Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1994 Dec;94(6):2295–2300. doi: 10.1172/JCI117593

Relation of pressor responsiveness to angiotensin II and insulin resistance in hypertension.

C L Gaboury 1, D C Simonson 1, E W Seely 1, N K Hollenberg 1, G H Williams 1
PMCID: PMC330057  PMID: 7989585

Abstract

To test the hypothesis that the hypertension associated with insulin resistance is secondary to an altered responsiveness of the vasculature to pressor agents, we evaluated the relationship between insulin resistance and pressor responses to angiotensin II (AII) in 21 hypertensive (HT) and 8 normotensive (NT) subjects on both a high (200 meq) and a low (10 meq) sodium diet. When sodium balance was achieved, each supine fasting subject underwent an AII infusion at a rate of 3 ng/kg per min for 60 min, with blood pressure monitored every 2 min. On the next day under similar conditions, a euglycemic hyperinsulinemic clamp was performed, with plasma glucose clamped at 90 mg/dl for 120 min. There was no significant relationship between the glucose disposal rate (M) or the insulin sensitivity index (M divided by the mean insulin level [M/I]) and blood pressure response to AII in the NTs, but a highly significant (P < 0.019) negative correlation (r = -0.55) in the HTs. Furthermore, in eight lean HTs whose body mass index was identical to that observed in the NTs, the relationship was even more striking (P < 0.008; r = -0.85). The results on high and low salt diets were similar; however, the M and M/I were significantly increased (P < 0.05) in the NTs but not HTs with sodium restriction. In conclusion, HTs but not NTs display a striking correlation between pressor response to AII and insulin resistance. This relationship is independent of the level of sodium intake. Furthermore, sodium intake modifies insulin sensitivity in NTs but not HTs. These results strongly suggest that a primary change in pressor response to vasoactive agents in insulin-resistant subjects can contribute to their elevated blood pressure.

Full text

PDF
2295

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baron A. D., Brechtel G. Insulin differentially regulates systemic and skeletal muscle vascular resistance. Am J Physiol. 1993 Jul;265(1 Pt 1):E61–E67. doi: 10.1152/ajpendo.1993.265.1.E61. [DOI] [PubMed] [Google Scholar]
  2. Braley L. M., Menachery A. I., Brown E. M., Williams G. H. Comparative effect of angiotensin II, potassium, adrenocorticotropin, and cyclic adenosine 3',5'-monophosphate on cytosolic calcium in rat adrenal cells. Endocrinology. 1986 Sep;119(3):1010–1019. doi: 10.1210/endo-119-3-1010. [DOI] [PubMed] [Google Scholar]
  3. Bruschi G., Bruschi M. E., Caroppo M., Orlandini G., Spaggiari M., Cavatorta A. Cytoplasmic free [Ca2+] is increased in the platelets of spontaneously hypertensive rats and essential hypertensive patients. Clin Sci (Lond) 1985 Feb;68(2):179–184. doi: 10.1042/cs0680179. [DOI] [PubMed] [Google Scholar]
  4. Cooper R. S., Shamsi N., Katz S. Intracellular calcium and sodium in hypertensive patients. Hypertension. 1987 Mar;9(3):224–229. doi: 10.1161/01.hyp.9.3.224. [DOI] [PubMed] [Google Scholar]
  5. DeFronzo R. A., Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991 Mar;14(3):173–194. doi: 10.2337/diacare.14.3.173. [DOI] [PubMed] [Google Scholar]
  6. DeFronzo R. A., Simonson D., Ferrannini E. Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1982 Oct;23(4):313–319. doi: 10.1007/BF00253736. [DOI] [PubMed] [Google Scholar]
  7. DeFronzo R. A., Tobin J. D., Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214–E223. doi: 10.1152/ajpendo.1979.237.3.E214. [DOI] [PubMed] [Google Scholar]
  8. Dluhy R. G., Axelrod L., Williams G. H. Serum immunoreactive insulin and growth hormone response to potassium infusion in normal man. J Appl Physiol. 1972 Jul;33(1):22–26. doi: 10.1152/jappl.1972.33.1.22. [DOI] [PubMed] [Google Scholar]
  9. Donovan D. S., Solomon C. G., Seely E. W., Williams G. H., Simonson D. C. Effect of sodium intake on insulin sensitivity. Am J Physiol. 1993 May;264(5 Pt 1):E730–E734. doi: 10.1152/ajpendo.1993.264.5.E730. [DOI] [PubMed] [Google Scholar]
  10. Draznin B., Lewis D., Houlder N., Sherman N., Adamo M., Garvey W. T., LeRoith D., Sussman K. Mechanism of insulin resistance induced by sustained levels of cytosolic free calcium in rat adipocytes. Endocrinology. 1989 Nov;125(5):2341–2349. doi: 10.1210/endo-125-5-2341. [DOI] [PubMed] [Google Scholar]
  11. Draznin B., Sussman K. E., Eckel R. H., Kao M., Yost T., Sherman N. A. Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia. J Clin Invest. 1988 Dec;82(6):1848–1852. doi: 10.1172/JCI113801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Draznin B., Sussman K., Kao M., Lewis D., Sherman N. The existence of an optimal range of cytosolic free calcium for insulin-stimulated glucose transport in rat adipocytes. J Biol Chem. 1987 Oct 25;262(30):14385–14388. [PubMed] [Google Scholar]
  13. Emanuel R. L., Cain J. P., Williams G. H. Double antibody radioimmunoassay of renin activity and angiotensin II in human peripheral plasma. J Lab Clin Med. 1973 Apr;81(4):632–640. [PubMed] [Google Scholar]
  14. Erne P., Bolli P., Bürgisser E., Bühler F. R. Correlation of platelet calcium with blood pressure. Effect of antihypertensive therapy. N Engl J Med. 1984 Apr 26;310(17):1084–1088. doi: 10.1056/NEJM198404263101705. [DOI] [PubMed] [Google Scholar]
  15. Falkner B., Hulman S., Tannenbaum J., Kushner H. Insulin resistance and blood pressure in young black men. Hypertension. 1990 Dec;16(6):706–711. doi: 10.1161/01.hyp.16.6.706. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Fraze E., Donner C. C., Swislocki A. L., Chiou Y. A., Chen Y. D., Reaven G. M. Ambient plasma free fatty acid concentrations in noninsulin-dependent diabetes mellitus: evidence for insulin resistance. J Clin Endocrinol Metab. 1985 Nov;61(5):807–811. doi: 10.1210/jcem-61-5-807. [DOI] [PubMed] [Google Scholar]
  18. Gordon M. S., Steunkel C. A., Conlin P. R., Hollenberg N. K., Williams G. H. The role of dopamine in nonmodulating hypertension. J Clin Endocrinol Metab. 1989 Aug;69(2):426–432. doi: 10.1210/jcem-69-2-426. [DOI] [PubMed] [Google Scholar]
  19. Haffner S. M., Stern M. P., Hazuda H. P., Mitchell B. D., Patterson J. K. Increased insulin concentrations in nondiabetic offspring of diabetic parents. N Engl J Med. 1988 Nov 17;319(20):1297–1301. doi: 10.1056/NEJM198811173192001. [DOI] [PubMed] [Google Scholar]
  20. Halkin H., Modan M., Shefi M., Almog S. Altered erythrocyte and plasma sodium and potassium in hypertension, a facet of hyperinsulinemia. Hypertension. 1988 Jan;11(1):71–77. doi: 10.1161/01.hyp.11.1.71. [DOI] [PubMed] [Google Scholar]
  21. Kahn A. M., Seidel C. L., Allen J. C., O'Neil R. G., Shelat H., Song T. Insulin reduces contraction and intracellular calcium concentration in vascular smooth muscle. Hypertension. 1993 Nov;22(5):735–742. doi: 10.1161/01.hyp.22.5.735. [DOI] [PubMed] [Google Scholar]
  22. Kelly K. L., Deeney J. T., Corkey B. E. Cytosolic free calcium in adipocytes. Distinct mechanisms of regulation and effects on insulin action. J Biol Chem. 1989 Aug 5;264(22):12754–12757. [PubMed] [Google Scholar]
  23. Laakso M., Sarlund H., Mykkänen L. Essential hypertension and insulin resistance in non-insulin-dependent diabetes. Eur J Clin Invest. 1989 Dec;19(6):518–526. doi: 10.1111/j.1365-2362.1989.tb00269.x. [DOI] [PubMed] [Google Scholar]
  24. Levy J., Gavin J. R., 3rd, Hammerman M. R., Avioli L. V. Ca2+-Mg2+-ATPase activity in kidney basolateral membrane in non-insulin-dependent diabetic rats. Effect of insulin. Diabetes. 1986 Aug;35(8):899–905. doi: 10.2337/diab.35.8.899. [DOI] [PubMed] [Google Scholar]
  25. Manolio T. A., Savage P. J., Burke G. L., Liu K. A., Wagenknecht L. E., Sidney S., Jacobs D. R., Jr, Roseman J. M., Donahue R. P., Oberman A. Association of fasting insulin with blood pressure and lipids in young adults. The CARDIA study. Arteriosclerosis. 1990 May-Jun;10(3):430–436. doi: 10.1161/01.atv.10.3.430. [DOI] [PubMed] [Google Scholar]
  26. Mbanya J. C., Thomas T. H., Wilkinson R., Alberti K. G., Taylor R. Hypertension and hyperinsulinaemia: a relation in diabetes but not essential hypertension. Lancet. 1988 Apr 2;1(8588):733–734. doi: 10.1016/s0140-6736(88)91538-3. [DOI] [PubMed] [Google Scholar]
  27. McGuire E. A., Helderman J. H., Tobin J. D., Andres R., Berman M. Effects of arterial versus venous sampling on analysis of glucose kinetics in man. J Appl Physiol. 1976 Oct;41(4):565–573. doi: 10.1152/jappl.1976.41.4.565. [DOI] [PubMed] [Google Scholar]
  28. Nagy K., Grunberger G., Levy J. Insulin antagonistic effects of insulin receptor antibodies on plasma membrane (Ca2+ + Mg2+) ATPase activity: a possible etiology of type B insulin resistance. Endocrinology. 1990 Jan;126(1):45–52. doi: 10.1210/endo-126-1-45. [DOI] [PubMed] [Google Scholar]
  29. Pollare T., Lithell H., Berne C. Insulin resistance is a characteristic feature of primary hypertension independent of obesity. Metabolism. 1990 Feb;39(2):167–174. doi: 10.1016/0026-0495(90)90071-j. [DOI] [PubMed] [Google Scholar]
  30. Pollare T., Lithell H., Selinus I., Berne C. Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients. BMJ. 1989 Apr 29;298(6681):1152–1157. doi: 10.1136/bmj.298.6681.1152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pritchard K., Raine A. E., Ashley C. C., Castell L. M., Somers V., Osborn C., Ledingham J. G., Conway J. Correlation of blood pressure in normotensive and hypertensive individuals with platelet but not lymphocyte intracellular free calcium concentrations. Clin Sci (Lond) 1989 Jun;76(6):631–635. doi: 10.1042/cs0760631. [DOI] [PubMed] [Google Scholar]
  32. Quinn S. J., Williams G. H., Tillotson D. L. Calcium oscillations in single adrenal glomerulosa cells stimulated by angiotensin II. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5754–5758. doi: 10.1073/pnas.85.15.5754. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Reaven G. M., Hoffman B. B. Hypertension as a disease of carbohydrate and lipoprotein metabolism. Am J Med. 1989 Dec 8;87(6A):2S–6S. doi: 10.1016/0002-9343(89)90488-9. [DOI] [PubMed] [Google Scholar]
  34. Saad M. F., Lillioja S., Nyomba B. L., Castillo C., Ferraro R., De Gregorio M., Ravussin E., Knowler W. C., Bennett P. H., Howard B. V. Racial differences in the relation between blood pressure and insulin resistance. N Engl J Med. 1991 Mar 14;324(11):733–739. doi: 10.1056/NEJM199103143241105. [DOI] [PubMed] [Google Scholar]
  35. Sechi L. A., Griffin C. A., Grady E. F., Kalinyak J. E., Schambelan M. Insulin receptor concentration and gene expression are modulated by sodium intake in the rat kidney. J Hypertens Suppl. 1991 Dec;9(6):S212–S213. [PubMed] [Google Scholar]
  36. 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]
  37. Shoback D. M., Williams G. H., Moore T. J., Dluhy R. G., Podolsky S., Hollenberg N. K. Defect in the sodium-modulated tissue responsiveness to angiotensin II in essential hypertension. J Clin Invest. 1983 Dec;72(6):2115–2124. doi: 10.1172/JCI111176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Simonson D. C., Delprato S., Castellino P., Groop L., DeFronzo R. A. Effect of glyburide on glycemic control, insulin requirement, and glucose metabolism in insulin-treated diabetic patients. Diabetes. 1987 Feb;36(2):136–146. doi: 10.2337/diab.36.2.136. [DOI] [PubMed] [Google Scholar]
  39. Underwood R. H., Williams G. H. The simultaneous measurement of aldosterone, cortisol, and corticosterone in human peripheral plasma by displacement analysis. J Lab Clin Med. 1972 May;79(5):848–862. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES