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. 1992 Jul;90(1):24–29. doi: 10.1172/JCI115842

Abnormal sympathetic overactivity evoked by insulin in the skeletal muscle of patients with essential hypertension.

G Lembo 1, R Napoli 1, B Capaldo 1, V Rendina 1, G Iaccarino 1, M Volpe 1, B Trimarco 1, L Saccà 1
PMCID: PMC443058  PMID: 1634611

Abstract

The reason why hyperinsulinemia is associated with essential hypertension is not known. To test the hypothesis of a pathophysiologic link mediated by the sympathetic nervous system, we measured the changes in forearm norepinephrine release, by using the forearm perfusion technique in conjunction with the infusion of tritiated NE, in patients with essential hypertension and in normal subjects receiving insulin intravenously (1 mU/kg per min) while maintaining euglycemia. Hyperinsulinemia (50-60 microU/ml in the deep forearm vein) evoked a significant increase in forearm NE release in both groups of subjects. However, the response of hypertensives was threefold greater compared to that of normotensives (2.28 +/- 45 ng.liter-1.min-1 in hypertensives and 0.80 +/- 0.27 ng.liter-1 in normals; P less than 0.01). Forearm glucose uptake rose to 5.1 +/- .7 mg.liter-1.min-1 in response to insulin in hypertensives and to 7.9 +/- 1.3 mg.liter-1.min-1 in normotensives (P less than 0.05). To clarify whether insulin action was due to a direct effect on muscle NE metabolism, in another set of experiments insulin was infused locally into the brachial artery to expose only the forearm tissues to the same insulin levels as in the systemic studies. During local hyperinsulinemia, forearm NE release remained virtually unchanged both in hypertensive and in normal subjects. Furthermore, forearm glucose disposal was activated to a similar extent in both groups (5.0 +/- 0.6 and 5.2 +/- 1.1 mg.liter-1.min-1 in hypertensives and in normals, respectively). These data demonstrate that: (a) insulin evokes an abnormal muscle sympathetic overactivity in essential hypertension which is mediated by mechanisms involving the central nervous system; and (b) insulin resistance associated with hypertension is demonstrable in the skeletal muscle tissue only with systemic insulin administration which produces muscle sympathetic overactivity. The data fit the hypothesis that the sympathetic system mediates the pathophysiologic link between hyperinsulinemia and essential hypertension.

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Selected References

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  1. ANDRES R., ZIERLER K. L., ANDERSON H. M., STAINSBY W. N., CADER G., GHRAYYIB A. S., LILIENTHAL J. L., Jr Measurement of blood flow and volume in the forearm of man; with notes on the theory of indicator-dilution and on production of turbulence, hemolysis, and vasodilatation by intra-vascular injection. J Clin Invest. 1954 Apr;33(4):482–504. doi: 10.1172/JCI102919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. ANTON A. H., SAYRE D. F. A study of the factors affecting the aluminum oxide-trihydroxyindole procedure for the analysis of catecholamines. J Pharmacol Exp Ther. 1962 Dec;138:360–375. [PubMed] [Google Scholar]
  3. Alexander W. D., Oake R. J. The effect of insulin on vascular reactivity to norepinephrine. Diabetes. 1977 Jul;26(7):611–614. doi: 10.2337/diab.26.7.611. [DOI] [PubMed] [Google Scholar]
  4. Anderson E. A., Hoffman R. P., Balon T. W., Sinkey C. A., Mark A. L. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest. 1991 Jun;87(6):2246–2252. doi: 10.1172/JCI115260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Anderson E. A., Sinkey C. A., Lawton W. J., Mark A. L. Elevated sympathetic nerve activity in borderline hypertensive humans. Evidence from direct intraneural recordings. Hypertension. 1989 Aug;14(2):177–183. doi: 10.1161/01.hyp.14.2.177. [DOI] [PubMed] [Google Scholar]
  6. Berne C., Fagius J., Niklasson F. Sympathetic response to oral carbohydrate administration. Evidence from microelectrode nerve recordings. J Clin Invest. 1989 Nov;84(5):1403–1409. doi: 10.1172/JCI114313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bhagat B., Burke W. J., Dhalla N. S. Insulin-induced enhancement of uptake of noradrenaline in atrial strips. Br J Pharmacol. 1981 Oct;74(2):325–332. doi: 10.1111/j.1476-5381.1981.tb09975.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Blaes N., Boissel J. P. Growth-stimulating effect of catecholamines on rat aortic smooth muscle cells in culture. J Cell Physiol. 1983 Aug;116(2):167–172. doi: 10.1002/jcp.1041160207. [DOI] [PubMed] [Google Scholar]
  9. Capaldo B., Lembo G., Napoli R., Rendina V., Albano G., Saccà L., Trimarco B. Skeletal muscle is a primary site of insulin resistance in essential hypertension. Metabolism. 1991 Dec;40(12):1320–1322. doi: 10.1016/0026-0495(91)90036-v. [DOI] [PubMed] [Google Scholar]
  10. Capaldo B., Napoli R., Di Bonito P., Albano G., Saccà L. Dual mechanism of insulin action on human skeletal muscle: identification of an indirect component not mediated by FFA. Am J Physiol. 1991 Mar;260(3 Pt 1):E389–E394. doi: 10.1152/ajpendo.1991.260.3.E389. [DOI] [PubMed] [Google Scholar]
  11. Desbuquois B., Aurbach G. D. Use of polyethylene glycol to separate free and antibody-bound peptide hormones in radioimmunoassays. J Clin Endocrinol Metab. 1971 Nov;33(5):732–738. doi: 10.1210/jcem-33-5-732. [DOI] [PubMed] [Google Scholar]
  12. Ferrannini E., Buzzigoli G., Bonadonna R., Giorico M. A., Oleggini M., Graziadei L., Pedrinelli R., Brandi L., Bevilacqua S. Insulin resistance in essential hypertension. N Engl J Med. 1987 Aug 6;317(6):350–357. doi: 10.1056/NEJM198708063170605. [DOI] [PubMed] [Google Scholar]
  13. Ferrari P., Weidmann P., Shaw S., Giachino D., Riesen W., Allemann Y., Heynen G. Altered insulin sensitivity, hyperinsulinemia, and dyslipidemia in individuals with a hypertensive parent. Am J Med. 1991 Dec;91(6):589–596. doi: 10.1016/0002-9343(91)90211-f. [DOI] [PubMed] [Google Scholar]
  14. Hwang I. S., Ho H., Hoffman B. B., Reaven G. M. Fructose-induced insulin resistance and hypertension in rats. Hypertension. 1987 Nov;10(5):512–516. doi: 10.1161/01.hyp.10.5.512. [DOI] [PubMed] [Google Scholar]
  15. Izzo J. L., Jr The sympathoadrenal system in the maintenance of elevated arterial pressure. J Cardiovasc Pharmacol. 1984;6 (Suppl 3):S514–S521. [PubMed] [Google Scholar]
  16. Kirkendall W. M., Burton A. C., Epstein F. H., Freis E. D. Recommendations for human blood pressure determination by sphygmomanometers. Circulation. 1967 Dec;36(6):980–988. doi: 10.1161/01.cir.36.6.980. [DOI] [PubMed] [Google Scholar]
  17. Landsberg L. Diet, obesity and hypertension: an hypothesis involving insulin, the sympathetic nervous system, and adaptive thermogenesis. Q J Med. 1986 Dec;61(236):1081–1090. [PubMed] [Google Scholar]
  18. Landsberg L., Young J. B. Insulin-mediated glucose metabolism in the relationship between dietary intake and sympathetic nervous system activity. Int J Obes. 1985;9 (Suppl 2):63–68. [PubMed] [Google Scholar]
  19. Modan M., Halkin H., Almog S., Lusky A., Eshkol A., Shefi M., Shitrit A., Fuchs Z. Hyperinsulinemia. A link between hypertension obesity and glucose intolerance. J Clin Invest. 1985 Mar;75(3):809–817. doi: 10.1172/JCI111776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Natali A., Santoro D., Palombo C., Cerri M., Ghione S., Ferrannini E. Impaired insulin action on skeletal muscle metabolism in essential hypertension. Hypertension. 1991 Feb;17(2):170–178. doi: 10.1161/01.hyp.17.2.170. [DOI] [PubMed] [Google Scholar]
  21. Noma A., Okabe H., Kita M. A new colorimetric micro-determination of free fatty acids in serum. Clin Chim Acta. 1973 Feb 12;43(3):317–320. doi: 10.1016/0009-8981(73)90468-3. [DOI] [PubMed] [Google Scholar]
  22. Reaven G. M., Ho H., Hoffman B. B. Attenuation of fructose-induced hypertension in rats by exercise training. Hypertension. 1988 Aug;12(2):129–132. doi: 10.1161/01.hyp.12.2.129. [DOI] [PubMed] [Google Scholar]
  23. Reaven G. M., Ho H., Hoffmann B. B. Somatostatin inhibition of fructose-induced hypertension. Hypertension. 1989 Aug;14(2):117–120. doi: 10.1161/01.hyp.14.2.117. [DOI] [PubMed] [Google Scholar]
  24. Rizza R. A., Cryer P. E., Haymond M. W., Gerich J. E. Adrenergic mechanisms for the effects of epinephrine on glucose production and clearance in man. J Clin Invest. 1980 Mar;65(3):682–689. doi: 10.1172/JCI109714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rocchini A. P., Key J., Bondie D., Chico R., Moorehead C., Katch V., Martin M. The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med. 1989 Aug 31;321(9):580–585. doi: 10.1056/NEJM198908313210905. [DOI] [PubMed] [Google Scholar]
  26. Rowe J. W., Young J. B., Minaker K. L., Stevens A. L., Pallotta J., Landsberg L. Effect of insulin and glucose infusions on sympathetic nervous system activity in normal man. Diabetes. 1981 Mar;30(3):219–225. doi: 10.2337/diab.30.3.219. [DOI] [PubMed] [Google Scholar]
  27. Sacca L., Perez G., Carteni G., Rengo F. Evaluation of the role of the sympathetic nervous system in the glucoregulatory response to insulin-induced hypoglycemia in the rat. Endocrinology. 1977 Oct;101(4):1016–1022. doi: 10.1210/endo-101-4-1016. [DOI] [PubMed] [Google Scholar]
  28. Sacca L., Perez G., Rengo F., Pascucci I., Condorelli M. Effects of theophylline on glucose kinetics in normal and sympathectomized rats. Diabetes. 1975 Mar;24(3):249–256. doi: 10.2337/diab.24.3.249. [DOI] [PubMed] [Google Scholar]
  29. Saccà L., Cicala M., Trimarco B., Ungaro B., Vigorito C. Differential effects of insulin on splanchnic and peripheral glucose disposal after an intravenous glucose load in man. J Clin Invest. 1982 Jul;70(1):117–126. doi: 10.1172/JCI110583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Saccà L., Eigler N., Cryer P. E., Sherwin R. S. Insulin antagonistic effects of epinephrine and glucagon in the dog. Am J Physiol. 1979 Dec;237(6):E487–E492. doi: 10.1152/ajpendo.1979.237.6.E487. [DOI] [PubMed] [Google Scholar]
  31. Saccà L., Vigorito C., Cicala M., Ungaro B., Sherwin R. S. Mechanisms of epinephrine-induced glucose intolerance in normal humans. J Clin Invest. 1982 Feb;69(2):284–293. doi: 10.1172/JCI110451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sauter A., Goldstein M., Engel J., Ueta K. Effect of insulin on central catecholamines. Brain Res. 1983 Feb 7;260(2):330–333. doi: 10.1016/0006-8993(83)90691-1. [DOI] [PubMed] [Google Scholar]
  33. Shen D. C., Shieh S. M., Fuh M. M., Wu D. A., Chen Y. D., Reaven G. M. Resistance to insulin-stimulated-glucose uptake in patients with hypertension. J Clin Endocrinol Metab. 1988 Mar;66(3):580–583. doi: 10.1210/jcem-66-3-580. [DOI] [PubMed] [Google Scholar]
  34. Simpson P. Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alpha 1 adrenergic response. J Clin Invest. 1983 Aug;72(2):732–738. doi: 10.1172/JCI111023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Singer P., Gödicke W., Voigt S., Hajdu I., Weiss M. Postprandial hyperinsulinemia in patients with mild essential hypertension. Hypertension. 1985 Mar-Apr;7(2):182–186. doi: 10.1161/01.hyp.7.2.182. [DOI] [PubMed] [Google Scholar]
  36. Trimarco B., Lembo G., De Luca N., Volpe M., Ricciardelli B., Condorelli G., Rosiello G., Condorelli M. Blunted sympathetic response to cardiopulmonary receptor unloading in hypertensive patients with left ventricular hypertrophy. A possible compensatory role of atrial natriuretic factor. Circulation. 1989 Oct;80(4):883–892. doi: 10.1161/01.cir.80.4.883. [DOI] [PubMed] [Google Scholar]
  37. Van Houten M., Posner B. I. Circumventricular organs: receptors and mediators of direct peptide hormone action on brain. Adv Metab Disord. 1983;10:269–289. doi: 10.1016/b978-0-12-027310-2.50015-3. [DOI] [PubMed] [Google Scholar]
  38. Welborn T. A., Breckenridge A., Rubinstein A. H., Dollery C. T., Fraser T. R. Serum-insulin in essential hypertension and in peripheral vascular disease. Lancet. 1966 Jun 18;1(7451):1336–1337. doi: 10.1016/s0140-6736(66)92132-5. [DOI] [PubMed] [Google Scholar]
  39. Yagi S., Takata S., Kiyokawa H., Yamamoto M., Noto Y., Ikeda T., Hattori N. Effects of insulin on vasoconstrictive responses to norepinephrine and angiotensin II in rabbit femoral artery and vein. Diabetes. 1988 Aug;37(8):1064–1067. doi: 10.2337/diab.37.8.1064. [DOI] [PubMed] [Google Scholar]
  40. Yamori Y., Mano M., Nara Y., Horie R. Catecholamine-induced polyploidization in vascular smooth muscle cells. Circulation. 1987 Jan;75(1 Pt 2):I92–I95. [PubMed] [Google Scholar]
  41. Young J. B., Landsberg L. Impaired suppression of sympathetic activity during fasting in the gold thioglucose-treated mouse. J Clin Invest. 1980 May;65(5):1086–1094. doi: 10.1172/JCI109761. [DOI] [PMC free article] [PubMed] [Google Scholar]

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