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

We have measured the contractile activities and relative potencies (EC(50)s ) of six thrombin PAR receptor-derived receptor-activating peptides (PAR-AP s): AparafluroFRChaCit-y-NH2 (Cit-NH2); SFLLRNP(P7); SFLLRNP-NH2 (P7-NH2): SFLLR (P5); SFLLR-NH2 (PS-NH2); TFLLR-NH2 (TF-NH2) and a PAR, receptor acti vating peptide [SLIGRL-NH2 (SL-NH2)] (a) in a guinea-pig lung peripheral pa renchymal strip preparation and (b) in a gastric longitudinal smooth muscle preparation. 2 The relative potencies of the PAR-APs in the lung preparation (Cit-NH(2)c ongruent to TF-NH(2)congruent to P5-NH2>P7 congruent to P5 congruent to P7- NH2; SL-NH2 not active) differed appreciably from their relative potencies in the gastric preparation: Cit-NH(2)congruent to TF-NH(2)congruent to P7-N H(2)congruent to P5-NH2>P7>P5 congruent to SL-NH2. 3 The contractile actions of the PARI-selective peptide, TF-NH2 in the gast ric preparation were entirely dependent on extracellular calcium and were b locked by tyrosine kinase inhibitors (genistein, tyrphostin 47/AG213, PPI) and by the cyclooxygenase inhibitor, indomethacin, whereas in the lung prep aration. the PAR(1)-mediated contractile response was only partially depend ent on extracellular calcium and was refractory to the actions of either ty rosine: kinase inhibitors or indomethacin. 4 Partial sequencing of the PAR cDNAs detected by RT PCR both in whole lung and in the peripheral parenchymal strip bioassay tissue demonstrated the p resence of both PAR(1) and PAR(2) mRNA; the expression of PAR was detected by immunohistochemistry. 5 The data point to the presence of distinct receptor systems for the PAR(1 )-APs in guinea-pig lung parenchymal and gastric smooth muscle and indicate that PAR(2) does not regulate contractile activity in peripheral parenchym al guinea-pig lung tissue.