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Biomedical subjects

J Alanko

Publications and source records attributed to J Alanko.

10 recordsLinked to original sources
PubMed1992

Effects of catecholamines on eicosanoid synthesis with special reference to prostanoid/leukotriene ratio.

Catecholamines (adrenaline, dopamine, and noradrenaline) stimulate prostanoid synthesis by acting as "cosubstrates." On the other hand, many inhibitors of leukotriene synthesis, such as nordihydroguaiaretic acid and caffeic acid, have a catecholic structure. Catecholamines have opposite effects on prostanoid and leukotriene synthesis in human polymorphonuclear leukocytes and whole blood. Basic phenols (catechol, hydroquinone, and phenol) also increase the prostanoid/leukotriene ratio in polymorphonuclear leukocytes. These actions correlate to their antioxidant capacities and oxidation potentials, and they are not mediated via adrenergic receptors. There is only limited knowledge about the effects of natural catecholamines on the prostanoid/leukotriene ratio in vitro and in vivo. Indirect data suggest that catecholamines could increase prostanoid production in physiological or pathological situations, such as heavy physical exercise, myocardial infarction, and surgical stress. This interaction may also be of clinical importance in asthma, gastric ulcer, and psoriasis, where decreased prostanoid/leukotriene ratios have been reported.

Animals↗
PubMed1992

Adrenaline stimulates thromboxane and inhibits leukotriene synthesis in man.

Catecholamines and other catecholic compounds have opposite effects on the cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism in human polymorphonuclear leukocytes and whole blood in vitro. The hypothesis that high levels of adrenaline, found e.g. in myocardial infarction, are involved in the regulation of arachidonic acid metabolism was tested. Adrenaline (0.1 micrograms/kg per min for 45 min and thereafter 0.2 micrograms/kg per min for 15 min) was infused to healthy male volunteers to mimic relationships between high levels of adrenaline and arachidonic acid metabolism in myocardial infarction. Adrenaline infusion increased Ca ionophore A23187-induced TXB2 formation in whole blood. The effect was smaller when spontaneous clotting was used as a stimulus. Urinary 11-dehydro-TXB2 excretion, an indicator of total in vivo thromboxane synthesis, increased twofold. Adrenaline infusion decreased both LTB4 and LTE4 synthesis in A23187-stimulated whole blood. These results demonstrate that high levels of adrenaline influence the cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism differentially in man.

Adult↗
PubMed1991

Catecholamines decrease leukotriene B4 and increase thromboxane B2 synthesis in A23187-stimulated human whole blood.

Catecholamines (adrenaline, dopamine, isoprenaline, noradrenaline) and caffeic acid (catecholic compound without adrenergic receptor activity) decreased leukotriene (LT)B4 synthesis in A23187-stimulated human whole blood. Salbutamol, a non-catecholic beta 2-adrenergic agonist, did not influence LTB4 synthesis. Catecholamines stimulated thromboxane (TX)B2 synthesis with a concomitant inhibition of LTB4 synthesis; caffeic acid and salbutamol did not stimulate TXB2 synthesis. These results, obtained in A23187-stimulated whole blood, which also takes into account the complex interaction between different cell types, are similar to our previous results with polymorphonuclear leukocytes. Catecholamines show an opposite effect on lipoxygenase and cyclooxygenase pathways, which may give rise to a marked change in LT/TX ratio in physiological or pathological conditions where sufficient concentrations of catecholamines are present.

Calcimycin↗
PubMed1990

Catecholamines inhibit leukotriene formation and decrease leukotriene/prostaglandin ratio.

Adrenaline, noradrenaline, isoprenaline, and to a lesser extent dopamine inhibit the release of leukotriene (LT) B2 from calcium ionophore-stimulated human polymorphonuclear leukocytes, while the release of prostaglandin (PG) E2 is proportionally elevated. The inactivity of salbutamol, a noncatechol adrenergic beta 2-receptor agonist, and the inability of propranolol to antagonize the effects of adrenaline, suggest the mediation through beta-receptor independent mechanisms. Neither are alpha-1-receptors involved, as prazosin, a specific antagonist, fails to inhibit the reaction. As the principles for biochemical regulation of LT- and PG-production are met by catecholamines in several tissues, the mechanism is considered to be of general physiological importance. Catecholamines may function as coenzymes/antioxidants which, by altering the redox state of the enzyme iron or heme, decrease the LT/PG ratio thus protecting the organism against tissue anaphylaxis and other LT-related pathophysiology.

Albuterol↗
PubMed1989

Eicosanoid production in rheumatoid synovitis.

Leukotriene B4 (LTB4) synthesis in rheumatoid synovitis was studied using peripheral and synovial fluid polymorphonuclear leukocytes (PMNs) and rheumatic synovial lining cells. No differences were found in LTB4 synthesis between peripheral PMNs from healthy volunteers and rheumatoid arthritis patients. When peripheral and synovial PMNs from the same RA patient were compared, arachidonic acid-induced LTB4 synthesis in synovial fluid PMNs was increased 1.7-7.2 fold, whereas the response to Ca ionophore A23187 stimulation was similar. This suggests 5-lipoxygenase stimulating factor(s) in inflamed joints. Rheumatic synovial lining cells in a primary cell culture produced small amounts of LTB4, the concentrations being less than 0.1 per cent of those of prostaglandin E2 (PGE2). PGE2 synthesis in synovial cells was increased when arachidonic acid or interleukin-1 was added to the culture, whereas LTB4 production remained unaltered. The present results suggest that in inflamed joints LTB4 originates mainly from PMNs whereas synovial lining cells are the source for PGE2.

Adult↗
PubMed1989

Orally administered tolfenamic acid inhibits leukotriene synthesis in isolated human peripheral polymorphonuclear leukocytes.

Special interest has been focused on the development of dual inhibitors of the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism. In contrast to other classic NSAIDs, some fenamates in clinically achievable concentrations have been shown to inhibit synthesis of 5-lipoxygenase products in vitro. In the present work, we studied the effect of orally administered tolfenamic acid (600 mg) on Ca ionophore A 23187 -induced leukotriene synthesis in isolated human polymorphonuclear leukocytes. Leukotriene production was reduced in all 14 subjects studied, the mean inhibition of LTB4 synthesis being 16 +/- 3% and that of LTC4 33 +/ 7%. The inhibition correlated positively with serum acid concentrations. We suggest that inhibition of leukotriene synthesis is an additional mechanism of the anti-inflammatory, antimigraine and antidysmenorrhoeic effects of tolfenamic acid, and a possible explanation for its rare gastric and bronchoconstrictive side-effects.

Adult↗
PubMed1988

Effects of antirheumatic drugs on leukotriene B4 and prostanoid synthesis in human polymorphonuclear leukocytes in vitro.

The effects of D-penicillamine, sodium aurothiomalate, indomethacin, timegadine and tolfenamic acid on the lipoxygenase and cyclo-oxygenase pathways of arachidonic acid metabolism were studied in human polymorphonuclear leukocytes (PMNs) in vitro. In short-term incubations, D-penicillamine and aurothiomalate did not affect leukotriene B4 (LTB4), prostaglandin E2 (PGE2) or thromboxane B2 (TXB2) production. Each of the three non-steroidal anti-inflammatory drugs (NSAIDs) used were potent inhibitors of prostanoid synthesis. In higher concentrations they also reduced LTB4 production; timegadine and tolfenamic acid were effective in concentrations comparable to those measured in plasma during drug therapy, whereas indomethacin was needed in ten times higher concentrations. The different effects of NSAIDs on 5-lipoxygenase activity may be of importance in their therapeutic actions as well as in the appearance of some side-effects, e.g. gastric irritation and "aspirin-induced" asthma.

Anti-Inflammatory Agents↗
PubMed1988

CP-66,248, a new anti-inflammatory agent, is a potent inhibitor of leukotriene B4 and prostanoid synthesis in human polymorphonuclear leucocytes in vitro.

The effects of (Z)-5-chloro-2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1H- indole-1-carboxamide (CP-66,248), a new anti-inflammatory agent, were tested on the synthesis of the pro-inflammatory arachidonic acid metabolites, LTB4 and PGE2, in isolated human peripheral polymorphonuclear leucocytes. At clinically achievable (i.e. plasma) drug concentration, CP-66,248 reduced A 23187-stimulated LTB4 (IC50 18 +/- 1 microM) and PGE2 (IC50 32 +/- 8 nM) synthesis. The corresponding IC50 values for arachidonic acid-induced LTB4 and PGE2 production were 13 +/- 4 microM and 65 +/- 15 nM, respectively. The inhibitory action of CP-66,248 towards 5-lipoxygenase was comparable with that of timegadine and exceeded that of caffeic acid, and its action against the cyclo-oxygenase pathway was similar to that of other NSAIDs tested. The dual inhibition of cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism is likely to be involved in the anti-inflammatory, antipyretic and analgetic action of CP-66,248 detected in a variety of experimental models.

Anti-Inflammatory Agents, Non-Steroidal↗