Multiple mechanisms of vascular smooth muscle relaxation by the activation of Proteinase‐Activated Receptor 2 in mouse mesenteric arterioles

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Abstract
Activation of PAR2 in second‐order mesenteric arteriole (MA) rings from C57BL/6J, NOS3 (−/−) and PAR2 (−/−) mice was assessed for the contributions of NO, cyclo‐oxygenases, guanylyl cyclase, adenylyl cyclase, and of K+channel activation to vascular smooth muscle relaxation. PAR2 agonist, SLIGRL‐NH2(0.1 to 30 μM), induced relaxation of cirazoline‐precontracted MA from C57BL/6J and NOS3 (−/−), but not PAR2 (−/−) mice. Maximal relaxation (Emax) was partially reduced by a combination ofL‐GN‐nitroarginine methyl ester (L‐NAME), 1H‐[1,2,4]‐oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ) and indomethacin. An ODQ/L‐NAME/indomethacin resistant relaxation was also caused by trypsin (30 nM) in PAR2 (+/+), but not in PAR2 (−/−) mice. Relaxation was endothelium‐dependent and inhibited by either 30 mMKCl‐precontraction, or pretreatment with apamin, charybdotoxin, and their combination; iberiotoxin did not substitute for charybdotoxin nor did scyllatoxin substitute fully for apamin. Tetraethylammonium (TEA), glibenclamide, tetrodotoxin, 17‐octadecynoic acid, carboxy‐2‐phenyl‐4,4,5,5,‐tetramethyl‐imidazoline‐1‐oxyl‐3‐oxide, SQ22536, carbenoxolone, arachidonyl trifluoromethyl ketone, 7‐nitroindazole, N‐(3‐(aminomethyl)benzyl)acetamidine (1400W), N‐(2‐cyclohexyloxy‐4‐nitrophenyl)‐methanesulfonamide (NS‐398) and propanolol did not inhibit relaxation. 4‐aminopyridine significantly increased the potency of SLIGRL‐NH2. A combination of 30 μMBaCl2and 10 μMouabain significantly reduced the potency for relaxation, and in the presence ofL‐NAME, ODQ and indomethacin, Emaxwas reduced. We conclude PAR2‐mediated relaxation of mouse MA utilizes multiple mechanisms that are both NO‐cGMP‐dependent, and ‐independent. The data are also consistent with a role for endothelium‐dependent hyperpolarization of vascular smooth muscle that involves the activation of an apamin/charybdotoxin‐sensitive K+channel(s) and, in part, may be mediated by K+. British Journal of Pharmacology(2002)135, 155–169; doi:10.1038/sj.bjp.0704469