Contractile actions of proteinase-activated receptor-derived polypeptides in guinea-pig gastric and lung parenchymal strips: evidence for distinct receptor systems

摘要

class="enumerated" style="list-style-type:decimal">We have measured the contractile activities and relative potencies (EC50s) of six thrombin PAR1 receptor-derived receptor-activating peptides (PAR-APs): AparafluroFRChaCit-y-NH2 (Cit-NH2); SFLLRNP(P7); SFLLRNP-NH2 (P7-NH2); SFLLR (P5); SFLLR-NH2 (P5-NH2); TFLLR-NH2 (TF-NH2) and a PAR2 receptor activating peptide [SLIGRL-NH2 (SL-NH2)] (a) in a guinea-pig lung peripheral parenchymal strip preparation and (b) in a gastric longitudinal smooth muscle preparation.The relative potencies of the PAR-APs in the lung preparation (Cit-NH2≅TF-NH2≅P5-NH2>P7≅P5≅P7-NH₂; SL-NH₂ not active) differed appreciably from their relative potencies in the gastric preparation: Cit-NH₂≅TF-NH₂≅P7-NH₂≅P5-NH₂>P7≅percnt;SL-NH₂.The contractile actions of the PAR₁-selective peptide, TF-NH₂ in the gastric preparation were entirely dependent on extracellular calcium and were blocked by tyrosine kinase inhibitors (genistein, tyrphostin 47/AG213, PP1) and by the cyclooxygenase inhibitor, indomethacin, whereas in the lung preparation, the PAR₁-mediated contractile response was only partially dependent on extracellular calcium and was refractory to the actions of either tyrosine kinase inhibitors or indomethacin.Partial sequencing of the PAR cDNAs detected by RT – PCR both in whole lung and in the peripheral parenchymal strip bioassay tissue demonstrated the presence of both PAR₁ and PAR₂ mRNA; the expression of PAR₂ was detected by immunohistochemistry.The data point to the presence of distinct receptor systems for the PAR₁-APs in guinea-pig lung parenchymal and gastric smooth muscle and indicate that PAR₂ does not regulate contractile activity in peripheral parenchymal guinea-pig lung tissue