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Molecular and pharmacological evidence for modulation of kinin B 1 receptor expression by endogenous glucocorticoids hormones in rats
Author(s) -
Cabrini Daniela A,
Campos Maria M,
Tratsk Karla S,
Merino Vanessa F,
Silva José A,
Souza Glória E P,
Avellar Maria C W,
Pesquero João B,
Calixto João B
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703846
Subject(s) - dexamethasone , medicine , endocrinology , agonist , glucocorticoid receptor , receptor , kinin , glucocorticoid , chemistry , endogeny , hormone , bradykinin , pharmacology
The effect of endogenous glucocorticoid hormones on the expression of rat B 1 receptors was examined by means of molecular and pharmacological functional approaches. Rats were adrenalectomized (ADX), and 7 days after this procedure the intradermal injection of B 1 receptor agonist des‐Arg 9 ‐BK produced a significant increase in the paw volume, while only a weak effect was observed in sham‐operated animals. A similar increase in the contractile responses mediated by B 1 agonist des‐Arg 9 ‐BK was also observed in the rat portal vein in vitro . Chemical ADX performed with mitotane (a drug that reduces corticosteroid synthesis) produced essentially the same up‐regulation of B 1 receptors as that observed in ADX rats. The modulation of B 1 receptor expression was evaluated by ribonuclease protection assay, employing mRNA obtained from the lungs and paw of ADX rats. Additionally, both paw oedema and contraction of portal vein mediated by B 1 agonist des‐Arg 9 ‐BK in ADX rats, were markedly inhibited by treatment with dexamethasone, or COX‐2 inhibitor meloxican, or with the NF‐κB inhibitor PDTC. Interestingly, the same degree of inhibition was achieved when the animals were treated with a combination of submaximal doses of dexamethasone and PDTC. The involvement of NF‐κB pathway was further confirmed by mobility shift assay using nuclear extracts from lung, paw and heart of ADX rats. It was also confirmed that the treatment of ADX rats with dexamethasone, PDTC or dexamethasone plus PDTC completely inhibit NF‐κB activation caused by absence of endogenous glucucorticoid. Together, the results of the present study provide, for the first time, molecular and pharmacological evidence showing that B 1 kinin receptor expression can be regulated through endogenous glucocorticoids by a mechanism dependent on NF‐κB pathway. Clinical significance of the present findings stem from evidence showing the importance of B 1 kinin receptors in the mediation of inflammatory and pain related responses.British Journal of Pharmacology (2001) 132 , 567–577; doi: 10.1038/sj.bjp.0703846