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Proteinase-activated receptor-2 activating peptides: Distinct canine coronary artery receptor systems

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American Journal of Physiology - Heart and Circulatory Physiology





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In canine coronary artery preparations, the proteinase-activated receptor-2 (PAR2) activating peptides (PAR2-APs) SLIGRL-NH 2 and 2-furoyl-LIGRLO-NH2 caused both an endothelium-dependent relaxation and an endothelium-independent contraction. Relaxation was caused at peptide concentrations 10-fold lower than those causing a contractile response. Although trans-cinnamoyl-LIGRLO-NH2, like other PAR2-APs, caused relaxation, it was inactive as a contractile agonist and instead antagonized the contractile response to SLIGRL-NH 2. RT-PCR-based sequencing of canine PAR2 revealed a cleavage/activation (indicated by underlines) sequence (SKGR/SLIGKTDSSLQITGKG) that is very similar to the human PAR2 sequence (R/SLIGKV). As a synthetic peptide, the canine PAR-AP (SLIGKT-NH2) was a much less potent agonist than either SLIGRL-NH2 or 2-furoyl-LIGRLO-NH 2, either in the coronary contractile assay or in a Madin-Darby canine kidney (MDCK) cell PAR2 calcium signaling assay. In the MDCK signaling assay, the order of potencies was as follows: 2-furoyl-LIGRLO-NH 2 ≫ SLIGRL-NH2 = trans-cinnamoyl-LIGRLO-NH2 ≫ SLIGKT-NH2, as expected for PAR2 responses. In the coronary contractile assay, however, the order of potencies was very different: SLIGRL-NH2 ≫ 2-furoyl-LIGRLO-NH2 ≫ SLIGKT-NH 2, trans-cinnamoyl-LIGRLO-NH2 = antagonist. Because of 1) the distinct agonist (relaxant) and antagonist (contractile) activity of trans-cinnamoyl-LIGRLO-NH2 in the canine coronary contractile assays, 2) the different concentration ranges over which the peptides caused either relaxation or contraction in the same coronary preparation, and 3) the markedly distinct structure-activity profiles for the PAR-APs in the coronary contractile assay, compared with those for PAR2-mediated MDCK cell calcium signaling, we suggest that the canine coronary tissue possesses a receptor system for the PAR-APs that is distinct from PAR2 itself. Copyright © 2007 the American Physiological Society.

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