effect of current NSAIDs is achieved through inhibition of COX 2, whereas their side effects (such as antral ulceration) result as a consequence of inhibition of gastric COX 1. The recently described selective inhibitor of COX 2, NS398, has been shown to be analgesic and anti-inflammatory without causing gastric ulceration (Futaki et al., 1993; Masferrer et al., 1994). If key mechanisms (such as alterations in blood flow) of NSAID-induced antral damage can be identified, then it would be hypothesised that selective inhibitors of COX 1 would be ulcerogenic and reduce antral blood flow, whereas inhibitors of COX 2 would not share either of these properties. If this hypothesis can be substantiated, then inhibitors of COX 2 may be the next generation of "gastric safe" NSAIDs.
Animals↗
Further investigations into adenosine A1 receptor-mediated contraction in rat colonic muscularis mucosae and its augmentation by certain alkylxanthine antagonists.
1. The alkylxanthine antagonists, 8-phenyltheophylline (8-PT), 8-p-sulphophenyltheophylline (8-SPT) and 1,3,7-trimethylxanthine (caffeine) produced rightward displacements of contractile concentration-effect curves to 5'-N-ethylcarboxamidoadenosine (NECA) in rat isolated colonic muscularis mucosae (RCMM) with concentration-ratios consistent with adenosine receptor blockade. The non-xanthine antagonist, 9 fluro-2-(2-furyl)-5,6-dihydro [1,2,4] triazo to [1,5-c]-quinazin-imine (CGS15943A) also antagonized contractions to NECA with an affinity (pKB8.1-8.5) consistent with adenosine A1 receptor blockade. 2. In addition to producing rightward shifts of the concentration-response curves, the maximum contractions to 5'-N-ethylcarboxamidoadenosine (NECA) were also markedly increased in the presence of 8-PT (by 83 +/- 16% at 1 microM), 8-SPT (by 37 +/- 7% at 10 microM) and caffeine (by 45 +/- 5% at 100 microM) but were unaffected by CGS15943A (at 0.01 and 0.03 microM). 3. As with NECA, the maximum contractions to the adenosine A1 receptor agonists R-phenylisopropyladenosine (R-PIA) and N-[(1S, trans)-2-hydroxyclopentyl] adenosine (GR79236) were both antagonized and augmented by 8-PT. In addition, the contractions to NECA in the presence of 8-PT (1 microM) were inhibited by nanomolar concentrations of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). 4. The non-selective phosphodiesterase (PDE) inhibitor, 3-isobutyl-1-methylxanthine (1 microM) produced a marked increase in the NECA maximum without producing a rightward shift in the NECA curve, whereas a higher concentration (10 microM) virtually abolished responses. The PDE type III inhibitor,milrinone (1 microM), the type IV inhibitor, rolipram (10 microM), and the type V PDE inhibitor, zaprinast(3 microM), were all without effect on NECA responses in RCMM.5. Partial inhibitions of contractions to NECA were produced by indomethacin (at 3 or 10 micro M) or piroxicam (at 3 microM). Responses to GR79236 were also partially inhibited by indomethacin. In the presence of indomethacin, 8-PT was still able to enhance markedly the maximum contractions obtained to NECA in RCMM.6. The present study has shown that certain alkylxanthine antagonists (but not the non-xanthineCGS15943A) produced a marked augmentation of adenosine Al receptor-mediated contractions inRCMM. The mechanism of this augmentation is, as yet, not known but is unlikely to result from inhibition of PDE. This study has also shown that adenosine Al receptor-induced contractions inRCMM are mediated, in part, via products of the cyclo-oxygenase pathway.
Adenosine↗
An unusual cause for severe dyspnea and sudden death in a young man.
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Adrenal Gland Neoplasms↗
The effects of GR79236 on plasma fatty acid concentrations, heart rate and blood pressure in the conscious rat.
GR79236 (N-[(1S,trans)-2-hydroxycyclopentyl]adenosine) is an orally active adenosine A1 receptor agonist, which decreases plasma non-esterified fatty acid levels in fasted rats. This study has quantified the effects of GR79236 on plasma non-esterified fatty acid levels, blood pressure and heart rate in conscious rats. Blood pressure and heart rate were continuously recorded in rats for 30 min before and 1 h after oral dosing with GR79236 (0.03-3 mg/kg) or vehicle. Plasma non-esterified fatty acid concentrations were determined in blood sampled before and 1 h after dosing. GR79236 produced dose-related reductions in plasma non-esterified fatty acid concentrations, with an almost maximal effect (63.2%) occurring after 1 mg/kg. This dose induced a small but significant decrease in heart rate (12.0%), and a non-significant decrease in mean blood pressure (6.3%). Thus, in the conscious rat, GR79236 can exert profound antilipolytic effects with minimal effects on blood pressure and heart rate.
Adenosine↗
Leukotrienes do not contribute to the pathogenesis of indomethacin-induced ulceration of the gastric antrum in the re-fed rat.
The potential involvement of leukotrienes in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum has been studied. Pretreatment with the leukotriene biosynthesis inhibitor, MK886 (30 mg/kg p.o.), inhibited the increases in blood and antral leukotriene B4 release ex vivo associated with the evolution of antral ulceration. Despite this, however, there was no significant reduction in either the area of antral ulceration, or in the associated blood neutrophilia and neutrophil infiltration into the gastric antrum. Similarly, pretreatment with the leukotriene B4 antagonist, SC41930 (50 mg/kg p.o.) or the peptidyl leukotriene antagonist ICI198,615 (50 mg/kg p.o.) did not inhibit the area of antral ulceration induced by indomethacin. Thus, in contrast to published reports studying fundic ulceration, our results suggest that leukotrienes do not play a major role either in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum or neutrophil infiltration into the damaged antrum.
Administration, Oral↗
Neutrophil infiltration does not contribute to the ulcerogenic effects of indomethacin in the rat gastric antrum.
We have previously suggested (Trevethick et al., Gut 34, 156-160) that indomethacin-induced ulceration of the rat gastric antrum may be a neutrophil-dependent process. Accordingly, in this study we have used an anti-neutrophil serum (ANS) to investigate the effects of neutrophil depletion on this pathology. In animals pretreated with the ANS to induce a nearly total neutropaenia, indomethacin-induced increases in blood neutrophilia and cell infiltration into the gastric antrum (assessed as LTB4 release ex vivo) were eliminated. In marked contrast, however, ANS pretreatment affected neither the area of mucosa damaged nor the microscopic characteristics or distribution of the lesions. These results suggest that, in contrast to the published reports examining indomethacin-induced ulceration of the gastric fundus, neutrophil infiltration is not involved in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum.
Animals↗
1,3-Dipropyl-8-cyclopentyl xanthine (DPCPX): a useful tool for pharmacologists and physiologists?
There is now ample evidence in the literature to demonstrate the selectivity of action of DPCPX for adenosine A1 vs other adenosine receptor types in tissues derived from a wide range of species. However, care has to be exercised to ensure that its physiochemical properties do not result in the production of quantitatively misleading data. In experiments using canine tissues the still limited data available in the literature clearly and consistently demonstrate that DPCPX has a lower affinity than expected in preparations which would be anticipated to contain A1 receptors. A range of in vitro experiments also demonstrate that DPCPX is not always a "neutral" or "silent" antagonist. The mechanism underlying these additional effects is unclear, but may result from an ability of the compound to disrupt the normal interaction of the A1 receptor with Gi, or may be indicative of a lack of specificity of action. The limited evidence available suggests that the compound retains its selectivity and specificity of action in vivo, and early work indicates that the compound is proving to be a useful tool with which to explore the potential of activation of adenosine A1 receptors as an important mechanism in physiological and pathophysiological processes.
Adipose Tissue↗
Improvement of ketoacidosis in the diabetic rat after the administration of the oral antilipolytic agent GR 79236.
1. We assessed the effect of a novel oral antilipolytic agent, N-[(1S, trans)-2-hydroxycyclopentyl]adenosine (GR 79236), in experimental diabetic ketoacidosis. Ketotic rats were gavaged with GR 79236 (1 mg/kg) or water (vehicle) and their blood/plasma/serum biochemistry and haematological profile was determined. 2. We found that GR 79236 reduced the plasma non-esterified fatty acid concentration. This effect was associated with the correction of blood/plasma/serum biochemical variables (beta-hydroxybutyrate, acetoacetate, triacylglycerol) directly related to diabetic ketoacidosis, and of others (cholesterol, creatinine, creatine kinase and aspartate transaminase) which are not directly related to this metabolic abnormality. 3. There was, however, no evidence of GR 79236 lowering blood glucose in this model. One possible explanation for this observation is that GR 79236 stimulated gastric emptying leading to enhanced absorption of stomach contents when compared with untreated animals.
Adenosine↗
Failure of CGS15943A to block the hypotensive action of agonists acting at the adenosine A3 receptor.
1. Adenosine receptor agonists were evaluated for their activity at the putative adenosine A3 receptor which mediates a 'xanthine-resistant' hypotensive response in the anaesthetized rat. The compounds tested were: the A1/A3 receptor agonist, N-[2-(4-aminophenyl)ethyl]adenosine (APNEA), the non-selective adenosine receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA), the adenosine A1 receptor-selective agonists, N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (GR79236) and N6-cyclopentyl adenosine (CPA), the A2a receptor-selective agonists, 2-[[2-[4-(2-carboxyethyl) phenyl] ethyl] amino]-N- ethylcarboxamidoadenosine (CGS21680) and 2-phenylaminoadenosine (CV1808), and the moderately A2b selective agonist, N-[(2-methylphenyl)methyl]adenosine (metrifudil). 2. In confirmation of literature findings, APNEA (1-1000 nmol kg-1) induced hypotension and bradycardia; the hypotension was not blocked by pretreatment with the xanthine antagonist, 8-P-sulphophenyltheophylline (8-sPT; 40 mg kg-1, i.v.), whereas the bradycardia was attenuated. The non-xanthine antagonist, 9-fluoro-2-(2-furyl)-5,6-dihydro [1,2,4]triazolo[1,5-c]- quinazin-5-imine (CGS15943A; 3 mg kg-1 i.v.), also attenuated the bradycardia without affecting the hypotension. 3. The adenosine A1 receptor-selective agonists, GR79236 and CPA, both produced dose-dependent falls in blood pressure and heart rate which were antagonized by 8-sPT (40 mg kg-1) and CGS15943A (3 mg kg-1). 4. The adenosine A2a receptor-selective agonists, CGS21680 and CV1808, produced only a hypotensive response which was antagonized by 8-sPT (40 mg kg-1) and to a much greater extent by CGS15943A (3 mg kg-1), consistent with the response being mediated solely by A2a receptors. 5. The modestly A2b receptor-selective agonist, metrifudil, produced a dose-dependent fall in blood pressure and at higher doses a fall in heart rate. The hypotension induced by metrifudil was not antagonized by either 8-sPT (40 mg kg-1) or CGS15943A (3 mg kg-1) even though the bradycardia was abolished, suggesting that this agonist activates the putative A3 receptor.6. The non-selective adenosine receptor agonist, NECA, produced a hypotension and bradycardia that was attenuated by 8-sPT (40 mg kg-1), confirming previous work. The non-xanthine antagonist,CGS15943A (3 mg kg-'), also attenuated the hypotension and bradycardia. The bradycardia was blocked to a much greater extent, suggesting that NECA may therefore induce hypotension partly by activating the putative A3 receptor.7. In conclusion, we have confirmed that the putative A3 receptor mediating hypotension in the anaesthetized rat is not blocked by 8-sPT, and further shown that it is not blocked by CGS15943A. The A2a agonists CGS21680 and CV1808 showed no discernible activity at the A3 receptor, whereas APNEA,NECA, CPA and metrifudil appear to activate this receptor. The adenosine A1 receptor agonist,GR79236, shows considerable selectivity for the A1 receptor but may activate the A3 receptor at high doses.
Adenosine↗
Characterization of the adenosine receptors mediating hypothermia in the conscious mouse.
1. The effects of a range of adenosine receptor-selective ligands on body temperature were investigated following intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) injection in conscious mice. The compounds tested were the non-selective adenosine receptor agonist 5'-N-ethyl-carboxamidoadenosine (NECA), the adenosine A1 receptor-selective agonists cyclopentyl-adenosine (CPA), N6-(9R-phenyl-isopropyl)-adenosine (R-PIA) and N-(1S,trans)-[2-hydroxyclopentyl]-adenosine (GR79236), the A2a receptor selective agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxyamidoaden osine (CGS-21680), the A2b receptor agonist N-[(2-methylphenyl)methyl[adenosine (metrifudil) and the A3 receptor agonist N6-(4-aminophenylethyl)adenosine (APNEA). 2. NECA (0.01-1 microgram, i.c.v.), all of the A1-selective agonists (0.01-1 microgram, i.c.v.) and APNEA (0.1-3 micrograms i.c.v.) produced profound and dose-related hypothermia and sedation. However, CGS-21680 (0.1-10 micrograms i.c.v.) and metrifudil (0.01-1 microgram i.c.v.), produced only mild hypothermia at the highest doses tested. 3. The hypothermic response to the A1 receptor-selective agonists, GR79236 and R-PIA was dose-dependently antagonized by peripheral administration of either the non-selective adenosine receptor antagonist, 8-phenyltheophylline (8-PT, approximately 40 and 30 fold rightward shifts of the dose-response curves respectively at 10 mg kg-1, i.p.), or the adenosine A1 receptor-selective antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, approximately 20 fold shift of the GR79236 dose-response curve at 1 mg kg-1, i.p.). The hypothermic response to APNEA was similarly dose-dependently antagonized by the A1 receptor-selective antagonist, DPCPX (5 fold shift at 0.1 mg kg-1, i.p.). 4.8(p-Sulphophenyl)theophylline (8-SPT, 10 and 30 mg kg-1, i.p.), a non-selective adenosine receptorantagonist that penetrates the blood brain barrier poorly, produced only modest antagonism (approximately 2 fold shift at 30 mg kg-1, i.p.) of the hypothermic response to GR79236.5. These data suggest that hypothermia induced by adenosine analogues in the conscious mouse is mediated via adenosine A1 receptors, which are probably located in the CNS.
Adenosine↗
Characterization of the prejunctional adenosine receptors in the rat anococcygeus muscle.
Adenosine receptor agonists inhibited electrically-evoked contractions of the rat isolated anococcygeus muscle. The compounds tested were: N6-cyclopentyladenosine (CPA), N((S, trans)-2-hydroxycyclopentyl)adenosine (GR79236), the R- and S-isomers of phenylisopropyladenosine (PIA), 5'-N-ethylcarboxamidoadenosine (NECA), ((2-(4-(2-carboxyethyl)phenyl)ethyl)amino)-N-ethylcarbox-amidoa denosine (CGS 21680) and N-((2-methylphenyl)methyl)adenosine (metrifudil). The rank order of agonist potency was: CPA = R-PIA = GR79236 = NECA >> S-PIA > metrifudil > CGS 21680, which is consistent with an effect mediated by adenosine A1 receptors. A similar rank order of potency was obtained for inhibition of electrically-evoked contractions of the guinea-pig ileum. However, there may be a lower receptor reserve in rat anococcygeus compared with the guinea-pig ileum, since higher concentrations of agonists were necessary to produce effects in the anococcygeus than in the guinea-pig ileum and S-PIA behaved as a partial agonist. The effect of NECA was antagonized in rat anococcygeus and guinea-pig ileum by the mixed A1/A2 receptor antagonist, 8-phenyltheophylline (pA2 values of 6.8 and 6.9, respectively). The selective A1-receptor antagonist, 8-cyclopentyl-1,3- dipropylxanthine (DPCPX), also blocked the inhibitory response to NECA in both tissues. Here, however, the pA2 values (9.6 and 8.6, respectively) were slightly but significantly different. These values confirm that the prejunctional adenosine receptors of the rat anococcygeus are of the A1 type, and suggest that they are similar but not necessarily identical to those of the guinea-pig ileum. The differing potencies of DPCPX as an antagonist of NECA between the preparations may reflect a tissue-dependent variation in sensitivity to this antagonist.
Adenosine↗