C. Cicala et al., Bronchoconstrictor effect of thrombin and thrombin receptor activating peptide in guinea-pigs in vivo, BR J PHARM, 126(2), 1999, pp. 478-484
1 Several thrombin cellular effects are dependent upon stimulation of prote
inase activated receptor-1 (PAR-1) localized over the cellular surface. Fol
lowing activation by thrombin, a new N-terminus peptide is unmasked on PAR-
1 receptor, which functions as a tethered ligand for the receptor itself. S
ynthetic peptides called thrombin receptor activating peptides (TRAPs), cor
responding to the N-terminus residue unmasked, reproduce several thrombin c
ellular effects, but are devoid of catalytic activity. We have evaluated th
e bronchial response to intravenous administration of human alpha-thrombin
or a thrombin receptor activating peptide (TRAP-9) in anaesthetized, artifi
cially ventilated guinea-pigs.
2 Intravenous injection of thrombin (100 u kg(-1)) caused bronchoconstricti
on that was recapitulated by injection of TRAP-9 (1 mg kg(-1)). animal pret
reatment with the thrombin inhibitor Hirulog(TM) (10 mg kg(-1) i.v.) preven
ted thrombin-induced bronchoconstriction, but did not affect bronchoconstri
ction induced by TRAP-9. Both agents did not induce bronchoconstriction whe
n injected intravenously to rats.
3 The bronchoconstrictor effect of thrombin and TRAP-9 was subjected to tol
erance: however, in animals desensitized to thrombin effect, TRAP-9 was sti
ll capable of inducing bronchoconstriction, but not vice versa.
4 Depleting animals of circulating platelets prevented bronchoconstriction
induced by both thrombin and TRAP-9.
5 Bronchoconstriction was paralleled by a biphasic change in arterial blood
pressure, characterized by a hypotensive phase followed by a hypertensive
phase. Thrombin-induced hypotension was not subject to tolerance and was in
hibited by Hirulog(TM); conversely, hypertension was subject to tolerance a
nd was not inhibited by Hirulog(TM). Hypotension and hypertension induced b
y TRAP-9 were neither subject to tolerance nor inhibited by Hirulog(TM)
6 Our results indicate that thrombin causes bronchoconstriction in guinea-p
igs through a mechanism that requires proteolytic activation of its recepto
r and the exposure of the tethered ligand peptide. Platelet activation migh
t be triggered by the thrombin effect.