Vascular Actions of Insulin in Health and Disease

Role of the Endothelium
  • Alain D. Baron
  • Helmut O. Steinberg
Part of the Contemporary Endocrinology book series (COE, volume 1)


Insulin has specific and physiologic cardiovascular actions in humans, and causes an increase in skeletal muscle blood flow (SMBF) and a fall in vascular resistance. In this chapter, the physiologic role of insulin-induced skeletal muscle vasodilation and its mechanism including the interaction between insulin and the endothelium to modulate the endothelium-derived nitric oxide (NO) system are reviewed. Finally, the effect of insulin resistance on the vascular actions of insulin is also explored. The latter has important clinical consequences given that insulin resistance is a common feature of obesity, of noninsulin-dependent diabetes mellitus (NIDDM), and hypertension, and is associated with an increased risk of macrovascular disease (1,2)


Nitric Oxide Mean Arterial Pressure Vascular Action Stimulate Glucose Uptake Skeletal Muscle Blood Flow 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Nosadini R, Manzato E, Solini A, Fioretto P, Brocco E, Zambon S, Morocutti A, Sambataro M, Velussi M, Cipollina MR, Crepaldi G. Peripheral, rather than hepatic, insulin resistance and atherogenic lipoprotein phenotype predict cardiovascular complications in NIDDM. EurJ Clin Invest 1994;24:258–266.CrossRefGoogle Scholar
  2. 2.
    Lindahl B, Asplund K, Hallmans G. High serum insulin, insulin resistance and their associations with cardiovascular risk factors. The Northern Sweden Monica population study. J Int Med 1993;234:263–270.Google Scholar
  3. 3.
    Page MM, Smith RBW, Watkins PJ. Cardiovascular effects of insulin. Br J Pharmacol 1976;1:430–432.Google Scholar
  4. 4.
    Liang C-S, Doherty JU, Faillace R, Maekawa K, Arnold S, Gavras H, Hood WB. Insulin infusion in conscious dogs. Effects on systemic and coronary hemodynamics, regional blood flows, and plasma catecholamines. J Clin Invest 1982;69:1321–1336.PubMedCrossRefGoogle Scholar
  5. 5.
    Baron AD, Brechtel G. Insulin differentially regulates systemic and skeletal muscle vascular resistance. Am J Physiol (Endocrinol Metab 28) 1993;265:E61–E67.PubMedGoogle Scholar
  6. 6.
    Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese men. J Clin Invest 1990;85:1844–1852.PubMedCrossRefGoogle Scholar
  7. 7.
    Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest 1991;87:2246–2252.PubMedCrossRefGoogle Scholar
  8. 8.
    Bennett WM, Connacher AA, Scrimegeour CM. Euglycemic hyperinsulinemia augments amino acid uptake by human leg tissues during hyperaminoacidemia. Am J Physiol 1990;259:E185–E194.Google Scholar
  9. 9.
    Neahring JM, Stepniakowski K, Greene AS, Egan BM. Insulin does not reduce forearm alphavasoreactivity in obese hypertensive or lean normotensive men. Hypertension 1993;22:584–590.PubMedCrossRefGoogle Scholar
  10. 10.
    Vollenweider P, Tappy L, Randin D, Schneiter P, Jequier E, Nicod P, Scherrer U. Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest 1993;92:147–154.PubMedCrossRefGoogle Scholar
  11. 11.
    Ueda S, Petrie JR, Elliott HL, Connell JM. Insulin mediated vasodilation is dependent on local glucose concentrations. Hypertension 1995;25:561.CrossRefGoogle Scholar
  12. 12.
    Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. J Clin Invest 1994;94:1172–1179.PubMedCrossRefGoogle Scholar
  13. 13.
    Furchgott RF, Zawadzki JV.The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373–382.PubMedCrossRefGoogle Scholar
  14. 14.
    Moncada S, Radomski MW, Palmer RMJ. Endothelium derived relaxing factor: identification as nitric oxide and role in the control of vascular tone and platelet function. Biochem Pharmacol 1988;37:2495–2501.PubMedCrossRefGoogle Scholar
  15. 15.
    Palmer RMJ, Rees DD, Ashton DS, Moncada S. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Comm 1988;153:1251–1256.PubMedCrossRefGoogle Scholar
  16. 16.
    Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide fromL-arginine. Nature 1988;333:524–526.CrossRefGoogle Scholar
  17. 17.
    Marietta MA. Nitric oxide synthase: aspects concerning structure and catalysis. Cell 1994;78:927–931.CrossRefGoogle Scholar
  18. 18.
    Ignarro LJ. Nitric oxide: a novel signal transduction mechanism for transcellular communication. Hypertension 1990;16:477–483.PubMedCrossRefGoogle Scholar
  19. 19.
    Gupta S, McArthur C, Grady C, Ruderman NB. Stimulation of vascular Na-K-ATPase activity by nitric oxide: a cGMP-independent effect. Am J Physiol 1994;266:H2146–H2151.PubMedGoogle Scholar
  20. 20.
    Gupta S, McArthur C, Grady C, Ruderman NB. Role of endothelium-derived nitric oxide in stimulation of Na(+)-K(+)-ATPase activity by endothelin in rabbit aorta. Am J Physiol 1994;266:H577–H582.PubMedGoogle Scholar
  21. 21.
    Vanhoutte PM, Miller VM. Heterogeneity of endothelium-dependent responses in mammalian blood vessels. J Cardiovasc Pharmacol 1985;7(Suppl. 3):S12–S23.PubMedCrossRefGoogle Scholar
  22. 22.
    D’Orleans-Juste P, Dion S, Mizrahi J, Regoli D. Effects of peptides and non-peptides on isolated arterial smooth muscles: role of endothelium. Eur J Pharmacol 1985;114:9–21.PubMedCrossRefGoogle Scholar
  23. 23.
    Suzuki H, Ikenaga H, Hishikawa K, Nakaki T, Kato R, Saruta T. Increases in NO2-/NO3-excretion in the urine as an indicator of the release of endothelium-derived relaxing factor during elevation of blood pressure. Clinical Sci 1992;82:631–634.Google Scholar
  24. 24.
    Rees DD, Palmer RMJ, Hodson HF, Moncada S. A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium dependent relaxation. Br J Pharmacol 1989;96:418–424.PubMedCrossRefGoogle Scholar
  25. 25.
    Rees DD, Palmer RMJ, Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci USA 1989;86:3375–3378.PubMedCrossRefGoogle Scholar
  26. 26.
    Valiance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 1989;2:997–1000.CrossRefGoogle Scholar
  27. 27.
    Baylis C, Mitruka B, Deng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest 1992;90:278–281.PubMedCrossRefGoogle Scholar
  28. 28.
    Stammler JS, Loh E, Roddy M-A, Currie KE, Creager MA. Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans. Circulation 1994;89:2035–2040.CrossRefGoogle Scholar
  29. 29.
    Nagao T, Illiano S, Vanhoutte PM. Heterogeneous distribution of endothelium-dependent relaxations resistant to Ng-nitro-L-arginine in rats. Am J Physiol 1992;263:H1090–H1094.PubMedGoogle Scholar
  30. 30.
    Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P. Nitric oxide release accounts for insulin’s vascular effects in humans. J Clin Invest 1994;94:2511–2515.PubMedCrossRefGoogle Scholar
  31. 31.
    Taddei S, Virdis A, Mattei P, Natali A, Ferrannini E, Salvetti A. Effect of insulin on acetylcholine-induced vasodilation in the forearm of normotensive subjects. Hypertension 1995;25:552.CrossRefGoogle Scholar
  32. 32.
    Brayden JE. Membrane hyperpolarization is a mechanism of endothelium-dependent cerebral vasodilation. Am J Physiol 1990;259:H669–H673.Google Scholar
  33. 33.
    Kahn AM, Allen JC, Seidel CL, Shelat H, Song T. Insulin reduces contraction and intracellular calcium concentration in vascular smooth muscle. Hypertension 1993;22:735–742.PubMedCrossRefGoogle Scholar
  34. 34.
    Standley PR, Zhang F, Ram JL, Zemel MB, Sowers JR. Insulin attenuates vasopressin-induced calcium transients and a voltage-dependent calcium response in rat vascular smooth muscle cells. J Clin Invest 1991;88:1230–1236.PubMedCrossRefGoogle Scholar
  35. 35.
    Tirupattur PR, Ram JL, Standley PR, Sowers JR. Regulation on Na+, K+-ATPase gene expression by insulin in vascular smooth muscle cells. Am J Hypertens 1993; 6:626–629.PubMedCrossRefGoogle Scholar
  36. 36.
    Sowers JR, Eptstein M. Diabetes mellitus and associated hypertension, vascular disease, and nephropathy: an update. Hypertension 1995;26:869–879.PubMedCrossRefGoogle Scholar
  37. 37.
    Laakso M, Edelman SV, Brechtel G, Baron AD. Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes 1992;41:1076–1083.PubMedCrossRefGoogle Scholar
  38. 38.
    Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graciadei L, Pedrinelli R, Brandi L, Bevilacqua D. Insulin resistance in essential hypertension. N Engl J Med 1987;317:350–357.PubMedCrossRefGoogle Scholar
  39. 39.
    Pollare T, Lithell H, Berne C. Insulin resistance is a characteristic feature of primary hypertension independent of obesity. Metabolism 1990;39:167–174PubMedCrossRefGoogle Scholar
  40. 40.
    Shen D-C, Shieh S-M, Fuh M M-T, Wu C-A, Chen Y-D I, Reaven GM. Resistance to insulin stimulated glucose uptake in patients with hypertension. J Clin Endo Metab 1988;66:580–583.CrossRefGoogle Scholar
  41. 41.
    Baron AD, Brechtel-Hook G, Johnson A, Hardin D. Skeletal mule blood flow-a possible link between insulin resisstance and blood pressure. Hypertension 1993;21:129–135.PubMedCrossRefGoogle Scholar
  42. 42.
    Grover A, Padginton C, Wilson MF, Sung BH, Izzo JL Jr, Dandona P. Insulin attenuates norepinephrineinduced venoconstriction. An ultrasonographic study. Hypertension 1995;25(4 Pt 2):779–784.PubMedCrossRefGoogle Scholar
  43. 43.
    Panza JA, Quyyumy A, Brush JE, Epstein SE. Abnortpal endothelium dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990;323:22–27.PubMedCrossRefGoogle Scholar
  44. 44.
    Panza JA, Casino PR, Badar DM, Quyyumi AA. Effect of increased availability of endothelium-derivednitric-oxide precursor on endothelium-dependent vascular relaxation in normal subjects and in patients with essential hypertension. Circulation 1993;87:1475–1481.PubMedCrossRefGoogle Scholar
  45. 45.
    Taddei S, Virdis A, Mattei P, Arzilli F, Salvetti A. Endothelium-dependent forearm vasodilation is reduced in normotensive subjects with familial history of hypertension. J Cardiovasc Pharmacol 1992;20(Suppl. 12):193–195.CrossRefGoogle Scholar
  46. 46.
    Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 1993;87:1468–1474.PubMedCrossRefGoogle Scholar
  47. 47.
    Calver A, Collier J, Moncada S, Vallance P. Effect of local infra-arterial NG-monomethyl-L-arginine in patients with hypertension: the nitric oxide dilator mechanism appears abnormal. J Hypertens 1992;10:1025–1031.PubMedCrossRefGoogle Scholar
  48. 48.
    Smits P, Kapma J-A, Jacobs M-C, Lutterman J, Thien T. Endothelium-dependent vascular relaxation in patients with type 1 diabetes. Diabetes 1993;42:148–153.PubMedCrossRefGoogle Scholar
  49. 49.
    Calver A, Collier J, Vallance P. Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest 1992;90:2548–2554.PubMedCrossRefGoogle Scholar
  50. 50.
    Johnstone MT, Craeger SJ, Scales KM, Cusco JA, Lee BK, Craeger MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993;88: 2510–2516.PubMedCrossRefGoogle Scholar
  51. 51.
    McVeigh GE, Brennan GM, Johnston GD, McDermott BJ, McGrath LT, Andrews JW, Hayes JR. Impaired endothelium dependent and independent vasodilation in patients with type 2 (non-insulindependent) diabetes mellitus. Diabetologia 1992;35:771–776.PubMedGoogle Scholar
  52. 52.
    Angus JA, Lew M. Interpretation of the acetylcholine test of endothelial dysfunction in hypertension. J Hypertension 1992;10(Suppl. 7): S 179-S186.CrossRefGoogle Scholar
  53. 53.
    Castillo L, Sanchez M, Vogt J, Chapman TE, DeRoj as-Walker TC, Tannenbaum SR, Ajami AM, Young VR. Plasma arginine, citrulline, and omithine kinetics in adults, with observation on nitric oxide synthesis. Am J Physiol 1995;268:E360–E367.PubMedGoogle Scholar
  54. 54.
    Castillo L, DeRojas TC, Chapman TE, Vogt J, Burke JF, Tannenbaum SR, Young VR. Splanchnic metabolism of dietary arginine in relation to nitric oxide synthesis in normal adult man. Proc Natl Acad Sci USA 1993;90:193–197.PubMedCrossRefGoogle Scholar
  55. 55.
    Edelman SV, Laakso M, Wallace P, Brechtel G, Olefsky JM, Baron AD. Kinetics of insulin-mediated and non-insulin-mediated glucose uptake in humans. Diabetes 1990;39:955–964.PubMedCrossRefGoogle Scholar
  56. 56.
    Baron AD, Laakso M, Brechtel G, Edelman SV. Mechanism of insulin resistance in insulin-dependent diabetes mellitus: a major role for reduced skeletal muscle blood flow. J Clin Endo Metab 1991;73:637–643.CrossRefGoogle Scholar
  57. 57.
    Baron AD, Steinberg HO, Chaker H, Learning R, Johnson A, Brechtel G. Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans. J Clin Invest 1995;96:786–792.PubMedCrossRefGoogle Scholar
  58. 58.
    Baron AD, Brechtel G, Johnson A, Fineberg N, Henry DP, Steinberg HO. Interactions between insulin and norepinephrine on blood pressure and insulin sensitivity. J Clin Invest 1994;93:2453–2462.PubMedCrossRefGoogle Scholar
  59. 59.
    Steinberg H, Brechtel G, Johnson A, Baron AD. Insulin mediated endothelium dependent vasodilation is impaired in obesity. Diabetes 1994;43(Suppl. 1):101A.Google Scholar
  60. 60.
    Radomski MW, Palmer RMJ, Moncada S. The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol 1987;92:639–646.PubMedCrossRefGoogle Scholar
  61. 61.
    Mollace V, Salvemini D, Anggard E, Vane J. Nitric oxide from vascular smooth muscle cells: regulation of platelet reactivity and smooth muscle cell guanylate cyclase. Br J Pharmacol 1991;104:633–638.PubMedCrossRefGoogle Scholar
  62. 62.
    Kopalkov V, Gordon D, Kulik TJ. Nitric oxide-generating compounds inhibit total protein and collagen synthesis in cultured vascular smooth muscle cells. Circ Res 1995;76:305–309.CrossRefGoogle Scholar
  63. 63.
    Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989;83:1774–1777.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Alain D. Baron
  • Helmut O. Steinberg

There are no affiliations available

Personalised recommendations