Role of kinins in anaphylactic-induced bronchoconstriction mediated by tachykinins in guinea-pigs.
1. In the present study, we have investigated the role of kinins in allergen-induced bronchoconstriction. 2. Anaesthetized guinea-pigs were sensitized to ovalbumin, ventilated artificially, pretreated with atropine (1.4 mumol kg-1, i.v.) and total pulmonary resistance (RL) measured. In preliminary studies in the presence of the neutral endopeptidase inhibitor, phosphoramidon (4.5 mumol kg-1, i.v.), the bradykinin B2 receptor antagonist Hoe 140 (0.1 mumol kg-1, i.v.) completely abolished the increase in RL following aerosolized bradykinin (1 mM, 40 breaths), but had no effect on the increase in RL following aerosolized neurokinin A (NKA, 10 microM, 40 breaths). On the other hand, a combination of the NK1 (CP-96,345, 2 mumol kg-1, i.v.) and NK2 (SR 48968, 0.3 mumol kg-1, i.v.) tachykinin receptor antagonists abolished completely the increase in RL produced by NKA and partially inhibited the increase in RL produced by bradykinin. These results confirm previous studies that suggest that bradykinin induces the release of tachykinins from sensory nerves in guinea-pig airways. 3. Aerosolized ovalbumin (0.5%, 5 breaths) increased RL in sensitized guinea-pigs pretreated with atropine (1.4 mmol kg-1, i.v.), an effect that began within 2 min and reached a maximum within 5 min; RL remained above baseline at 20 min. Pretreatment with the bradykinin B2 receptor antagonist, Hoe 140, decreased the bronchoconstrictor effect of ovalbumin markedly at 10 to 20 min. In the presence of phosphoramidon (4.5 mumol kg-1, i.v.) the inhibition induced by Hoe 140 was apparent earlier and remained over the 20 min period of study. 4. Pretreatment with a combination of NK1 (CP-96,345) and NK2 (SR 48968) tachykinin receptor antagonists also markedly inhibited ovalbumin-induced bronchoconstriction; addition of the bradykinin B2 receptor antagonist to the NK1 and NK2 tachykinin receptor antagonists had no additional inhibitory effect on antigen-induced bronchoconstriction.5. These findings confirm that activation of sensory nerves to release tachykinins in guinea-pig airways contribute to antigen-induced bronchoconstriction, and provide evidence that tachykinin release is due to kinins generated during the allergic response.
Cardiovascular Research Institute, University of California San Francisco.
F L
FL
Ricciardolo
J A
JA
Nadel
P D
PD
Graf
C
C
Bertrand
S
S
Yoshihara
P
P
Geppetti
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000403:Airway Resistance / Q000187:drug effects; D000707:Anaphylaxis / Q000503:physiopathology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology*; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007705:Kinins / Q000502:physiology*; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors; D015320:Tachykinins / Q000502:physiology*
D000319:Adrenergic beta-Antagonists; D001549:Benzamides; D001713:Biphenyl Compounds; D006020:Glycopeptides; D006993:Hypnotics and Sedatives; D007705:Kinins; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018041:Receptors, Neurokinin-2; D015320:Tachykinins; C073839:SR 48968; C065679:icatibant; D015260:Neprilysin; D001920:Bradykinin; C008890:phosphoramidon; C066892:CP 96345