Testosterone increases bradykinin-induced relaxation in the coronary bed of hypertensive rats

in Journal of Molecular Endocrinology
View More View Less
  • 1 Department of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, Brazil
  • 2 Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences from Ribeirão Preto, University of São Paulo, São Paulo, Brazil

Correspondence should be addressed to R L dos Santos: rogerlyrio@hotmail.com
Restricted access

Physiological or supraphysiological levels of testosterone appear to be associated with the development of risk factors for cardiovascular diseases such as hypertension, as this hormone modulates the release of endothelial factors. However, its actions are still controversial, especially in the coronary circulation of hypertensive animals. This study was designed to assess the effects of testosterone treatment (T) on endothelium-dependent coronary vascular reactivity in orchiectomized SHR. The animals were divided into SHAM, orchiectomized (ORX), ORX+T and ORX+T+aromatase inhibitor (AI). All treatments lasted 15 days. Blood pressure (BP) was measured. Dose–response curves to bradykinin (BK) were constructed using the Langendorff technique, followed by inhibition of endothelium mediators (NO, prostanoids, EETs) and potassium channels. The intensity of eNOS, COX-1, COX-2, Akt, and gp91phox protein expression was quantified by Western blotting. BP was elevated in SHAM, ORX+T, and ORX+T+AI groups. However, we did not observe differences in the ORX group. Baseline coronary perfusion pressure (CPP) remained unaffected. Orchiectomy did not change the BK-induced relaxation compared to the SHAM group, whereas testosterone treatment increased it. This response was diminished in the absence of NO, prostanoids, and EETs in the SHAM and ORX groups, while in ORX+T group the relaxation was diminished only in the absence of NO and EETs. There was no difference in eNOS, COX-1, COX-2, and gp91phox protein expression, though Akt expression was increased in ORX and ORX+T groups. These results show that testosterone treatment can modulate endothelial function, especially in the coronary circulation under hypertension conditions, via NO and EETs pathways.

 

      Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 193 193 193
Full Text Views 11 11 11
PDF Downloads 11 11 11
  • Adams MR, Williams JK & Kaplan JR 1995 Effects of androgens on coronary artery atherosclerosis and atherosclerosis-related impairment of vascular responsiveness. Arteriosclerosis, Thrombosis, and Vascular Biology 15 . (https://doi.org/10.1161/01.ATV.15.5.562)

    • Search Google Scholar
    • Export Citation
  • Altintas D, Kokcu A, Kandemir B, Tosun M & Cetinkaya MB 2010 Comparison of the effects of raloxifene and anastrozole on experimental endometriosis. European Journal of Obstetrics, Gynecology, and Reproductive Biology 150 . (https://doi.org/10.1016/j.ejogrb.2010.02.004)

    • Search Google Scholar
    • Export Citation
  • Bell RM, Mocanu MM & Yellon DM 2011 Retrograde heart perfusion: the Langendorff technique of isolated heart perfusion. Journal of Molecular and Cellular Cardiology 50 . (https://doi.org/10.1016/j.yjmcc.2011.02.018)

    • Search Google Scholar
    • Export Citation
  • Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R et al. 2018 Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation 137 e67e492. (https://doi.org/10.1161/CIR.0000000000000558)

    • Search Google Scholar
    • Export Citation
  • Blanco-Rivero J, Sagredo A, Balfagón G & Ferrer M 2006a Orchidectomy increases expression and activity of Cu/Zn-superoxide dismutase, while decreasing endothelial nitric oxide bioavailability. Journal of Endocrinology 190 . (https://doi.org/10.1677/joe.1.06887)

    • Search Google Scholar
    • Export Citation
  • Blanco-Rivero J, Balfagón G & Ferrer M 2006b Orchidectomy modulates α2-adrenoceptor reactivity in rat mesenteric artery through increased thromboxane A2 formation. Journal of Vascular Research 43 . (https://doi.org/10.1159/000089791)

    • Search Google Scholar
    • Export Citation
  • Blanco-Rivero J, Sagredo A, Balfagón G & Ferrer M 2007 Protein kinase C activation increases endothelial nitric oxide release in mesenteric arteries from orchidectomized rats. Journal of Endocrinology 192 . (https://doi.org/10.1677/joe.1.07079)

    • Search Google Scholar
    • Export Citation
  • Bucci M, Mirone V, Di Lorenzo A, Vellecco V, Roviezzo F, Brancaleone V, Ciro I & Cirino G 2009 Hydrogen sulphide is involved in testosterone vascular effect. European Urology 56 . (https://doi.org/10.1016/j.eururo.2008.05.014)

    • Search Google Scholar
    • Export Citation
  • Buvat J, Maggi M, Guay A & Torres LO 2013 Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. Journal of Sexual Medicine 10 . (https://doi.org/10.1111/j.1743-6109.2012.02783.x)

    • Search Google Scholar
    • Export Citation
  • Campbell WB & Harder DR 2001 Prologue: EDHF–what is it? American Journal of Physiology: Heart and Circulatory Physiology 280 H2413H2416. (https://doi.org/10.1152/ajpheart.2001.280.6.H2413)

    • Search Google Scholar
    • Export Citation
  • Chignalia AZ, Schuldt EZ, Camargo LL, Montezano AC, Callera GE, Laurindo FR, Lopes LR, Avellar MCW, Carvalho MHC & Fortes ZB et al. 2012 Testosterone induces vascular smooth muscle cell migration by NADPH oxidase and c-Src-dependent pathways. Hypertension 59 . (https://doi.org/10.1161/HYPERTENSIONAHA.111.180620)

    • Search Google Scholar
    • Export Citation
  • Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JLJ, Jones DW, Materson BJ, Oparil S & Wright JTJ et al. 2003 The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 289 2560–2572. (https://doi.org/10.1001/jama.289.19.2560)

    • Search Google Scholar
    • Export Citation
  • Cohen RA, Plane F, Najibi S, Huk I, Malinski T & Garland CJ 1997 Nitric oxide is the mediator of both endothelium-dependent relaxation and hyperpolarization of the rabbit carotid artery. PNAS 94 . (https://doi.org/10.1073/pnas.94.8.4193)

    • Search Google Scholar
    • Export Citation
  • Deenadayalu VP, White RE, Stallone JN, Gao X & Garcia AJ 2001 Testosterone relaxes coronary arteries by opening the large-conductance, calcium-activated potassium channel. American Journal of Physiology: Heart and Circulatory Physiology 281 H1720H1727. (https://doi.org/10.1152/ajpheart.2001.281.4.H1720)

    • Search Google Scholar
    • Export Citation
  • Deenadayalu V, Puttabyatappa Y, Liu AT, Stallone JN & White RE 2012 Testosterone-induced relaxation of coronary arteries: activation of BK Ca channels via the cGMP-dependent protein kinase. American Journal of Physiology: Heart and Circulatory Physiology 302 H115H123. (https://doi.org/10.1152/ajpheart.00046.2011)

    • Search Google Scholar
    • Export Citation
  • Dregan A, Stewart R & Gulliford MC 2013 Cardiovascular risk factors and cognitive decline in adults aged 50 and over: a population-based cohort study. Age and Ageing 42 . (https://doi.org/10.1093/ageing/afs166)

    • Search Google Scholar
    • Export Citation
  • Farhat MY, Lavigne MC & Ramwell PW 1996 The vascular protective effects of estrogen. FASEB Journal 10 . (https://doi.org/10.1096/fasebj.10.5.8621060)

    • Search Google Scholar
    • Export Citation
  • Fischer M, Baessler A & Schunkert H 2002 Renin angiotensin system and gender differences in the cardiovascular system. Cardiovascular Research 53 . (https://doi.org/10.1016/S0008-6363(0100479-5)

    • Search Google Scholar
    • Export Citation
  • Fisslthaler B, Popp R, Kiss L, Potente M, Harder DR, Fleming I & Busse R 1999 Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature 401 . (https://doi.org/10.1038/46816)

    • Search Google Scholar
    • Export Citation
  • Fritz M & Rinaldi G 2008 Blood pressure measurement with the tail-cuff method in Wistar and spontaneously hypertensive rats: influence of adrenergic- and nitric oxide-mediated vasomotion. Journal of Pharmacological and Toxicological Methods 58 . (https://doi.org/10.1016/j.vascn.2008.08.002)

    • Search Google Scholar
    • Export Citation
  • Fujii K, Tominaga M, Ohmori S, Kobayashi K, Koga T, Takata Y & Fujishima M 1992 Decreased endothelium-dependent hyperpolarization to acetylcholine in smooth muscle of the mesenteric artery of spontaneously hypertensive rats. Circulation Research 70 . (https://doi.org/10.1161/01.res.70.4.660)

    • Search Google Scholar
    • Export Citation
  • Fulton D, Mahboubi K, McGiff JC & Quilley J 1995 Cytochrome P450-dependent effects of bradykinin in the rat heart. British Journal of Pharmacology 114 . (https://doi.org/10.1111/j.1476-5381.1995.tb14911.x)

    • Search Google Scholar
    • Export Citation
  • Gonzales RJ, Krause DN & Duckles SP 2004 Testosterone suppresses endothelium-dependent dilation of rat middle cerebral arteries. American Journal of Physiology: Heart and Circulatory Physiology 286 H552H560. (https://doi.org/10.1152/ajpheart.00663.2003)

    • Search Google Scholar
    • Export Citation
  • Haring R, John U, Völzke H, Nauck M, Dörr M, Felix SB & Wallaschofski H 2012 Low testosterone concentrations in men contribute to the gender gap in cardiovascular morbidity and mortality. Gender Medicine 9 . (https://doi.org/10.1016/j.genm.2012.10.007)

    • Search Google Scholar
    • Export Citation
  • Ibrahim J, Berk BC & Hughes AD 2006 Comparison of simultaneous measurements of blood pressure by tail-cuff and carotid arterial methods in conscious spontaneously hypertensive and Wistar-Kyoto rats. Clinical and Experimental Hypertension 28 . (https://doi.org/10.1080/10641960500386817)

    • Search Google Scholar
    • Export Citation
  • James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD & Ogedegbe O et al. 2014 2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 311 . (https://doi.org/10.1001/jama.2013.284427)

    • Search Google Scholar
    • Export Citation
  • Jenkins C, Salisbury R & Ely D 1994 Castration lowers and testosterone restores blood pressure in several rat strains on high sodium diets. Clinical and Experimental Hypertension 16 . (https://doi.org/10.3109/10641969409067965)

    • Search Google Scholar
    • Export Citation
  • Jones RD, English KM, Jones TH & Channer KS 2004 Testosterone-induced coronary vasodilatation occurs via a non-genomic mechanism: evidence of a direct calcium antagonism action. Clinical Science 107 . (https://doi.org/10.1042/CS20030386)

    • Search Google Scholar
    • Export Citation
  • Kilpatrick EV & Cocks TM 1994 Evidence for differential roles of nitric oxide (NO) and hyperpolarization in endothelium‐dependent relaxation of pig isolated coronary artery. British Journal of Pharmacology 112 . (https://doi.org/10.1111/j.1476-5381.1994.tb13110.x)

    • Search Google Scholar
    • Export Citation
  • Liu Y, Terata K, Chai Q, Li H, Kleinman LH & Gutterman DD 2002 Peroxynitrite inhibits Ca2+-activated K+ channel activity in smooth muscle of human coronary arterioles. Circulation Research 91 . (https://doi.org/10.1161/01.RES.0000046003.14031.98)

    • Search Google Scholar
    • Export Citation
  • Luscher TF & Vanhoutte PM 1986 Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension 8 . (https://doi.org/10.1161/01.HYP.8.4.344)

    • Search Google Scholar
    • Export Citation
  • MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A & Stamler J 1990 Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 335 . (https://doi.org/10.1016/0140-6736(9090878-9)

    • Search Google Scholar
    • Export Citation
  • Mangelsdorf DJ & Evans RM 1995 The RXR heterodimers and orphan receptors. Cell 83 . (https://doi.org/10.1016/0092-8674(9590200-7)

  • Mark Herman SM, Robinson JTC, McCredie RJ, Adams MR, Boyer MJ & Celermajer DS 1997 Androgen deprivation is associated with enhanced endothelium-dependent dilatation in adult men. Arteriosclerosis, Thrombosis, and Vascular Biology 17 . (https://doi.org/10.1161/01.atv.17.10.2004)

    • Search Google Scholar
    • Export Citation
  • Martín MC, Balfagón G, Minoves N, Blanco-Rivero J & Ferrer M 2005 Androgen deprivation increases neuronal nitric oxide metabolism and its vasodilator effect in rat mesenteric arteries. Nitric Oxide: Biology and Chemistry 12 . (https://doi.org/10.1016/j.niox.2005.02.003)

    • Search Google Scholar
    • Export Citation
  • Martorell A, Blanco-Rivero J, Aras-López R, Sagredo A, Balfagón G & Ferrer M 2008 Orchidectomy increases the formation of prostanoids and modulates their role in the acetylcholine-induced relaxation in the rat aorta. Cardiovascular Research 77 . (https://doi.org/10.1093/cvr/cvm059)

    • Search Google Scholar
    • Export Citation
  • Masubuchi Y, Kumai T, Uematsu A, Komoriyama K & Hirai M 1982 Gonadectomy-induced reduction of blood pressure in adult spontaneously hypertensive rats. Acta Endocrinologica 101 . (https://doi.org/10.1530/acta.0.1010154)

    • Search Google Scholar
    • Export Citation
  • Moazed B, Quest D & Gopalakrishnan V 2009 Des-acyl ghrelin fragments evoke endothelium-dependent vasodilatation of rat mesenteric vascular bed via activation of potassium channels. European Journal of Pharmacology 604 . (https://doi.org/10.1016/j.ejphar.2008.10.032)

    • Search Google Scholar
    • Export Citation
  • Montaño LM, Calixto E, Figueroa A, Flores-Soto E, Carbajal V & Perusquía M 2008 Relaxation of androgens on rat thoracic aorta: testosterone concentration dependent agonist/antagonist L-type Ca2+ channel activity, and 5β-dihydrotestosterone restricted to L-type Ca2+ channel blockade. Endocrinology 149 . (https://doi.org/10.1210/en.2007-1288)

    • Search Google Scholar
    • Export Citation
  • Moysés MR, Barker LA & Cabral AM 2001 Sex hormone modulation of serotonin-induced coronary vasodilation in isolated heart. Brazilian Journal of Medical and Biological Research 34 . (https://doi.org/10.1590/S0100-879X2001000700014)

    • Search Google Scholar
    • Export Citation
  • Nakao J, Chang WC, Murota SI & Orimo H 1981 Testosterone inhibits prostacyclin production by rat aortic smooth muscle cells in culture. Atherosclerosis 39 . (https://doi.org/10.1016/0021-9150(8190070-8)

    • Search Google Scholar
    • Export Citation
  • Nishikawa Y, Stepp DW & Chilian WM 2000 Nitric oxide exerts feedback inhibition on EDHF-induced coronary arteriolar dilation in vivo. American Journal of Physiology: Heart and Circulatory Physiology 279 H459H465. (https://doi.org/10.1152/ajpheart.2000.279.2.H459)

    • Search Google Scholar
    • Export Citation
  • Qiu Y & Quilley J 2001 Apamin/charybdotoxin-sensitive endothelial K+ channels contribute to acetylcholine-induced, NO-dependent vasorelaxation of rat aorta. Medical Science Monitor 7 .

    • Search Google Scholar
    • Export Citation
  • Rouver WN, Delgado NTB, Menezes JB, Santos RL & Moyses MR 2015 Testosterone replacement therapy prevents alterations of coronary vascular reactivity caused by hormone deficiency induced by castration. PLoS ONE 10 e0137111. (https://doi.org/10.1371/journal.pone.0137111)

    • Search Google Scholar
    • Export Citation
  • Santos RL, Marin EB, Gonçalves WLS, Bissoli NS, Abreu GR & Moysés MR 2010 Sex differences in the coronary vasodilation induced by 17β-oestradiol in the isolated perfused heart from spontaneously hypertensive rats. Acta Physiologica 200 . (https://doi.org/10.1111/j.1748-1716.2010.02140.x)

    • Search Google Scholar
    • Export Citation
  • Shores MM, Smith NL, Forsberg CW, Anawalt BD & Matsumoto AM 2012 Testosterone treatment and mortality in men with low testosterone levels. Journal of Clinical Endocrinology and Metabolism 97 . (https://doi.org/10.1210/jc.2011-2591)

    • Search Google Scholar
    • Export Citation
  • Svartberg J, von Mühlen D, Schirmer H, Barrett-Connor E, Sundfjord J & Jorde R 2004 Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromsø Study. European Journal of Endocrinology 150 . (https://doi.org/10.1530/eje.0.1500065)

    • Search Google Scholar
    • Export Citation
  • Vasan RS, Larson MG, Leip EP, Evans JC, O’Donnell CJ, Kannel WB & Levy D 2001 Impact of high-normal blood pressure on the risk of cardiovascular disease. New England Journal of Medicine 345 . (https://doi.org/10.1056/NEJMoa003417)

    • Search Google Scholar
    • Export Citation
  • Vigen R, O’Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME & Plomondon ME et al. 2013 Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 310 . (https://doi.org/10.1001/jama.2013.280386)

    • Search Google Scholar
    • Export Citation
  • Weston AH, Porter EL, Harno E & Edwards G 2010 Impairment of endothelial SK Ca channels and of downstream hyperpolarizing pathways in mesenteric arteries from spontaneously hypertensive rats. British Journal of Pharmacology 160 . (https://doi.org/10.1111/j.1476-5381.2010.00657.x)

    • Search Google Scholar
    • Export Citation
  • Zhao J, Liu GL, Wei Y, Jiang LH, Bao PL & Yang QY 2016 Low-dose testosterone alleviates vascular damage caused by castration in male rats in puberty via modulation of the PI3K/AKT signaling pathway. Molecular Medicine Reports 14 . (https://doi.org/10.3892/mmr.2016.5562)

    • Search Google Scholar
    • Export Citation
  • Zhou P, Fu L, Pan Z, Ma D, Zhang Y, Qu F, Guo L, Cao J, Gao Q & Han Y 2008 Testosterone deprivation by castration impairs expression of voltage-dependent potassium channels in rat aorta. European Journal of Pharmacology 593 . (https://doi.org/10.1016/j.ejphar.2008.07.014)

    • Search Google Scholar
    • Export Citation