Dual modulation by thrombin of the motility of rat oesophageal muscularis mucosae via two distinct protease‐activated receptors (PARs): a novel role for PAR‐4 as opposed to PAR‐1

• Published in: British journal of pharmacology Vol. 131; no. 3; pp. 578 - 584
• Main Authors: Kawabata, Atsufumi, Kuroda, Ryotaro, Kuroki, Naoko, Nishikawa, Hiroyuki, Kawai, Kenzo
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2000; Nature Publishing
• Subjects: Animals; Biological and medical sciences; Carbachol - pharmacology; Cell receptors; Cell structures and functions; Cholinergic Agents - pharmacology; Esophagus - drug effects; Esophagus - physiology; Fundamental and applied biological sciences. Psychology; Humans; In Vitro Techniques; L‐type Ca2+ channels; Male; Miscellaneous; Molecular and cellular biology; motility modulation; Muscle Contraction - drug effects; Muscle Relaxation; Na+ permeability; oesophageal muscularis mucosae; Protease (proteinase)‐activated receptor (PAR); protease-activated receptors; Rats; Rats, Wistar; Receptor, PAR-1; Receptors, Thrombin - physiology; thrombin; Thrombin - physiology; Trypsin - pharmacology; Agonist; Motility; Rat; Enzyme; Digestive system; Rodentia; Contractility; Smooth muscle; Ionic channel; Biological activity; Esophagus; Peptidases; Vertebrata; Mammalia; Calcium ion; Thrombin(drug); Animal; Sodium ion; Hydrolases; Muscularis; Biological receptor
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0703590

Since protease‐activated receptors (PARs) are distributed throughout the gastrointestinal tract, we investigated the role of PARs in modulation of the motility of the rat oesophageal muscularis mucosae. Thrombin produced contraction of segments of the upper and lower part of the smooth muscle. Trypsin contracted both the muscle preparations only at high concentrations. SFLLR‐NH2 and TFLLR‐NH2 (PAR‐1‐activating peptides), but not the PAR‐1‐inactive peptide FSLLR‐NH2, evoked a marked contraction. In contrast, the PAR‐2 agonist SLIGRL‐NH2 and the PAR‐4 agonist GYPGKF‐NH2 caused no or only a negligible contraction. In oesophageal preparations precontracted with carbachol, thrombin produced a dual action i.e. relaxation followed by contraction. TFLLR‐NH2 further contracted the precontracted preparations with no preceding relaxation. GYPGKF‐NH2, but not the inactive peptide GAPGKF‐NH2, produced marked relaxation. Trypsin or SLIGRL‐NH2 caused no relaxation. The PAR‐1‐mediated contraction was completely abolished in Ca2+‐free medium and considerably attenuated by nifedipine (1 μM) and in a low Na+ medium. The PAR‐4‐mediated relaxation was resistant to tetrodotoxin (10 μM), apamin (0.1 μM), charybdotoxin (0.1 μM), L‐NG‐nitroarginine methyl ester (100 μM), indomethacin (3 μM), propranolol (5 μM) or adenosine 3′,5′‐cyclic monophosphorothioate, 8‐bromo, Rp‐isomer (30 μM). Thus, thrombin plays a dual role in modulating the motility of the oesophageal muscularis mucosae, producing contraction via PAR‐1 and relaxation via PAR‐4. The PAR‐1‐mediated effect appears to occur largely through increased Na+ permeability followed by activation of L‐type Ca2+ channels and subsequent influx of extracellular Ca2+. Our data could provide evidence for a novel role of PAR‐4 as opposed to PAR‐1, although the underlying mechanisms are still open to question. British Journal of Pharmacology (2000) 131, 578–584; doi:10.1038/sj.bjp.0703590