Multiple mechanisms of vascular smooth muscle relaxation by the activation of proteinase-activated receptor 2 in mouse mesenteric arterioles

John J. McGuire, Morley D. Hollenberg, Patricia Andrade-Gordon, Christopher Triggle

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

1. 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. 2. 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 of L-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 mM KCl-precontraction, or pretreatment with apamin, charybdotoxin, and their combination; iberiotoxin did not substitute for charybdotoxin nor did scyllatoxin substitute fully for apamin. 3. 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-cyclo-hexyloxy-4-nitrophenyl)-methanesulfonamide (NS-398) and propanolol did not inhibit relaxation. 4-aminopyridine significantly increased the potency of SLIGRL-NH2. A combination of 30 μM BaCl2 and 10 μM ouabain significantly reduced the potency for relaxation, and in the presence of L-NAME, ODQ and indomethacin, Emax was reduced. 4. 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+.

Original languageEnglish
Pages (from-to)155-169
Number of pages15
JournalBritish Journal of Pharmacology
Volume135
Issue number1
DOIs
Publication statusPublished - 2002
Externally publishedYes

Fingerprint

PAR-2 Receptor
Muscle Relaxation
Arterioles
Charybdotoxin
Apamin
Vascular Smooth Muscle
Nitroarginine
Indomethacin
Esters
Endothelium
Carbenoxolone
Imidazolines
4-Aminopyridine
Tetraethylammonium
Glyburide
Guanylate Cyclase
Tetrodotoxin
Ouabain
Prostaglandin-Endoperoxide Synthases
Adenylyl Cyclases

Keywords

  • Endothelium-dependent hyperpolarizing factor
  • Endothelium-dependent relaxing factors
  • Mesentery artery
  • Nitric oxide synthase
  • Proteinase-activated receptor 2

ASJC Scopus subject areas

  • Pharmacology

Cite this

Multiple mechanisms of vascular smooth muscle relaxation by the activation of proteinase-activated receptor 2 in mouse mesenteric arterioles. / McGuire, John J.; Hollenberg, Morley D.; Andrade-Gordon, Patricia; Triggle, Christopher.

In: British Journal of Pharmacology, Vol. 135, No. 1, 2002, p. 155-169.

Research output: Contribution to journalArticle

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AU - Triggle, Christopher

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N2 - 1. 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. 2. 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 of L-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 mM KCl-precontraction, or pretreatment with apamin, charybdotoxin, and their combination; iberiotoxin did not substitute for charybdotoxin nor did scyllatoxin substitute fully for apamin. 3. 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-cyclo-hexyloxy-4-nitrophenyl)-methanesulfonamide (NS-398) and propanolol did not inhibit relaxation. 4-aminopyridine significantly increased the potency of SLIGRL-NH2. A combination of 30 μM BaCl2 and 10 μM ouabain significantly reduced the potency for relaxation, and in the presence of L-NAME, ODQ and indomethacin, Emax was reduced. 4. 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+.

AB - 1. 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. 2. 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 of L-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 mM KCl-precontraction, or pretreatment with apamin, charybdotoxin, and their combination; iberiotoxin did not substitute for charybdotoxin nor did scyllatoxin substitute fully for apamin. 3. 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-cyclo-hexyloxy-4-nitrophenyl)-methanesulfonamide (NS-398) and propanolol did not inhibit relaxation. 4-aminopyridine significantly increased the potency of SLIGRL-NH2. A combination of 30 μM BaCl2 and 10 μM ouabain significantly reduced the potency for relaxation, and in the presence of L-NAME, ODQ and indomethacin, Emax was reduced. 4. 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+.

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KW - Mesentery artery

KW - Nitric oxide synthase

KW - Proteinase-activated receptor 2

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