Abstract
Objectives
The effect of oestrogen in hormonal dysfunction is not clear, especially in the coronary vascular bed. This study aimed at estradiol action (E2) in the coronary vascular bed from sham-operated and gonadectomized female and male spontaneously hypertensive rats (SHRs).
Methods
Male and female SHRs had their mean arterial pressure (MAP) and baseline coronary perfusion pressure (CPP) determined. The effects of E2 (10 μM) were evaluated in isolated hearts by in bolus infusion before and after endothelium denudation (0.25 μM sodium deoxycholate) or perfusion with 100 μM NG-nitro-l-arginine methyl ester (L-NAME), 2.8 μM indomethacin, 0.75 μM clotrimazole, L-NAME after endothelium denudation, L-NAME plus indomethacin, or 4 mM tetraethylammonium (TEA).
Results
MAP was higher in males than in females, with gonadectomy increasing in females and reducing in males. CPP was higher in female group, remaining unaltered after gonadectomy. E2-induced vasorelaxation was observed in all groups, with no differences having been found between sexes even after gonadectomy. Perfusion with TEA, L-NAME, L-NAME plus indomethacin, and L-NAME after endothelium removal attenuated the relaxing response in all groups. Clotrimazole inhibited vasorelaxation only in female groups, and indomethacin did so only in gonadectomized groups. Endothelium participation was confirmed in female groups and in the gonadectomized male group.
Conclusions
Our results indicated that the vasodilator effect of E2 was mediated by an indirect mechanism – via endothelium – as well as by direct action – via vascular smooth muscle – in both groups. The characterization of these mechanisms in coronary arteries might shed light on the functional basis of hormonal dysfunction symptoms in hypertension.
Award Identifier / Grant number: 85142409
Research funding: This work was supported by FAPES (85142409). The funding organization played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Author contributions: 1. Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; 2. drafting the work or revising it critically for important intellectual content; 3. final approval of the version to be published; 4. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.WNR1,2,3,4 CRSF1,2,3,4 NTBD1,2,3,4 RLS1,2,3,4.
All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship.
Competing interests: Authors state no conflict of interest.
Ethical approval: The research related to animals’ use has complied with all the relevant national regulations and institutional policies (CEUA/UFES) for the care and use of animals. Moreover, all procedures were conducted in accordance with the recommendations of the Brazilian Guidelines for the Care and Use of animals for Scientific and Didactic Purposes and the Guidelines for the Practice of Euthanasia and approved by the Animal Ethics Committee from the Federal University of Espirito Santo under protocol # 029/2011.
References
1. Benjamin, EJ, Virani, SS, Callaway, CW, Chamberlain, AM, Chang, AR, Cheng, S, et al.. Heart disease and stroke statistics - 2018 update: a report from the American Heart Association. Circulation 2018;137:E67–492.10.1161/CIR.0000000000000558Search in Google Scholar PubMed
2. dos Santos, RL, da Silva, FB, Ribeiro, RF, Stefanon, I. Sex hormones in the cardiovascular system. Horm Mol Biol Clin Invest 2014;18:89–103. https://doi.org/10.1515/hmbci-2013-0048.Search in Google Scholar
3. Lee, A-S, Chen, W-Y, Chan, H-C, Hsu, J-F, Shen, M-Y, Chang, C-M, et al.. Gender disparity in LDL-induced cardiovascular damage and the protective role of estrogens against electronegative LDL. Cardiovasc Diabetol 2014;13:64. https://doi.org/10.1186/1475-2840-13-64.Search in Google Scholar
4. Dimopoulos, GJ, Langner, RO. Inhibition of phosphodiesterase has an additive effect on estrogen’s ability to inhibit collagen synthesis in vascular smooth muscle cells. Vasc Pharmacol 2009;50:78–82. https://doi.org/10.1016/j.vph.2008.10.003.Search in Google Scholar
5. Odenlund, M, Ekblad, E, Nilsson, B-O. Stimulation of oestrogen receptor-expressing endothelial cells with oestrogen reduces proliferation of cocultured vascular smooth muscle cells. Clin Exp Pharmacol Physiol 2008;35:245–8. https://doi.org/10.1111/j.1440-1681.2007.04870.x.Search in Google Scholar
6. Miller, VM, Duckles, SP. Vascular actions of estrogens: functional implications. Pharmacol Rev 2008;60:210–41. https://doi.org/10.1124/pr.107.08002.Search in Google Scholar
7. Santos, RL, Abreu, GR, Bissoli, NS, Moysés, MR. Endothelial mediators of 17ß-estradiol-induced coronary vasodilation in the isolated rat heart. Braz J Med Biol Res 2004;37:569–75. https://doi.org/10.1590/s0100-879x2004000400014.Search in Google Scholar
8. Santos, RL, Marin, EB, Gonçalves, WLS, Bissoli, NS, Abreu, GR, Moysés, MR. Sex differences in the coronary vasodilation induced by 17 β-oestradiol in the isolated perfused heart from spontaneously hypertensive rats. Acta Physiol 2010;200:203–10. https://doi.org/10.1111/j.1748-1716.2010.02140.x.Search in Google Scholar
9. Santos, RL, Lima, JT, Rouver, WN, Moysés, MR. Deficiency of sex hormones does not affect 17-ß-estradiol-induced coronary vasodilation in the isolated rat heart. Braz J Med Biol Res 2016;49. https://doi.org/10.1590/1414-431x20165058.Search in Google Scholar
10. Gisclard, V, Miller, VM, Vanhoutte, PM. Effect of 17 beta-estradiol on endothelium-dependent responses in the rabbit. J Pharmacol Exp Therapeut 1988;244:19–22.Search in Google Scholar
11. Han, G, Ma, H, Chintala, R, Miyake, K, Fulton, DJR, Barman, SA, et al.. Nongenomic, endothelium-independent effects of estrogen on human coronary smooth muscle are mediated by type I (neuronal) NOS and PI3-kinase-Akt signaling. Am J Physiol Heart Circ Physiol 2007;293:H314–21. https://doi.org/10.1152/ajpheart.01342.2006.Search in Google Scholar
12. Alda, JO, Valero, MS, Pereboom, D, Gros, P, Garay, RP. Endothelium-independent vasorelaxation by the selective alpha estrogen receptor agonist propyl pyrazole triol in rat aortic smooth muscle. J Pharm Pharmacol 2009;61:641–6. https://doi.org/10.1211/jpp.61.05.0013.Search in Google Scholar
13. Moysés, MR, Barker, LA, Cabral, AM. Sex hormone modulation of serotonin-induced coronary vasodilation in isolated heart. Braz J Med Biol Res 2001;34:949–58. https://doi.org/10.1590/s0100-879x2001000700014.Search in Google Scholar
14. Pretorius, M, van Guilder, GP, Guzman, RJ, Luther, JM, Brown, NJ. 17Beta-estradiol increases basal but not bradykinin-stimulated release of active t-PA in young postmenopausal women. Hypertens (Dallas, Tex 1979) 2008;51:1190–6.10.1161/HYPERTENSIONAHA.107.105627Search in Google Scholar PubMed PubMed Central
15. Haynes, MP, Li, L, Sinha, D, Russell, KS, Hisamoto, K, Baron, R, et al.. Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen. J Biol Chem 2003;278:2118–23. https://doi.org/10.1074/jbc.m210828200.Search in Google Scholar
16. Brosnihan, KB, Li, P, Figueroa, JP, Ganten, D, Ferrario, CM. Estrogen, nitric oxide, and hypertension differentially modulate agonist-induced contractile responses in female transgenic (mRen2)27 hypertensive rats. Am J Physiol Heart Circ Physiol 2008;294:H1995–2001. https://doi.org/10.1152/ajpheart.01193.2007.Search in Google Scholar
17. Egan, KM, Lawson, JA, Fries, S, Koller, B, Rader, DJ, Smyth, EM, et al.. COX-2-derived prostacyclin confers atheroprotection on female mice. Science 2004;306:1954–7. https://doi.org/10.1126/science.1103333.Search in Google Scholar
18. Burger, NZ, Kuzina, OY, Osol, G, Gokina, NI. Estrogen replacement enhances EDHF-mediated vasodilation of mesenteric and uterine resistance arteries: role of endothelial cell Ca2+. Am J Physiol Endocrinol Metab 2009;296:E503–12. https://doi.org/10.1152/ajpendo.90517.2008.Search in Google Scholar
19. Gauthier, KM, Edwards, EM, Falck, JR, Reddy, DS, Campbell, WB. 14,15-epoxyeicosatrienoic acid represents a transferable endothelium-dependent relaxing factor in bovine coronary arteries. Hypertension (Dallas) 2005;45:666–71. https://doi.org/10.1161/01.hyp.0000153462.06604.5d.Search in Google Scholar
20. Reckelhoff, JF, Zhang, H, Srivastava, K. Gender differences in development of hypertension in spontaneously hypertensive rats: role of the renin-angiotensin system. Hypertens (Dallas, Tex 1979) 2000;35:480–3.10.1161/01.HYP.35.1.480Search in Google Scholar
21. Tatchum-Talom, R, Eyster, KM, Kost, CK, Martin, DS. Blood pressure and mesenteric vascular reactivity in spontaneously hypertensive rats 7 months after gonadectomy. J Cardiovasc Pharmacol 2011;57:357–64. https://doi.org/10.1097/fjc.0b013e31820b7dc9.Search in Google Scholar
22. Pingili, AK, Kara, M, Khan, NS, Estes, AM, Lin, Z, Li, W, et al.. 6β-Hydroxytestosterone, a cytochrome P450 1B1 metabolite of testosterone, contributes to angiotensin II–induced hypertension and its pathogenesis in male mice. Hypertension 2015;65:1279–87. https://doi.org/10.1161/hypertensionaha.115.05396.Search in Google Scholar
23. Tostes, RC, Carneiro, FS, Carvalho, MHC, Reckelhoff, JF. Reactive oxygen species: players in the cardiovascular effects of testosterone. Am J Physiol Integr Comp Physiol 2016;310:R1–14. https://doi.org/10.1152/ajpregu.00392.2014.Search in Google Scholar
24. Heringer, OA, Cassaro, KODS, Barbosa, NCMR, Brasil, GA, do Nascimento, AM, de Lima, EM, et al.. Relationship between male hormonal status, Bezold-Jarisch reflex function, and ACE activity (cardiac and plasmatic). Can J Physiol Pharmacol 2016;94:231–6. https://doi.org/10.1139/cjpp-2015-0144.Search in Google Scholar
25. Borrás, C, Gambini, J, Gómez-Cabrera, MC, Sastre, J, Pallardó, F V, Mann, GE, et al.. 17beta-oestradiol up-regulates longevity-related, antioxidant enzyme expression via the ERK1 and ERK2[MAPK]/NFkappaB cascade. Aging Cell 2005;4:113–8. https://doi.org/10.1111/j.1474-9726.2005.00151.x.Search in Google Scholar
26. Yu, X, Ma, H, Barman, SA, Liu, AT, Sellers, M, Stallone, JN, et al.. Activation of G protein-coupled estrogen receptor induces endothelium-independent relaxation of coronary artery smooth muscle. Am J Physiol Endocrinol Metab 2011;301:E882–8. https://doi.org/10.1152/ajpendo.00037.2011.Search in Google Scholar
27. Dubey, RK, Jackson, EK, Keller, PJ, Imthurn, B, Rosselli, M. Estradiol metabolites inhibit endothelin synthesis by an estrogen receptor-independent mechanism. Hypertens (Dallas, Tex 1979) 2001;37:640–4.10.1161/01.HYP.37.2.640Search in Google Scholar
28. Valverde, LF, Cedillo, FD, Ramos, ML, Cervera, EG, Quijano, K, Cordoba, J. Changes induced by estradiol-ethylenediamine derivative on perfusion pressure and coronary resistance in isolated rat heart: L-type calcium channel. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2011;155:27–32.10.5507/bp.2011.018Search in Google Scholar
29. Jiang, CW, Sarrel, PM, Lindsay, DC, Poole-Wilson, PA, Collins, P. Endothelium-independent relaxation of rabbit coronary artery by 17 beta-oestradiol in vitro. Br J Pharmacol 1991;104:1033–7. https://doi.org/10.1111/j.1476-5381.1991.tb12545.x.Search in Google Scholar
30. Sobrino, A, Vallejo, S, Novella, S, Lázaro-Franco, M, Mompeón, A, Bueno-Betí, C, et al.. Mas receptor is involved in the estrogen-receptor induced nitric oxide-dependent vasorelaxation. Biochem Pharmacol 2017;129:67–72. https://doi.org/10.1016/j.bcp.2017.01.012.Search in Google Scholar
31. Unemoto, T, Honda, H, Kogo, H. Differences in the mechanisms for relaxation of aorta induced by 17beta-estradiol or progesterone between normotensive and hypertensive rats. Eur J Pharmacol 2003;472:119–26. https://doi.org/10.1016/s0014-2999(03)01858-2.Search in Google Scholar
32. Mügge, A, Riedel, M, Barton, M, Kuhn, M, Lichtlen, PR. Endothelium independent relaxation of human coronary arteries by 17 beta-oestradiol in vitro. Cardiovasc Res 1993;27:1939–42. https://doi.org/10.1093/cvr/27.11.1939.Search in Google Scholar
33. Castardo-de-Paula, JC, de Campos, BH, de Jager, L, Amorim, EDT, Zanluqui, NG, de Farias, CC, et al.. Effects of inducible nitric oxide synthase inhibition on cardiovascular risk of adult endotoxemic female rats: role of estrogen. Front Physiol 2018;9:1020. https://doi.org/10.3389/fphys.2018.01020.Search in Google Scholar
34. Han, G, Ma, H, Chintala, R, Fulton, DJR, Barman, SA, White, RE. Essential role of the 90-kilodalton heat shock protein in mediating nongenomic estrogen signaling in coronary artery smooth muscle. J Pharmacol Exp Therapeut 2009;329:850–5. https://doi.org/10.1124/jpet.108.149112.Search in Google Scholar
35. Zhang, H, Du, Y, Cohen, RA, Chobanian, A V, Brecher, P. Adventitia as a source of inducible nitric oxide synthase in the rat aorta. Am J Hypertens 1999;12:467–75. https://doi.org/10.1016/s0895-7061(98)00271-4.Search in Google Scholar
36. Chignalia, AZ, Schuldt, EZ, Camargo, LL, Montezano, AC, Callera, GE, Laurindo, FR, et al.. Testosterone induces vascular smooth muscle cell migration by NADPH oxidase and c-Src-dependent pathways. Hypertension 2012;59:1263–71. https://doi.org/10.1161/hypertensionaha.111.180620.Search in Google Scholar
37. Chignalia, AZ, Oliveira, MA, Debbas, V, Dull, RO, Laurindo, FRM, Touyz, RM, et al.. Testosterone induces leucocyte migration by NADPH oxidase-driven ROS- and COX2-dependent mechanisms. Clin Sci (Lond) 2015;129:39–48. https://doi.org/10.1042/cs20140548.Search in Google Scholar
38. Zhang, X, Wang, L-Y, Jiang, T-Y, Zhang, H-P, Dou, Y, Zhao, J-H, et al.. Effects of testosterone and 17-beta-estradiol on TNF-alpha-induced E-selection and VCAM-1 expression in endothelial cells. Analysis of the underlying receptor pathways. Life Sci 2002;71:15–29. https://doi.org/10.1016/s0024-3205(02)01567-9.Search in Google Scholar
39. del Campo, M, Sagredo, A, del Campo, L, Villalobo, A, Ferrer, M. Time-dependent effect of orchidectomy on vascular nitric oxide and thromboxane A2 release. Functional implications to control cell proliferation through activation of the epidermal growth factor receptor. PloS One 2014;9: e102523. https://doi.org/10.1371/journal.pone.0102523.Search in Google Scholar
40. Case, J, Davison, CA. Estrogen alters relative contributions of nitric oxide and cyclooxygenase products to endothelium-dependent vasodilation. J Pharmacol Exp Therapeut 1999;291:524–30.Search in Google Scholar
41. Pérez-Torres, I, El Hafidi, M, Pavón, N, Infante, O, Avila-Casado, MC, Baños, G. Effect of gonadectomy on the metabolism of arachidonic acid in isolated kidney of a rat model of metabolic syndrome. Metabolism 2010;59:414–23. https://doi.org/10.1016/j.metabol.2009.08.014.Search in Google Scholar
42. Oni-Orisan, A, Edin, ML, Lee, JA, Wells, MA, Christensen, ES, Vendrov, KC, et al.. Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study. J Lipid Res 2016;57:109–19. https://doi.org/10.1194/jlr.m061697.Search in Google Scholar
43. Bernhardt, R. Cytochromes P450 as versatile biocatalysts. J Biotechnol 2006;124:128–45. https://doi.org/10.1016/j.jbiotec.2006.01.026.Search in Google Scholar
44. Imig, JD. Epoxides and soluble epoxide hydrolase in cardiovascular physiology. Physiol Rev 2012;92:101–30. https://doi.org/10.1152/physrev.00021.2011.Search in Google Scholar
45. Busse, R, Edwards, G, Félétou, M, Fleming, I, Vanhoutte, PM, Weston, AH. EDHF: bringing the concepts together. Trends Pharmacol Sci 2002;23:374–80. https://doi.org/10.1016/s0165-6147(02)02050-3.Search in Google Scholar
46. Taddei, S, Versari, D, Cipriano, A, Ghiadoni, L, Galetta, F, Franzoni, F, et al.. Identification of a cytochrome P450 2C9-derived endothelium-derived hyperpolarizing factor in essential hypertensive patients. J Am Coll Cardiol 2006;48:508–15. https://doi.org/10.1016/j.jacc.2006.04.074.Search in Google Scholar
47. Yang, Q, Yim, APC, He, G-W. The significance of endothelium-derived hyperpolarizing factor in the human circulation. Curr Vasc Pharmacol 2007;5:85–92. https://doi.org/10.2174/157016107779317206.Search in Google Scholar
48. Reddy Kilim, S, Chandala, SR. A comparative study of lipid profile and oestradiol in pre- and post-menopausal women. J Clin Diagn Res 2013;7:1596–8. https://doi.org/10.7860/JCDR/2013/6162.3234.Search in Google Scholar
49. Yosof Rezk, M, Elkatawy, HA, Shata, AM, Mohany, KM. Effects of testosterone replacement on insulin sensitivity, blood glucose, serum lipids and vitamin D concentration in a rat model of andropause. Int J Clin Exp Med Sci 2017;3:30. https://doi.org/10.11648/j.ijcems.20170303.11.Search in Google Scholar
50. Rouver, WN, Delgado, NTB, Menezes, JB, Santos, RL, Moyses, MR. Testosterone replacement therapy prevents alterations of coronary vascular reactivity caused by hormone deficiency induced by castration. He B, editor. PloS One 2015;10: e0137111. https://doi.org/10.1371/journal.pone.0137111.Search in Google Scholar
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