Presence and bronchomotor activity of protease-activated receptor-2 in guinea pig airways.
The protease activated receptor-2 (PAR-2) belongs to a family of G-protein-coupled receptors that are activated by proteolysis. Trypsin cleaves PAR-2, exposing an N-terminal tethered ligand (SLIGRL) that activates the receptor. Messenger RNA (mRNA) for PAR-2 was found in guinea pig airway tissue by reverse transcription-polymerase chain reaction, and PAR-2 was found by immunohistochemistry in airway epithelial and smooth-muscle cells. In anesthetized guinea pigs, trypsin and SLIGRL-NH(2) (given intratracheally or intravenously) caused a bronchoconstriction that was inhibited by the combination of tachykinin-NK(1) and -NK(2) receptor antagonists and was potentiated by inhibition of nitric oxide synthase (NOS). Trypsin and SLIGRL-NH(2) relaxed isolated trachea and main bronchi, and contracted intrapulmonary bronchi. Relaxation of main bronchi was abolished or reversed to contraction by removal of epithelium, administration of indomethacin, and NOS inhibition. PAR-1, PAR-3, and PAR-4 were not involved in the bronchomotor action of either trypsin or SLIGRL-NH(2), because ligands of these receptors were inactive either in vitro or in vivo, and because thrombin (a PAR-1 and PAR-3 agonist) did not show cross-desensitization with PAR-2 agonists in vivo. Thus, we have localized PAR-2 to the guinea-pig airways, and have shown that activation of PAR-2 causes multiple motor effects in these airways, including in vivo bronchoconstriction, which is in part mediated by a neural mechanism.
Ricciardolo
F L
FL
Department of Experimental and Clinical Medicine and Pharmaceutical Chemistry, University of Ferrara, Ferrara, Italy.
Steinhoff
M
M
Amadesi
S
S
Guerrini
R
R
Tognetto
M
M
Trevisani
M
M
Creminon
C
C
Bertrand
C
C
Bunnett
N W
NW
Fabbri
L M
LM
Salvadori
S
S
Geppetti
P
P
D000403:Airway Resistance / Q000502:physiology; D000818:Animals; D001980:Bronchi / Q000737:chemistry / Q000502:physiology*; D016084:Bronchoconstriction / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000032:analysis / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013917:Thrombin / Q000494:pharmacology; D014132:Trachea / Q000737:chemistry / Q000502:physiology*; D014357:Trypsin / Q000494:pharmacology
D009842:Oligopeptides; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; C109968:seryl-leucyl-isoleucyl--glycyl-lysyl-valine; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; D014357:Trypsin; D013917:Thrombin