title: Protease-activated receptor-2 activation causes EDHF-like coronary vasodilation: selective preservation in ischemia/reperfusion injury: involvement of lipoxygenase products, VR1 receptors, and C-fibers.
abstract: Activation of protease-activated receptor (PAR)-2 has been proposed to be protective in myocardial ischemia/reperfusion (I/R) injury, an effect possibly related to an action on the coronary vasculature. Therefore, we investigated the effects of PAR2 activation on coronary tone in isolated perfused rat hearts and elucidated the mechanisms of any observed effects. Although having a negligible effect on ventricular contractility, the PAR2 activating peptide SLIGRL produced an endothelium-dependent coronary vasodilatation (ED(50)=3.5 nmol). Following I/R injury, the response to SLIGRL was selectively preserved, whereas the dilator response to acetylcholine was converted to constriction. Trypsin also produced a vasodilator dose-response curve that was biphasic in nature (ED(50-1)=0.36 U, ED(50-2)=38.71 U). Desensitization of PAR2 receptors indicated that the high potency phase was mediated by PAR2. Removal of the endothelium but not treatment with L-NAME (300 micromol/L), indomethacin (5 micromol/L), or oxyhemoglobin (10 micromol/L) inhibited the response to SLIGRL and trypsin. Treatment with the K(+)-channel blockers TEA (10 mmol/L), charybdotoxin (20 nmol/L)/apamin (100 nmol/L), or elevated potassium (20 mmol/L) significantly suppressed responses. Similarly, inhibition of lipoxygenase with nordihydroguaiaretic acid (1 micromol/L), eicosatetraynoic acid (1 micromol/L), or baicalein (10 micromol/L), desensitization of C-fibers using capsaicin (1 micromol/L, 20 minutes), or blockade of vanilloid (VR1) receptors using capsazepine (3 micromol/L) inhibited the responses. This study shows, for the first time, that PAR2 activation causes endothelium-dependent coronary vasodilation that is preserved after I/R injury and is not mediated by NO or prostanoids, but involves the release of an endothelium-derived hyperpolarizing factor (EDHF), possibly a lipoxygenase-derived eicosanoid, and activation of VR1 receptors on sensory C-fibers.
authors.affiliation: Centre for Clinical Pharmacology, Department of Medicine, University College London, UK. a.ahluwalia@qmul.ac.uk
authors.forename: Peter G
authors.initials: PG
authors.lastname: McLean
authors.forename: Daniel
authors.initials: D
authors.lastname: Aston
authors.forename: David
authors.initials: D
authors.lastname: Sarkar
authors.forename: Amrita
authors.initials: A
authors.lastname: Ahluwalia
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008084:Lipoxygenase / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2; D011955:Receptors, Drug / Q000378:metabolism; D018179:Receptors, Thrombin / Q000187:drug effects / Q000378:metabolism*; D014357:Trypsin / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D001685:Biological Factors; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D026902:Potassium Channel Blockers; D044464:Receptor, PAR-2; D011955:Receptors, Drug; D018179:Receptors, Thrombin; C067410:endothelium-dependent hyperpolarization factor; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; D008084:Lipoxygenase; D014357:Trypsin; C071423:capsazepine; D000109:Acetylcholine; D011188:Potassium; D002211:Capsaicin