Angiotensin II in the Elderly: Impact of Angiotensin II Type 1 Receptor Sensitivity on Peripheral Hemodynamics

Ryan Harris, D Walter Wray, Steven Nishiyama, Russell S Richardson

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    26 Citations (Scopus)


    Exercise hyperemia is attenuated in the elderly, which may be attributed to local vasoregulatory pathways within the skeletal muscle vasculature. Therefore, we sought to determine whether healthy aging is associated with changes in angiotensin II (Ang II) receptor sensitivity through measurements of leg blood flow in resting and exercising skeletal muscle. In 12 (n6 young, 241 years; n6 older, 683 years) healthy volunteers, we determined changes in leg blood flow (ultrasound Doppler) before and during intra-arterial infusion of Ang II (0.8 ng/mL of leg blood flow per minute). Heart rate, arterial blood pressure, common femoral artery diameter, and mean blood velocity were measured at rest and during knee-extensor exercise at 20% and 40% of the maximal work rate (WRmax). At rest, Ang II infusion decreased leg blood flow to a greater extent in older (618%) subjects compared with younger subjects (315%). Compared with rest, Ang II–mediated vasoconstriction (leg blood flow) during exercise was diminished in both older and youngersubjects at 20% (older: 75%; younger: 212%) and 40% WRmax (older: 54%; younger: 93%). These data identify a clear age-related hypersensitivity to Ang II in the resting leg, which may contribute to the recognized decrement in leg blood flow in this cohort. However, the diminished vasoconstriction to Ang II during exercise suggests that the elevation in Ang II type 1 receptor sensitivity documented at rest does not contribute significantly to the blunted exercise hyperemia experienced with advancing age. (Hypertension. 2008;51:1611-1617.)
    Original languageEnglish
    Pages (from-to)1611-1616
    Publication statusPublished - 14 Apr 2008

    Bibliographical note

    Reference text: 1. Tsunoda K, Abe K, Goto T, Yasujima M, Sato M, Omata K, Seino M, Yoshinaga K. Effect of age on the renin-angiotensin-aldosterone system in normal subjects: simultaneous measurement of active and inactive renin, renin substrate, and aldosterone in plasma. J Clin Endocrinol
    Metab. 1986;62:384 –389.
    2. Duggan J, Nussberger J, Kilfeather S, O’Malley K. Aging and human hormonal and pressor responsiveness to angiotensin II infusion with simultaneous measurement of exogenous and endogenous angiotensin II. Am J Hypertens. 1993;6:641– 647.
    3. Duggan J, Kilfeather S, O’Brien E, O’Malley K, Nussberger J. Effects of aging and hypertension on plasma angiotensin II and platelet angiotensin II receptor density. Am J Hypertens. 1992;5:687– 693.
    4. Siebers MJ, Goodfriend TL, Ball D, Elliott ME. Analysis of angiotensin II binding to human platelets: differences in young and old subjects. J Gerontol. 1990;45:B42–B47.
    5. Takeda R, Morimoto S, Uchida K, Miyamori I, Hashiba T. Effect of age on plasma aldosterone response to exogenous angiotensin II in normotensive subjects. Acta Endocrinol (Copenh). 1980;94:552–558.
    6. Hogikyan RV, Supiano MA. Arterial alpha-adrenergic responsiveness is decreased and SNS activity is increased in older humans. Am J Physiol. 1994;266:E717–E724.
    7. Dinenno FA, Jones PP, Seals DR, Tanaka H. Limb blood flow and vascular conductance are reduced with age in healthy humans: relation to elevations in sympathetic nerve activity and declines in oxygen demand. Circulation. 1999;100:164 –170.
    8. Sundlof G, Wallin BG. Human muscle nerve sympathetic activity at rest. Relationship to blood pressure and age. J Physiol. 1978;274:621– 637.
    9. Seals DR, Dinenno FA. Collateral damage: cardiovascular consequences of chronic sympathetic activation with human aging. Am J Physiol Heart Circ Physiol. 2004;287:H1895–H1905.
    10. Dinenno FA, Dietz NM, Joyner MJ. Aging and forearm postjunctional alpha-adrenergic vasoconstriction in healthy men. Circulation. 2002;106: 1349–1354.
    11. Brewster UC, Setaro JF, Perazella MA. The renin-angiotensin-aldosterone system: cardiorenal effects and implications for renal and cardiovascular disease states. Am J Med Sci. 2003;326:15–24.
    12. Lawrenson L, Poole JG, Kim J, Brown C, Patel P, Richardson RS. Vascular and metabolic response to isolated small muscle mass exercise: effect of age. Am J Physiol Heart Circ Physiol. 2003;285:H1023–H1031.
    13. Poole JG, Lawrenson L, Kim J, Brown C, Richardson RS. Vascular and metabolic response to cycle exercise in sedentary humans: effect of age. Am J Physiol Heart Circ Physiol. 2003;284:H1251–H1259.
    14. Beere PA, Russell SD, Morey MC, Kitzman DW, Higginbotham MB. Aerobic exercise training can reverse age-related peripheral circulatory changes in healthy older men. Circulation. 1999;100:1085–1094.
    15. Proctor DN, Shen PH, Dietz NM, Eickhoff TJ, Lawler LA, Ebersold EJ, Loeffler DL, Joyner MJ. Reduced leg blood flow during dynamic exercise in older endurance-trained men. J Appl Physiol. 1998;85:68 –75.
    16. Dinenno FA, Masuki S, Joyner MJ. Impaired modulation of sympathetic alpha-adrenergic vasoconstriction in contracting forearm muscle of ageing men. J Physiol. 2005;567:311–321.
    17. Fadel PJ, Wang Z, Watanabe H, Arbique D, Vongpatanasin W, Thomas GD. Augmented sympathetic vasoconstriction in exercising forearms of postmenopausal women is reversed by oestrogen therapy. J Physiol. 2004;561:893–901.
    18. Brothers RM, Haslund ML, Wray DW, Raven PB, Sander M. Exerciseinduced inhibition of angiotensin II vasoconstriction in human thigh muscle. J Physiol. 2006;577:727–737.
    19. Andersen P, Adams RP, Sjogaard G, Thorboe A, Saltin B. Dynamic knee
    extension as model for study of isolated exercising muscle in humans21. Donato AJ, Uberoi A, Wray DW, Nishiyama S, Lawrenson L, Richardson RS. Differential effects of aging on limb blood flow in humans. Am J Physiol Heart Circ Physiol. 2006;290:H272–H278.
    22. Wray DW, Richardson RS. Aging, exercise, and limb vascular heterogeneity in humans. Med Sci Sports Exerc. 2006;38:1804 –1810.
    23. Dinenno FA, Joyner MJ. Alpha-adrenergic control of skeletal muscle circulation at rest and during exercise in aging humans. Microcirculation. 2006;13:329 –341.
    24. Belmin J, Levy BI, Michel JB. Changes in the renin-angiotensin-aldosterone axis in later life. Drugs Aging. 1994;5:391– 400.
    25. Dinenno FA, Eisenach JH, Dietz NM, Joyner MJ. Post-junctional alphaadrenoceptors and basal limb vascular tone in healthy men. J Physiol. 2002;540:1103–1110.
    26. Smith EG, Voyles WF, Kirby BS, Markwald RR, Dinenno FA. Ageing and leg postjunctional alpha-adrenergic vasoconstrictor responsiveness in healthy men. J Physiol. 2007;582:63–71.
    27. Dinenno FA, Tanaka H, Stauffer BL, Seals DR. Reductions in basal limb blood flow and vascular conductance with human ageing: role for augmented alpha-adrenergic vasoconstriction. J Physiol. 2001;536:977–983.
    28. Starke K. Action of angiotensin on uptake, release and metabolism of 14Cnoradrenaline by isolated rabbit hearts. Eur J Pharmacol. 1971;14:112–123.
    29. Gilles R, Vingerhoedt N, Howes J, Griffin M, Howes LG. Increase in systemic blood pressure during intra-arterial PD123319 infusion: evidence for functional expression of angiotensin type 2 receptors in normal volunteers. Blood Press. 2004;13:110 –114.
    30. Singh N, Prasad S, Singer DR, MacAllister RJ. Ageing is associated with impairment of nitric oxide and prostanoid dilator pathways in the human forearm. Clin Sci (Lond). 2002;102:595– 600.
    31. Dinenno FA, Joyner MJ. Blunted sympathetic vasoconstriction in contracting skeletal muscle of healthy humans: is nitric oxide obligatory? J Physiol. 2003;553:281–292.
    32. Wray DW, Fadel PJ, Smith ML, Raven P, Sander M. Inhibition of alpha-adrenergic vasoconstriction in exercising human thigh muscles. J Physiol. 2004;555:545–563.
    33. Rosenmeier JB, Dinenno FA, Fritzlar SJ, Joyner MJ. alpha1- and alpha2- adrenergic vasoconstriction is blunted in contracting human muscle. J Physiol. 2003;547:971–976.
    34. Wray DW, Nishiyama SK, Donato AJ, Sander M, Wagner PD, Richardson RS. Endothelin-1-mediated vasoconstriction at rest and during dynamic exercise in healthy humans. Amer J Physiol Heart Circ Physiol. 2007; 293:H2550–H2556.
    35. Tidgren B, Hjemdahl P, Theodorsson E, Nussberger J. Renal neurohormonal and vascular responses to dynamic exercise in humans. J Appl Physiol. 1991;70:2279 –2286.
    36. Stebbins CL, Symons JD. Role of angiotensin II in hemodynamic responses to dynamic exercise in miniswine. J Appl Physiol. 1995;78: 185–190.
    37. Symons JD, Stebbins CL. Effects of angiotensin II receptor blockade during exercise: comparison of losartan and saralasin. J Cardiovasc Pharmacol. 1996;28:223–231.
    38. Appel GB, Appel AS. Angiotensin II receptor antagonists: role in hypertension, cardiovascular disease, and renoprotection. Prog Cardiovasc Dis. 2004;47:105–115.
    39. Ferrario CM. Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research. J Renin Angiotensin Aldosterone Syst. 2006;7:3–14.
    40. Burnier M. Angiotensin II type 1 receptor blockers. Circulation. 2001; 103:904 –912.
    41. Rosendorff C. Vascular hypertrophy in hypertension: role of the reninangiotensin system. Mt Sinai J Med. 1998;65:108 –117.
    42. Newby DE, Goodfield NE, Flapan AD, Boon NA, Fox KA, Webb DJ. Regulation of peripheral vascular tone in patients with heart failure: contribution of angiotensin II. Heart. 1998;80:134 –140.
    43. Warner JG Jr, Metzger DC, Kitzman DW, Wesley DJ, Little WC. Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol. 1999;33:1567–1572.
    44. Simpson KL, McClellan KJ. Losartan: a review of its use, with special focus on elderly patients. Drugs Aging. 2000;16:227–250.
    45. Zucker IH, Wang W, Brandle M, Schultz HD, Patel KP. Neural regulation of sympathetic nerve activity in heart failure. Prog Cardiovasc Dis. 1995;37:397– 414.
    46. Rheaume C, Waib PH, Lacourciere Y, Cleroux J. Effects of angiotensin antagonism with tasosartan on regional and systemic haemodynamics hypertensive patients. J Hyper.1998;16:2085–2089.


    • basic science
    • elderly
    • blood flow regulation
    • exercise
    • angiotensin receptors


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