Horm Metab Res 2010; 42(2): 122-129
DOI: 10.1055/s-0029-1241843
Animals, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Testosterone Administration Induces Protection Against Global Myocardial Ischemia

S. E. Borst1 , 2 , J. C. Quindry3 , J. F. Yarrow1 , 2 , C. F. Conover1 , S. K. Powers2
  • 1Geriatric Research, Education and Clinical Center, Malcom Randall VA Medical Center, Gainesville, FL, USA
  • 2Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL, USA
  • 3Department of Kinesiology, Auburn University, Auburn, AL, USA
Further Information

Publication History

received 24.07.2009

accepted 16.09.2009

Publication Date:
27 October 2009 (online)

Abstract

We tested the hypothesis that chronic testosterone treatment would promote a cardioprotective phenotype against ischemia/reperfusion (I/R) injury. For this study, 3-month-old F344 male rats underwent sham-surgery, orchiectomy (ORX), or ORX plus 21 days testosterone treatment (1.0 mg testosterone/day). At sacrifice, cardiac performance was assessed in a working heart model of I/R (25 min of global ischemia and 45 min of reperfusion). ORX reduced serum testosterone by ∼98% and testosterone administration elevated serum testosterone to a concentration of 4.6-fold over that of Sham-operated controls (p<0.05). ORX did not significantly impair recovery of cardiac performance following I/R, but did increase cardiac release of lactate dehydrogenase (LDH) during pre- and post-ischemia (p<0.05). Testosterone administration prevented the ORX-induced increase in LDH during both pre- and post-ischemia and increased post-ischemic recovery of aortic flow, cardiac output, cardiac work, left ventricular developed pressure, and contractility (p<0.05) during reperfusion. Testosterone administration also increased left ventricular expression of catalase, but did not affect the expression of manganese superoxide dismutase, glutathione peroxidase, or sarcolemmal KATP channel protein Kir6.2. Neither circulating nor cardiac concentrations of estradiol were altered by either treatment. We conclude that administration of high-dose testosterone confers cardioprotection through yet to be identified androgen-dependent mechanism(s).

References

  • 1 Tsang S, Liu J, Wong TM. Testosterone and cardioprotection against myocardial ischemia.  Cardiovasc Hematol Disord Drug Targets. 2007;  7 119-125
  • 2 Swartz CM, Young MA. Low serum testosterone and myocardial infarction in geriatric male inpatients.  J Am Geriatr Soc. 1987;  35 39-44
  • 3 Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men.  J Clin Endocrinol Metab. 2004;  89 3313-3318
  • 4 Rosano GM, Leonardo F, Pagnotta P, Pelliccia F, Panina G, Cerquetani E, della Monica PL, Bonfigli B, Volpe M, Chierchia SL. Acute anti-ischemic effect of testosterone in men with coronary artery disease.  Circulation. 1999;  99 1666-1670
  • 5 Webb CM, Adamson DL, de Zeigler D, Collins P. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease.  Am J Cardiol. 1999;  83 437-439 , A439 
  • 6 Tsang S, Wu S, Liu J, Wong TM. Testosterone protects rat hearts against ischaemic insults by enhancing the effects of alpha(1)-adrenoceptor stimulation.  Br J Pharmacol. 2008;  153 693-709
  • 7 Callies F, Stromer H, Schwinger RH, Bolck B, Hu K, Frantz S, Leupold A, Beer S, Allolio B, Bonz AW. Administration of testosterone is associated with a reduced susceptibility to myocardial ischemia.  Endocrinology. 2003;  144 4478-4483
  • 8 Nam UH, Wang M, Crisostomo PR, Markel TA, Lahm T, Meldrum KK, Lillemoe KD, Meldrum DR. The effect of chronic exogenous androgen on myocardial function following acute ischemia-reperfusion in hosts with different baseline levels of sex steroids.  J Surg Res. 2007;  142 113-118
  • 9 Wang M, Tsai BM, Kher A, Baker LB, Wairiuko GM, Meldrum DR. Role of endogenous testosterone in myocardial proinflammatory and proapoptotic signaling after acute ischemia-reperfusion.  Am J Physiol Heart Circ Physiol. 2005;  288 H221-H226
  • 10 English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: A randomized, double-blind, placebo-controlled study.  Circulation. 2000;  102 1906-1911
  • 11 Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial.  Eur Heart J. 2006;  27 57-64
  • 12 Klapcinska B, Jagsz S, Sadowska-Krepa E, Gorski J, Kempa K, Langfort J. Effects of castration and testosterone replacement on the antioxidant defense system in rat left ventricle.  J Physiol Sci. 2008;  58 173-177
  • 13 Er F, Michels G, Gassanov N, Rivero F, Hoppe UC. Testosterone induces cytoprotection by activating ATP-sensitive K+ channels in the cardiac mitochondrial inner membrane.  Circulation. 2004;  110 3100-3107
  • 14 Grohe C, Kahlert S, Lobbert K, Vetter H. Expression of oestrogen receptor alpha and beta in rat heart: role of local oestrogen synthesis.  J Endocrinol. 1998;  156 R1-R7
  • 15 Thum T, Borlak J. Testosterone, cytochrome P450, and cardiac hypertrophy.  Faseb J. 2002;  16 1537-1549
  • 16 Nuedling S, Kahlert S, Loebbert K, Doevendans PA, Meyer R, Vetter H, Grohe C. 17 Beta-estradiol stimulates expression of endothelial and inducible NO synthase in rat myocardium in-vitro and in-vivo.  Cardiovasc Res. 1999;  43 666-674
  • 17 Barp J, Araujo AS, Fernandes TR, Rigatto KV, Llesuy S, Bello-Klein A, Singal P. Myocardial antioxidant and oxidative stress changes due to sex hormones.  Braz J Med Biol Res. 2002;  35 1075-1081
  • 18 Booth EA, Lucchesi BR. Estrogen-mediated protection in myocardial ischemia-reperfusion injury.  Cardiovasc Toxicol. 2008;  8 101-113
  • 19 Yarrow JF, Conover CF, Purandare AV, Bhakta AM, Zheng N, Conrad B, Altman MK, Franz SE, Wronski TJ, Borst SE. Supraphysiological testosterone enanthate administration prevents bone loss and augments bone strength in gonadectomized male and female rats.  Am J Physiol Endocrinol Metab. 2008;  295 E1213-E1222
  • 20 Sutherland FJ, Hearse DJ. The isolated blood and perfusion fluid perfused heart.  Pharmacol Res. 2000;  41 613-627
  • 21 Lennon SL, Quindry J, Hamilton KL, French J, Staib J, Mehta JL, Powers SK. Loss of exercise-induced cardioprotection after cessation of exercise.  J Appl Physiol. 2004;  96 1299-1305
  • 22 Lennon SL, Quindry JC, French JP, Kim S, Mehta JL, Powers SK. Exercise and myocardial tolerance to ischaemia-reperfusion.  Acta Physiol Scand. 2004;  182 161-169
  • 23 Lennon SL, Quindry JC, Hamilton KL, French JP, Hughes J, Mehta JL, Powers SK. Elevated MnSOD is not required for exercise-induced cardioprotection against myocardial stunning.  Am J Physiol Heart Circ Physiol. 2004;  287 H975-H980
  • 24 French JP, Quindry JC, Falk DJ, Staib JL, Lee Y, Wang KK, Powers SK. Ischemia-reperfusion-induced calpain activation and SERCA2a degradation are attenuated by exercise training and calpain inhibition.  Am J Physiol Heart Circ Physiol. 2006;  290 H128-H136
  • 25 Brown DA, Chicco AJ, Jew KN, Johnson MS, Lynch JM, Watson PA, Moore RL. Cardioprotection afforded by chronic exercise is mediated by the sarcolemmal, and not the mitochondrial, isoform of the KATP channel in the rat.  J Physiol. 2005;  569 913-924
  • 26 Kuhar P, Lunder M, Drevensek G. The role of gender and sex hormones in ischemic-reperfusion injury in isolated rat hearts.  Eur J Pharmacol. 2007;  561 151-159
  • 27 Liu J, Tsang S, Wong TM. Testosterone is required for delayed cardioprotection and enhanced heat shock protein 70 expression induced by preconditioning.  Endocrinology. 2006;  147 4569-4577
  • 28 Kohno H, Takahashi N, Shinohara T, Ooie T, Yufu K, Nakagawa M, Yonemochi H, Hara M, Saikawa T, Yoshimatsu H. Receptor-mediated suppression of cardiac heat-shock protein 72 expression by testosterone in male rat heart.  Endocrinology. 2007;  148 3148-3155
  • 29 Crisostomo PR, Wang M, Wairiuko GM, Morrell ED, Meldrum DR. Brief exposure to exogenous testosterone increases death signaling and adversely affects myocardial function after ischemia.  Am J Physiol Regul Integr Comp Physiol. 2006;  290 R1168-R1174
  • 30 Balthazart J, Baillien M, Cornil CA, Ball GF. Preoptic aromatase modulates male sexual behavior: slow and fast mechanisms of action.  Physiol Behav. 2004;  83 247-270
  • 31 Mayes JS, Watson GH. Direct effects of sex steroid hormones on adipose tissues and obesity.  Obes Rev. 2004;  5 197-216
  • 32 Bai CX, Kurokawa J, Tamagawa M, Nakaya H, Furukawa T. Nontranscriptional regulation of cardiac repolarization currents by testosterone.  Circulation. 2005;  112 1701-1710
  • 33 Lepage R. Measurement of testosterone and its sub-fractions in Canada.  Clin Biochem. 2006;  39 97-108
  • 34 Harnish DC, Liu X, Kenney T, Winneker RC, Chadwick C, Friedrichs GS, Kilbourne EJ. The pathway-selective estrogen receptor ligand WAY-169916 displays differential activity in ischemia-reperfusion injury models.  J Cardiovasc Pharmacol. 2006;  47 788-795
  • 35 Hunter JC, Kostyak JC, Novotny JL, Simpson AM, Korzick DH. Estrogen deficiency decreases ischemic tolerance in the aged rat heart: Roles of PKCdelta, PKCepsilon, Akt, and GSK3beta.  Am J Physiol Regul Integr Comp Physiol. 2007;  292 R800-R809
  • 36 Xu Y, Arenas IA, Armstrong SJ, Plahta WC, Xu H, Davidge ST. Estrogen improves cardiac recovery after ischemia/reperfusion by decreasing tumor necrosis factor-alpha.  Cardiovasc Res. 2006;  69 836-844
  • 37 Hilakivi-Clarke L, Cho E, Cabanes A, DeAssis S, Olivo S, Helferich W, Lippman ME, Clarke R. Dietary modulation of pregnancy estrogen levels and breast cancer risk among female rat offspring.  Clin Cancer Res. 2002;  8 3601-3610
  • 38 Farrell GC, Koltai A, Murray M. Source of raised serum estrogens in male rats with portal bypass.  J Clin Invest. 1988;  81 221-228
  • 39 Zumoff B, Miller LK, Strain GW. Reversal of the hypogonadotropic hypogonadism of obese men by administration of the aromatase inhibitor testolactone.  Metabolism. 2003;  52 1126-1128
  • 40 Hamilton KL. Antioxidants and cardioprotection.  Med Sci Sports Exerc. 2007;  39 1544-1553
  • 41 Quindry J, French J, Hamilton K, Lee Y, Mehta JL, Powers S. Exercise training provides cardioprotection against ischemia-reperfusion induced apoptosis in young and old animals.  Exp Gerontol. 2005;  40 416-425
  • 42 Criswell D, Powers S, Dodd S, Lawler J, Edwards W, Renshler K, Grinton S. High intensity training-induced changes in skeletal muscle antioxidant enzyme activity.  Med Sci Sports Exerc. 1993;  25 1135-1140
  • 43 Lawler JM, Powers SK, Visser T, Van Dijk H, Kordus MJ, Ji LL. Acute exercise and skeletal muscle antioxidant and metabolic enzymes: effects of fiber type and age.  Am J Physiol. 1993;  265 R1344-R1350
  • 44 Hoshida S, Yamashita N, Otsu K, Hori M. Repeated physiologic stresses provide persistent cardioprotection against ischemia-reperfusion injury in rats.  J Am Coll Cardiol. 2002;  40 826-831
  • 45 Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury.  Physiol Rev. 2008;  88 581-609
  • 46 Powers SK, Quindry JC, Kavazis AN. Exercise-induced cardioprotection against myocardial ischemia-reperfusion injury.  Free Radic Biol Med. 2008;  44 193-201
  • 47 Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, Bhasin S. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials.  J Gerontol A Biol Sci Med Sci. 2005;  60 1451-1457
  • 48 Negro-Vilar A. Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium.  J Clin Endocrinol Metab. 1999;  84 3459-3462

Correspondence

S. E. BorstPhD 

Malcom Randall VA Medical Center

GRECC – 182

1601 SW Archer Road

Gainesville

FL 32608-1197

USA

Phone: +1/352/374 61 14

Fax: +1/352/374 61 42

Email: seborst@ufl.edu

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