Horm Metab Res 2002; 34(9): 516-522
DOI: 10.1055/s-2002-34792
Original Clinical
© Georg Thieme Verlag Stuttgart · New York

Effects of Ovariectomy on Indices of Insulin Resistance, Hypertension, and Cardiac Energy Metabolism in Middle-Aged Spontaneously Hypertensive Rats (SHR)

A.  Swislocki 1 , E.  S.  Burgie 2 , K.  J.  Rodnick 2
  • 1Medical Service, VA Northern California Health Care System, Martinez, CA, and Department of Medicine, University of California, Davis, School of Medicine, Davis, CA, USA
  • 2Department of Biological Sciences, Idaho State University, Pocatello, ID, USA
Presented in part at the 13th Meeting of the American Society of Hypertension, New York, May, 1998.
Further Information

Publication History

Received: 8 November 2001

Accepted after revision: 15 May 2002

Publication Date:
17 October 2002 (online)

Abstract

Insulin resistance is a risk factor for coronary heart disease. The protection of young women from coronary events is sharply reduced with menopause. To assess the impact of menopause on glucose tolerance, insulin resistance, body weight gain, heart size, and cardiac energy metabolism, we studied 28-week-old female SHR and Wistar-Kyoto (WKY) rats, who were either ovariectomized (SHROVX and WKYOVX) or sham-operated (SHRSHAM and WKYSHAM). Animals underwent blood-pressure measurement and an oral glucose tolerance test (OGTT). Hearts were weighed and assayed for metabolic enzyme activities. Female SHR were 33 % lighter and hypertensive (+ 36 mmHg), with 33 % larger hearts (when corrected for body weight differences) compared to WKY. Although ovariectomized animals of both strains were heavier overall than their sham-operated counterparts, when heart weights were corrected for body weight, both OVX strains had lighter hearts than both SHAM strains. Glucose and insulin responses during OGTT were similar between the four groups; however, free fatty acid (FFA) responses were approximately 50 % greater in SHR than WKY, although less in SHROVX than SHRSHAM. WKYOVX demonstrated 8 % lower ventricular hexokinase activity than WKYSHAM, which may reflect reduced cardiac glucose utilization. We also noted 16 % higher citrate synthase activity in WKY hearts. In conclusion, the insulin resistance characteristic of younger SHR is blunted in middle-aged female rats, although FFA responses remain elevated. Ovariectomy did not alter in vivo glucose tolerance in this group; however, sex hormones may be important in maintaining normal heart size and the potential for cardiac glucose metabolism.

References

  • 1 Haffner S M, Agostino R D, Saad M F, O’Leary D H, Savage P J, Rewers M, Selby J, Bergman R N, Mykkanen L. Carotid artery atherosclerosis in type-2 diabetic and nondiabetic subjects with and without symptomatic coronary artery disease (The Insulin Resistance Atherosclerosis Study).  Am J Cardiol. 2000;  85 1395-1400
  • 2 Wenger N K. Coronary heart disease in women.  J Med Assoc Georgia. 1992;  81 679-681
  • 3 Gordon T, Kannel W B, Hjortland M C, McNamara P M. Menopause and coronary heart disease.  Ann Intern Med. 1978;  89 157-161
  • 4 Solymoss B C, Marcil M, Chaour M, Gilfix B M, Poitras A-M, Campeau L. Fasting hyperinsulinism, insulin resistance syndrome, and coronary artery disease in men and women.  Am J Cardiol. 1995;  76 1152-1156
  • 5 Portaluppi F, Pansini F, Manfredini R, Mollica G. Relative influence of menopausal status, age, and body mass index on blood pressure.  Hypertension. 1997;  29 976-979
  • 6 Swislocki A, Tsuzuki A. Insulin resistance and hypertension: glucose intolerance, hyperinsulinemia, and elevated free fatty acids in the lean spontaneously hypertensive rat.  Am J Med Sci. 1993;  306 282-286
  • 7 Gaboury C L, Karanja N, Holcomb S R, Torok J, McCarron D A. Patterns of insulin secretion and responsiveness in Wistar-Kyoto and spontaneously hypertensive rats.  Am J Hypertens. 1991;  8 661-666
  • 8 Reaven G M, Chang H. Relationship between blood pressure, plasma insulin and triglyceride concentration, and insulin action in spontaneous hypertensive and Wistar-Kyoto rats.  Am J Hypertens. 1991;  4 34-38
  • 9 Hulman S, Falkner B, Freyvogel N. Insulin resistance in the conscious spontaneously hypertensive rat: euglycemic hyperinsulinemic clamp study.  Metabolism. 1993;  42 14-18
  • 10 Picard F, Deshaies Y, Lalonde J, Samson p, Labrie C, Belanger A, Labrie F, Richard D. Effects of estrogen antagonist EM-652.HCl on energy balance and lipid metabolism in ovariectomized rats.  Int J Obest Relat Metab Disord. 2000;  24 830-840
  • 11 Kumagai S, Holmang A, Bjorntorp P. The effects of oestrogen and progesterone on insulin sensitivity in female rats.  Acta Physiol Scand. 1993;  149 91-97
  • 12 Nolan C, Proietto J. The effects of oophorectomy and female sex steroids on glucose kinetics in the rat.  Diabetes Res Clin Pract. 1995;  30 181-188
  • 13 Hansen P A, McCarthy T J, Pasia E N, Spina R J, Gulve E A. Effects of ovariectomy and exercise training on muscle GLUT-4 content and glucose metabolism in rats.  J Appl Physiol. 1996;  80 1605-1611
  • 14 Kava R A, West D B, Lukasik V A, Wypijewski C, Wojnar Z, Johnson P R, Greenwood M R. The effects of gonadectomy on glucose tolerance of genetically obese (fa/fa) rats: influence of sex and genetic background.  Int J Obest Relat Metab Disord. 1992;  16 103-111
  • 15 Iwase M, Wakisaka M, Yoshinari M, Sato Y, Yoshizumi H, Nunoi K, Fujishima M. Effect of gonadectomy and the development of diabetes mellitus, hypertension, and albuminuria in the rat model.  Metabolism. 1996;  45 155-161
  • 16 Chen Y F, Meng Q C. Sexual dimorphism of blood pressure in spontaneously hypertensive rats is androgen dependent.  Life Sci. 1991;  48 85-96
  • 17 Reckelhoff J F, Granger J P. Role of androgens in mediating hypertension and renal injury.  Clin Exp Pharmacol Physiol. 1999;  26 127-131
  • 18 Schaible T F, Malhotra A, Ciambrone G, Scheuer J. The effects of gonadectomy on left ventricular function and cardiac contractile proteins in male and female rats.  Circ Res. 1984;  54 38-49
  • 19 Malhotra A, Buttrick p, Scheuer J. Effects of sex hormones on development of physiological and pathological hypertrophy in male and female rats.  Am J Physiol. 1990;  259 H866-H871
  • 20 Sharkey L C, Holycross B J, Park S, Shiry L J, Hoepf T M. McCune SA, Radin MJ. Effect of ovariectomy and estrogen replacement on cardiovascular disease in heart failure-prone SHHF/Mcc-facp rats.  J Mol Cell Cardiol. 1999;  31 1527-1537
  • 21 Liang H, Ma Y, Pun S, Stimpel M, Jee W S. Aging- and ovariectomy-related skeletal changes in spontaneously hypertensive rats.  Anat Rec. 1997;  249 173-180
  • 22 Pyorala M, Miettinen H, Halonen p, Laakso M, Pyorala K. Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in healthy middle-aged men: The 22-year follow-up results of the Helsinki Policemen Study.  Arterioscl Thromb Vasc Biol. 2000;  20 538-544
  • 23 Hanson R l, Pratley R E, Bogardus C, Narayan K M, Roumain J M, Imperatore G, Fagot-Campagna A, Pettitt D J, Bennet P H, Knowler W C. Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies.  Am J Epidemiol. 2000;  151 190-198
  • 24 Legro R S, Finegood D, Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 1998;  83 2694-2698
  • 25 Crabtree B, Newsholme E A. The activities of phosphorylase, hexokinase, phosphofructokinase, lactate dehydrogenase and the glycerol 3-phosphate dehydrogenases in muscles from vertebrates and invertebrates.  Biochem J. 1972;  126 49-58
  • 26 Rodnick K J, Sidell B D. Cold acclimation increases carnitine palmitoyltransferase I activity in oxidative muscle of striped bass.  Am J Physiol. 1994;  266 R405-R412
  • 27 Hansen C A, Sidell B D. Atlantic hagfish cardiac muscle: metabolic basis of tolerance to anoxia.  Am J Physiol. 1983;  244 R356-R362
  • 28 Kinney LaPier T L, Swislocki A LM, Clark R J, Rodnick K J. Voluntary running improves glucose tolerance and insulin resistance in female spontaneously hypertensive rats.  Am J Hypertens. 2001;  14 708-725
  • 29 Iwase M, Kodama T, Himeno H, Yoshinari M, Tsutsu N, Sadoshima S, Fujishima M. Effect of aging on glucose tolerance in spontaneously hypertensive rats.  Clin Exp Hypertens. 1994;  16 67-76
  • 30 Walsh B A, Busch B L, Mullick A E, Reiser K M, Rutledge J C. 17β-estradiol reduces glycoxidative damage in the artery wall.  Arterioscler Thromb Vasc Biol. 1999;  19 840-846
  • 31 Kava R A, West D B, Lukasik V A, Wypijewski C, Wojnar Z, Johnson P R, Greenwood M R. The effects of gonadectomy on glucose tolerance of genetically obese (fa/fa) rats: influence of sex and genetic background.  Int J Obest Relat Metab Disord. 1992;  16 103-111
  • 32 McElroy J F, Wade G N. Short- and long-term effects of ovariectomy on food intake, body weight, carcass composition, and brown adipose tissue in rats.  Physiol Behav. 1987;  39 361-365
  • 33 Delorme J, Benassayag C, Christeff N, Vallette G, Savu L, Nunez E. Age-dependent responses of the serum non-esterified fatty acids to adrenalectomy and ovariectomy in developing rats.  Biochim Biophys Acta. 1984;  17 6-10
  • 34 Caprio S, Boulware S, Diamond M, Sherwin R S, Carpenter T O, Rubin K, Amiel S, Press M, Tamborlane W V. Insulin resistance: An early metabolic effect of Turner’s syndrome.  J Clin Endocrinol Metab. 1991;  72 832-836
  • 35 Gravholt C H, Naeraa R W, Nyholm B, Gerdes L U, Christiansen E, Schmitz O, Christiansen J S. Glucose metabolism, lipid metabolism, and cardiovascular risk factors in adult Turner’s syndrome. The impact of sex hormone replacement.  Diabetes Care. 1998;  21 1062-1070
  • 36 Pasquali R, Gambineri A, Anconetani B, Vicennati V, Colitta D, Caramelli E, Casimirri F, Morselli-Labate A M. The natural history of the metabolic syndrome in young women with the polycystic ovary syndrome and the effect of long-term oestrogen-progestagen treatment.  Clin Endocrinol. 1999;  50 517-527
  • 37 Davidge S T, Zhang Y, Stewart K G. A comparison of ovariectomy models for estrogen studies.  Am J Physiol. 2001;  280 R904-R907
  • 38 Niggeschulze A, Kast A. Maternal age, reproduction and chromosomal aberrations in Wistar derived rats.  Lab Anim. 1994;  28 55-62
  • 39 Mattheij J A, Swarts J J. Quantification and classification of pregnancy wastage in 5-day cyclic young through middle-aged rats.  Lab Anim. 1991;  25 30-34
  • 40 Matt D W, Lee J, Sarver P L, Judd H L, Lu J K. Chronological changes in fertility, fecundity and steroid hormone secretion during consecutive pregnancies in aging rats.  Biol Reprod. 1986;  34 478-487
  • 41 Hashimoto R, Kimura F. Puberty and ovulatory release of gonadotropins in spontaneously hypertensive rats.  Endocrinol Jpn. 1989;  36 675-680
  • 42 Brown-Grant K, Exley D, Naftolin F. Peripheral plasma oestradiol and luteinizing hormone concentrations during the oestrous cycle of the rat.  J Endocrinol. 1970;  48 295-296
  • 43 Lorenz R P, Picchio L P, Weisz J, Lloyd T. The relationship between reproductive performance and blood pressure in the spontaneously hypertensive rat.  Am J Obstet Gynecol. 1984;  150 519-523
  • 44 Pedersen S B, Bruun J M, Kristensen K, Richelsen B. Regulation of UCP1, UCP2, and UCP3 mRNA expression in brown adipose tissue, white adipose tissue, and skeletal muscle in rats by estrogen.  Biochem Biophys Res Commun. 2001;  288 191-197
  • 45 Toth M J, Poehlman E T, Matthews D E, Tchernof A, MacCoss M J. Effects of estradiol and progesterone on body composition, protein synthesis, and lipoprotein lipase in rats.  Am J Physiol Endocrinol Metab. 2001;  280 E496-E501
  • 46 Swislocki A LM, Kinney LaPier T L, Khuu D T, Fann K Y, Tait M, Rodnick K J. Metabolic, hemodynamic, and cardiac effects of captopril in young, spontaneously hypertensive rats.  Am J Hypertens. 1999;  12 581-589
  • 47 Scheuer J, Malhotra A, Schaible T F, Capasso J. Effects of gonadectomy and hormonal replacement or rat hearts.  Circ Res. 1987;  61 12-19
  • 48 Lopaschuk G D, Belke D D, Gamble J, Itoi T, Schonekess B O. Regulation of fatty acid oxidation in the mammalian heart in health and disease.  Biochim Biophys Acta. 1994;  1213 263-276
  • 49 Christe M E, Rodgers R L. Altered glucose and fatty acid oxidation in hearts of the spontaneously hypertensive rat.  J Mol Cell Cardiol. 1994;  26 1371-1375
  • 50 Paternostro G, Clarke K, Heath J, Seymour A M, Radda G K. Decreased GLUT-4 mRNA content and insulin-sensitive deoxyglucose uptake show insulin resistance in the hypertensive rat heart.  Cardiovasc Res. 1995;  30 205-211

A. Swislocki, M.D., F.A.C.P.

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