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Titolo:
THE INDUCTION OF A BIPHASIC BRONCHOSPASM BY THE ET(B) AGONIST, IRL-1620, DUE TO THROMBOXANE-A(2) GENERATION AND ENDOTHELIN-1 RELEASE IN GUINEA-PIGS
Autore:
NOGUCHI S; KASHIHARA Y; BERTRAND C;
Indirizzi:
CIBA GEIGY LTD,ASTHMA & ALLERGY DEPT CH-4002 BASEL SWITZERLAND CIBA GEIGY LTD,ASTHMA & ALLERGY DEPT CH-4002 BASEL SWITZERLAND CIBA GEIGY JAPAN,DIV PHARMA,DRUG DISCOVERY RES UNIT,RES & DEV TAKARAZUKA HYOGO 665 JAPAN
Titolo Testata:
British Journal of Pharmacology
fascicolo: 6, volume: 118, anno: 1996,
pagine: 1397 - 1402
SICI:
0007-1188(1996)118:6<1397:TIOABB>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
SMOOTH-MUSCLE; BRONCHOALVEOLAR LAVAGE; RECEPTOR ANTAGONIST; POTENT; CONTRACTION; CELLS; ET-1; LUNG; BRONCHOPULMONARY; ENKEPHALINASE;
Keywords:
IRL 1620; ET(B) SELECTIVE AGONIST; BQ 123; BQ 788; BRONCHOCONSTRICTION; THROMBOXANE A(2) (TXA(2)); AUTOCRINE RELEASE OF ET-1; PHOSPHORAMIDON;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
35
Recensione:
Indirizzi per estratti:
Citazione:
S. Noguchi et al., "THE INDUCTION OF A BIPHASIC BRONCHOSPASM BY THE ET(B) AGONIST, IRL-1620, DUE TO THROMBOXANE-A(2) GENERATION AND ENDOTHELIN-1 RELEASE IN GUINEA-PIGS", British Journal of Pharmacology, 118(6), 1996, pp. 1397-1402

Abstract

1 IRL 1620 (0.01-0.1 mg kg(-1), i.v.), a selective endothelin B (ET(B)) receptor agonist, induced a dose-dependent biphasic increase in total lung resistance and a decrease in dynamic compliance in anaesthetized and artificially ventilated guinea-pigs. After intravenous injection of IRL 1620 (0.03 mg kg(-1)), the first phase was observed within 2 min whereas the second phase started between 5 and 10 min after injection and was long lasting. 2 In order to characterize which endothelin receptors are involved in both phases of bronchoconstriction, we studied the effect of ET(A) and ET(B) receptor antagonists (BQ 123 and BQ 788, respectively). BQ 788 (0.1-1 mg kg(-1), i.v.) inhibited, in a dose-dependent manner, both phases of bronchoconstriction. BQ 123 (3 mg kg(-1), i.v.) markedly inhibited (by 76%) the second phase of bronchoconstriction but had no effect on the early component of the response. 3 The effect of atropine, neurokinin-1 (NK1) and neurokinin-2 (NK2) receptor antagonists (SR140333 and SR48968, respectively) were tested to investigate the possible involvement of cholinergic and sensory nerve activation, respectively, in the response to IRL 1620. Likewise, the role of arachidonic acid metabolites (leukotriene D-4 antagonist, ONO-1078 and thromboxane A(2) (TXA(2)) inhibitor, OKY-046) in this response was also investigated. OKY-046 (1 mg kg(-1), i.v.) and atropine (1 mg kg(-1), i.v.) partially inhibited the first phase (by 80% and 20%, respectively) without affecting the late phase of bronchoconstriction. Neither ONO-1078 (1 mg kg(-1), i.v.) nor the combination of SR140333 (0.2 mg kg(-1), i.v.) and SR 48968 (0.2 mg kg(-1), i.v.) modified IRL 1620-induced bronchoconstriction. 4 A low dose of IRL 1620 (0.005 mg kg(-1), i.v.) induced a monophasic bronchoconstriction. Pretreatment by phosphoramidon (100 mu mol kg(-1), i.v.) restored the second phase of bronchoconstriction. In this condition, BQ 123 (3 mg kg(-1), i.v.) was able to inhibit partially the second phase of bronchoconstriction. 5 These results suggest that both phases of bronchoconstriction induced byIRL 1620 were mediated primarily by ET(B) receptor activation, the first phase being a consequence of TXA(2) and acetylcholine release. Theinhibition by an ET(A) receptor antagonist and the restoration by a neutral endopeptidase (NEP) inhibitor of the second phase of bronchoconstriction suggests that primary activation of ET(B) receptors leads toautocrine/paracrine endothelin-1 (ET-1) release that would subsequently cause profound bronchoconstriction through both ET(A) and ET(B) receptor activation.

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Documento generato il 13/07/20 alle ore 16:18:11