Screening and Assessment of the Potency of Anti-Inflammatory Drugs in vitro

Gryglewski, Ryszard J.

doi:10.1007/978-3-642-66891-3_1

Cited by 26 publications

(24 citation statements)

References 262 publications

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“…This firlding is not surprising since naproxen is much less potent than indomethacin as an inhibitor of cyclooxygenase activity (24). The release of 45Ca in control cultures and in bradykinin-stimulated cultures was reduced by 5 , 8 , l l ,14-eicosatetraenoic acid, a competitive inhibitor of arachidonic acid metabolism through both the cyclooxygenase and lipoxygenase pathways (Table 5).…”

Section: Resultsmentioning

confidence: 95%

Bradykinin, a new potential mediator of inflammation‐induced bone resorption

Lerner

Jones

Gustafson

1987

Arthritis & Rheumatism

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The effect of bradykinin and desArg'-bradykinin on bone was studied in cultures of calvarial bones taken from 6-7-day-old mice. Bradykinin, at and above a 3-nM concentration, caused a dose-dependent stimulation of bone mineral mobilization and matrix degradation. Bradykinin-stimulated resorption was inhibited by calcitonin, an increased concentration of phosphate in the culture medium, hydrocortisone, dexamethasone, indomethacin, meclofenamic acid, naproxen, and 5,8,11,14-eicosatetraenoic acid. The results suggest that bradykinin stimulates osteoclast-mediated bone resorption by a process that is dependent on endogenous prostaglandin production. The stimulatory effect of bradykinin, but not of parathyroid hormone and prostaglandin E2, was potentiated by the angiotensinconverting enzyme inhibitor, BPPs,. Treatment with carboxypeptidase B did not affect the capacity of the peptide to stimulate 45Ca release. DesArg'-bradykinin (1 pnole/liter) stimulated 45Ca release to the same degree as did bradykinin. Bradykinin (3 pM) did not affect the degradation of cartilage proteoglycans, as assessed by the release of 35S-sulfate from prelabeled calf articular cartilage in organ culture. These findings suggest that generation of bradykinin in inflammatory lesions of rheumatoid arthritis and periodontitis may -____ contribute to the bone resorptive process seen in the joints and alveolar bone; however, bradykinin does not directly activate chondrocytes into a catabolic state.Destruction of soft tissues and mineralized tissues is a characteristic finding in rheumatoid arthritis (RA) and periodontitis, the most common chronic inflammatory processes. The inflammatory lesions of RA and periodontal disease are composed of different cell types that are capable of producing degradative enzymes. These enzymes can be released extracellularly and, thereby, contribute to the breakdown of surrounding cartilage and fibrous tissues. Bone destruction is a consequence of the interaction of inflammatory cells and multinuclear osteoclasts, the cells responsible for the breakdown of bones. Potential mediators involved in the communication between inflammatory mononuclear cells and osteoclasts include osteoclast-activating factor, which is synthesized by stimulated lymphocytes (for review, see ref. l), prostaglandin E2 (PGE2) (for review, see ref.2), and nonprostanoid products released by monocytes (3,4), especially interleukin-I (5,6). To this list, we have recently added thrombin (7), a serine esterase that is generated during the coagulation cascade.Bradykinin is a small vasoactive peptide that is formed by the cleavage of high molecular weight kininogen by kallikrein (for review, see ref. 8). It is known primarily for its effects on vascular tone and permeability (for review, see ref. 8). In areas of inflammation, bradykinin may be formed in parallel with the generation of thrombin, since prekallikrein is activated to kallikrein by coagulation factor XIIa (Hageman factor) (9,lO). This fact has prompted our study of the possible role of the k...

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Section: Resultsmentioning

confidence: 95%

Bradykinin, a new potential mediator of inflammation‐induced bone resorption

Lerner

Jones

Gustafson

1987

Arthritis & Rheumatism

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“…Gryglewski (1979) has shown that naproxen (1 pM) effectively inhibits cyclo-oxygenase. If the EP receptors were tonically activated by endogenous arachidonic acid metabolites, the exogenous prostaglandin would compete with the endogenously formed prostanoids resulting in an apparently lower potency of the exogenous agonist.…”

Section: Discussionmentioning

confidence: 99%

Modulation of noradrenaline release from the sympathetic nerves of the human saphenous vein and pulmonary artery by presynaptic EP₃‐ and DP‐receptors

Molderings

Colling²,

Likungu³

et al. 1994

British J Pharmacology

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1 Spirally cut strips of the human saphenous vein and pulmonary artery were used to determine the pharmacological properties of the presynaptic prostanoid receptors involved in the modulation of sympathetic [3H]-noradrenaline release. Strips preincubated with [3H]-noradenaline were superfused with physiological salt solution containing inhibitors of uptake, and uptake2 and rauwolscine to eliminate involvement of presynaptic M2-adrenoceptors. Tritium overflow was evoked by transmural electrical stimulation (standard frequency: 2 Hz).2 In the saphenous vein, prostaglandin E2 (PGE2) inhibited the electrically-evoked tritium overflow; at the highest concentration investigated, tritium overflow was inhibited by more than 75% and the pECO value was 7.00. These effects were mimicked by prostaglandin El, the EPI/EP3 receptor agonist, sulprostone and the EP2/EP3 receptor agonist, misoprostol with the rank order (pECm): sulprostone (8.60) > PGE1 (7.25) > misoprostol (6.96). This rank order of potency suggests that the inhibitory effect of the drugs is mediated by presynaptic EP3-receptors. In contrast, PGF2, did not inhibit evoked tritium overflow; the IP/EP1 receptor agonist iloprost and the stable thromboxane A2 analogue U 46619 (9, 11-dideoxy-lla,9a-epoxy-methanoprostaglandin F2.) produced inhibition only at concentrations above 1 JiM. 3 The EP1-receptor antagonist, AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) had no effect on the evoked tritium overflow nor did it modify the inhibitory effect of PGE2, further excluding involvement of inhibitory presynaptic EPI-receptors.4 PGD2 caused a facilitation of evoked tritium overflow in the saphenous vein; this facilitation is probably mediated by presynaptic DP-receptors, since it was abolished by the selective DP-receptor antagonist, BW A868C (3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamino)hydantoin). 5In the pulmonary artery, sulprostone (pECm value 8.35), misoprostol (7.70) and PGE2 (6.80) inhibited electrically-evoked tritium overflow. This rank order of potency is consistent with the involvement of inhibitory presynaptic EP3-receptors. 6 These results suggest that the sympathetic nerve fibres of both human saphenous vein and pulmonary artery are endowed with presynaptic inhibitory EP3 receptors. The EP3-receptors do not interact with the a2-autoreceptors. In addition, the human saphenous vein seems to be endowed with presynaptic facilitatory DP-receptors.

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“…The other possible mechanism by which this effect could be obtained might be through the inhibition of prostaglandins and thromboxane A2 synthesis and their release. It is well-established that non-steroidal antiinflammatory agents inhibit the conversion of arachidonic acid into prostaglandins and thromboxane A2 (Gryglewski, 1979). Inhibition of prostaglandin synthesis cannot be an anti-arrhythmic mechanism as this would facilitate the arrhythmia rather than prevent its appearance (Brasch, 1984).…”

Section: Discussionmentioning

confidence: 99%

Effect of some non‐steroidal anti‐inflammatory drugs on ouabain‐induced arrhythmias in guinea‐pigs

Tripathi

Kaushal

1988

British J Pharmacology

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Screening and Assessment of the Potency of Anti-Inflammatory Drugs in vitro

Cited by 26 publications

References 262 publications

Bradykinin, a new potential mediator of inflammation‐induced bone resorption

Bradykinin, a new potential mediator of inflammation‐induced bone resorption

Modulation of noradrenaline release from the sympathetic nerves of the human saphenous vein and pulmonary artery by presynaptic EP₃‐ and DP‐receptors

Effect of some non‐steroidal anti‐inflammatory drugs on ouabain‐induced arrhythmias in guinea‐pigs

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Screening and Assessment of the Potency of Anti-Inflammatory Drugs in vitro

Cited by 26 publications

References 262 publications

Bradykinin, a new potential mediator of inflammation‐induced bone resorption

Bradykinin, a new potential mediator of inflammation‐induced bone resorption

Modulation of noradrenaline release from the sympathetic nerves of the human saphenous vein and pulmonary artery by presynaptic EP3‐ and DP‐receptors

Effect of some non‐steroidal anti‐inflammatory drugs on ouabain‐induced arrhythmias in guinea‐pigs

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Modulation of noradrenaline release from the sympathetic nerves of the human saphenous vein and pulmonary artery by presynaptic EP₃‐ and DP‐receptors