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17 β -Estradiol induces vasorelaxation in a G protein-coupled receptor 30-independent manner

Reference Figure. 17 β -Estradiol induces vasorelaxation in a G protein-coupled receptor 30-independent manner Young Mi Seok 1 , Eun Jin Jang 2 , Oliver Reiser 3 , Markus Hager 3 , and In Kyeom Kim 1,2,4 *

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17 β -Estradiol induces vasorelaxation in a G protein-coupled receptor 30-independent manner

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  1. Reference Figure 17β-Estradiol induces vasorelaxation in a G protein-coupled receptor 30-independent manner Young Mi Seok1, Eun Jin Jang2, Oliver Reiser3,Markus Hager3, and In KyeomKim1,2,4* 1Cardiovascular Research Institute, 2Department of Pharmacology, 4Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, 700-422, Republic of Korea; 3Organic Chemistry institute, University of Regensburg, Universitätsstr.31, Regensburg, Germany *Correspondence and Proofs In Kyeom Kim, M.D., Ph.D. Department of Pharmacology Kyungpook National University School of Medicine 101 Dongin-2-Ga Daegu, 700-422, Republic of Korea Tel: +82-53-420-4833 Fax: +82-53-426-7345 E-mail: inkim@knu.ac.kr

  2. Reference Fig. 1 (a) (b) ** ** ** * ET(+) ET(+) 6.0 5.5 5.0 4.5 4.0 6.0 5.5 5.0 4.5 4.0

  3. Reference Fig. 1.Effect of various antagonists on vascular relaxation induced by 17β-estradiol (E2) orGPR30 agonist G1. E2 (a) or G1 (b) were added cumulatively to elicit relaxation when vascular contraction induced by U46619 (30 nmol/L) reached plateaus in endothelium-intact rat aortic rings pretreated with the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester (L-NAME, 100 μmol/L), the ERα/ERβ antagonist ICI 182,780 (10 μmol/L), the ERα-specific antagonist methyl-piperidino-pyrazole (MPP, 100 μmol/L) or vehicle (0.1% DMSO) for 30 minutes. Relaxation is expressed as a percentage of the maximal contraction. Data are expressed as mean ± SEM. Data were analyzed by repeated measures ANOVA followed by Tukey’s test (n=4 per group). One asterisk (*) P < 0.05, two asterisks (**) P < 0.01 vs. vehicle.

  4. Reference Fig. 2 1.0 3.0 10 30 100 SNP (100 nmol/L) (a) ET(+) 20 0 G1 (μmol/L) (mN) KCl 30 nmol/L U46619 1.0 3.0 10 (b) ET(-) 30 100 SNP (100 nmol/L) 20 0 (mN) G1 (μmol/L) KCl 30 nmol/L U46619

  5. Reference Fig. 2.Effect of sodium nitroprusside (SNP) on vascular relaxation induced by GPR30 agonist G1. Representative traces show relaxing responses to SNP. G1 was added cumulatively to elicit relaxation when vascular contraction induced by U46619 (30 nmol/L) reached plateaus in endothelium-intact (a) or –denuded (b) rat aortic rings. The addition of G1 was followed by 100 nmol/L SNP.

  6. Reference Fig. 3 # ** # ** * ET(+) 6.0 5.5 5.0 4.5 4.0

  7. Reference Fig. 3.Effect of GPR30 antagonist G15 on vascular relaxation induced by GPR30 agonist G1.G1 was added cumulatively to elicit relaxation when vascular contraction induced by U46619 (30 nmol/L) reached plateaus in endothelium-intact rat aortic rings pretreated with the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester (L-NAME, 100 μmol/L), L-NAME and G15 (100 μmol/L), G15 alone or vehicle (0.1% DMSO) for 30 minutes. Relaxation is expressed as a percentage of the maximal contraction. Data are expressed as mean ± SEM. Data were analyzed by repeated measures ANOVA followed by Tukey’s test (n=4 per group). One asterisk (*) P < 0.05, two asterisks (**) P < 0.01 vs. vehicle. One number sign (#) P < 0.05 vs. L-NAME alone.

  8. Reference Fig. 4 (a) (b) ** * ** ** ET(+) ET(+) 6.0 5.5 5.0 4.5 4.0 6.0 5.5 5.0 4.5 4.0 (c) (d) ET(-) ET(-) 6.0 5.5 5.0 4.5 4.0 6.0 5.5 5.0 4.5 4.0

  9. Reference Fig. 4.Effect of soluble guanylatecyclase blocker 1H-[1,2,4]-oxadizolo[4,3-a]quinoxalin-1-one (ODQ) on vascular relaxation induced by 17β-estradiol (E2) or GPR30 agonist G1. E2 or G1 were added cumulatively to elicit relaxation when vascular contraction induced by U46619 (30 nmol/L) reached plateaus in endothelium-intact [ET (+), a and b] or -denuded [ET (-), c and d] rat aortic rings pretreated with ODQ (1.0, or 10 μmol/L) or vehicle (0.1% DMSO) for 30 minutes. Relaxation is expressed as a percentage of the maximal contraction. Data are expressed as mean ± SEM. Data were analyzed by repeated measures ANOVA followed by Tukey’s test (n=4). One asterisk (*) P < 0.05, two asterisks (**) P < 0.01 vs. vehicle.

  10. Reference Fig. 5 17β-Estradiol attenuates vascular contraction through inhibition of RhoA/Rho kinase pathway. NaunynSchmiedebergs Arch Pharmacol. 2009 Jul;380(1):35-44.

  11. Reference Fig. 6 (a) (b) * * ET(+) ET(+) 6.0 5.5 5.0 4.5 4.0 6.0 5.5 5.0 4.5 4.0

  12. Reference Fig. 6.Effect of various antagonists on vascular relaxation induced by 17β-estradiol (E2). E2 was added cumulatively to elicit relaxation when vascular contraction induced by U46619 (30 nmol/L) reached plateaus in endothelium-intact rat aortic rings pretreated with the phosphatidylinositol3-kinase inhibitor LY294002 (10 μmol/L, a), the phosphatidylinositol 3-kinase inert LY analogue LY303511 (10 μmol/L, a), the cAMP-dependent protein kinase inhibitor H89 (10 μmol/L, b), or vehicle (0.1% DMSO) for 30 minutes. Relaxation is expressed as a percentage of the maximal contraction. Data are expressed as mean ± SEM. Data were analyzed by repeated measures ANOVA followed by Tukey’s test (n=4 per group). One asterisk (*) P < 0.05 vs. vehicle.

  13. Reference Fig. 7 10 100 0.01 0.1 1.0 (a) ET(+) Vehicle (DMSO) 20 Isoproterenol (μmol/L) 0 (mN) KCl 30 nmol/L U46619 100 0.01 0.1 10 1.0 1.0 μmol/L H89 20 Isoproterenol (μmol/L) 0 KCl (mN) 30 nmol/L U46619 100 0.01 0.1 1.0 10 10 μmol/L H89 20 Isoproterenol (μmol/L) 0 KCl (mN) 30 nmol/L U46619

  14. Reference Fig. 7 0.01 0.1 1.0 10 100 (b) ET(-) Vehicle (DMSO) 20 Isoproterenol (μmol/L) 0 (mN) KCl 30 nmol/L U46619 0.01 0.1 1.0 10 100 1.0 μmol/L H89 20 Isoproterenol (μmol/L) 0 (mN) KCl 30 nmol/L U46619 0.01 0.1 1.0 10 100 10 μmol/L H89 20 0 Isoproterenol (μmol/L) (mN) KCl 30 nmol/L U46619

  15. Reference Fig. 7.Effect of cAMP-dependent protein kinase inhibitor H89 on vascular relaxation induced by cAMP-dependent agent isoproterenol. Representative traces show relaxing responses. Isoproterenol was added cumulatively to elicit relaxation when vascular contraction induced by U46619 (30 nmol/L) reached plateaus in endothelium-intact (a) or -denuded (b) rat aortic rings pretreated with H89 (1.0 or 10 μmol/L) or vehicle (0.1% DMSO) for 30 minutes.

  16. Reference Fig. 8 Protein kinase A-dependent and -independent effects of isoproterenol in rat isolated mesenteric artery: interactions with levcromakalim. J Pharmacol Exp Ther. 2001 Sep;298(3):917-24.

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