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J Clin Invest. 1997 Aug 1; 100(3): 678–684.
PMCID: PMC508237

Improvement in endothelial function by angiotensin converting enzyme inhibition in insulin-dependent diabetes mellitus.


We postulated that nitric oxide (NO)-mediated endothelial function would be improved by acute and short-term treatment with an angiotensin converting enzyme (ACE) inhibitor in patients with type I diabetes mellitus, in whom endothelial function is depressed. Nine type I diabetic patients and eight healthy subjects underwent forearm blood flow measurement using strain gauge plethysmography during intraarterial infusion of incremental doses of endothelium-dependent (acetylcholine [ACh]) and endothelium-independent (sodium nitroprusside [SNP]) vasodilators. Pretreatment ACh responses were depressed in diabetic patients relative to the normal subjects (P < 0.05). No difference between the groups was evident in response to SNP. Acute ACE inhibition (with intrabrachial enalaprilat) enhanced ACh responses in the diabetic patients (P < 0.005), with a further improvement evident after 1 mo of oral therapy with enalapril (P < 0.001) when ACh responses were normalized. ACE inhibition did not affect SNP responses. We conclude that acute administration of the ACE inhibitor, enalaprilat, enhances NO-mediated endothelial function in type I diabetic patients, with further improvement evident after 4 wk of enalapril therapy.

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Selected References

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  • Chowienczyk PJ, Watts GF, Cockcroft JR, Ritter JM. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet. 1992 Dec 12;340(8833):1430–1432. [PubMed]
  • Calver A, Collier J, Moncada S, Vallance P. Effect of local intra-arterial NG-monomethyl-L-arginine in patients with hypertension: the nitric oxide dilator mechanism appears abnormal. J Hypertens. 1992 Sep;10(9):1025–1031. [PubMed]
  • Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J, Deanfield JE. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993 Nov;88(5 Pt 1):2149–2155. [PubMed]
  • Celermajer DS, Adams MR, Clarkson P, Robinson J, McCredie R, Donald A, Deanfield JE. Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N Engl J Med. 1996 Jan 18;334(3):150–154. [PubMed]
  • Reddy KG, Nair RN, Sheehan HM, Hodgson JM. Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis. J Am Coll Cardiol. 1994 Mar 15;23(4):833–843. [PubMed]
  • Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE. Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol. 1994 Nov 15;24(6):1468–1474. [PubMed]
  • Tesfamariam B, Brown ML, Deykin D, Cohen RA. Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. J Clin Invest. 1990 Mar;85(3):929–932. [PMC free article] [PubMed]
  • Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest. 1991 Feb;87(2):432–438. [PMC free article] [PubMed]
  • 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 Dec;90(6):2548–2554. [PMC free article] [PubMed]
  • Elliott TG, Cockcroft JR, Groop PH, Viberti GC, Ritter JM. Inhibition of nitric oxide synthesis in forearm vasculature of insulin-dependent diabetic patients: blunted vasoconstriction in patients with microalbuminuria. Clin Sci (Lond) 1993 Dec;85(6):687–693. [PubMed]
  • Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation. 1993 Dec;88(6):2510–2516. [PubMed]
  • Drexler H, Kurz S, Jeserich M, Münzel T, Hornig B. Effect of chronic angiotensin-converting enzyme inhibition on endothelial function in patients with chronic heart failure. Am J Cardiol. 1995 Nov 24;76(15):13E–18E. [PubMed]
  • Nakamura M, Funakoshi T, Arakawa N, Yoshida H, Makita S, Hiramori K. Effect of angiotensin-converting enzyme inhibitors on endothelium-dependent peripheral vasodilation in patients with chronic heart failure. J Am Coll Cardiol. 1994 Nov 1;24(5):1321–1327. [PubMed]
  • Hirooka Y, Imaizumi T, Masaki H, Ando S, Harada S, Momohara M, Takeshita A. Captopril improves impaired endothelium-dependent vasodilation in hypertensive patients. Hypertension. 1992 Aug;20(2):175–180. [PubMed]
  • Nakamura M, Funakoshi T, Yoshida H, Arakawa N, Suzuki T, Hiramori K. Endothelium-dependent vasodilation is augmented by angiotensin converting enzyme inhibitors in healthy volunteers. J Cardiovasc Pharmacol. 1992 Dec;20(6):949–954. [PubMed]
  • Mancini GB, Henry GC, Macaya C, O'Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H, Lüscher TF, Klibaner MI, et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation. 1996 Aug 1;94(3):258–265. [PubMed]
  • Bijlstra PJ, Smits P, Lutterman JA, Thien T. Effect of long-term angiotensin-converting enzyme inhibition on endothelial function in patients with the insulin-resistance syndrome. J Cardiovasc Pharmacol. 1995 Apr;25(4):658–664. [PubMed]
  • Viberti G, Mogensen CE, Groop LC, Pauls JF. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. European Microalbuminuria Captopril Study Group. JAMA. 1994 Jan 26;271(4):275–279. [PubMed]
  • Laffel LM, McGill JB, Gans DJ. The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria. North American Microalbuminuria Study Group. Am J Med. 1995 Nov;99(5):497–504. [PubMed]
  • Green DJ, Fowler DT, O'Driscoll JG, Blanksby BA, Taylor RR. Endothelium-derived nitric oxide activity in forearm vessels of tennis players. J Appl Physiol (1985) 1996 Aug;81(2):943–948. [PubMed]
  • Benjamin N, Calver A, Collier J, Robinson B, Vallance P, Webb D. Measuring forearm blood flow and interpreting the responses to drugs and mediators. Hypertension. 1995 May;25(5):918–923. [PubMed]
  • Green D, O'Driscoll G, Blanksby B, Taylor R. Lack of effect of vitamin E administration on basal nitric oxide function in male smokers and non-smokers. Clin Sci (Lond) 1995 Oct;89(4):343–348. [PubMed]
  • Antony I, Lerebours G, Nitenberg A. Angiotensin-converting enzyme inhibition restores flow-dependent and cold pressor test-induced dilations in coronary arteries of hypertensive patients. Circulation. 1996 Dec 15;94(12):3115–3122. [PubMed]
  • Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol. 1994 Aug;24(2):471–476. [PubMed]
  • Smits P, Kapma JA, Jacobs MC, Lutterman J, Thien T. Endothelium-dependent vascular relaxation in patients with type I diabetes. Diabetes. 1993 Jan;42(1):148–153. [PubMed]
  • Halkin A, Benjamin N, Doktor HS, Todd SD, Viberti G, Ritter JM. Vascular responsiveness and cation exchange in insulin-dependent diabetes. Clin Sci (Lond) 1991 Aug;81(2):223–232. [PubMed]
  • McVeigh GE, Brennan GM, Johnston GD, McDermott BJ, McGrath LT, Henry WR, Andrews JW, Hayes JR. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1992 Aug;35(8):771–776. [PubMed]
  • Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol. 1996 Mar 1;27(3):567–574. [PubMed]
  • Nitenberg A, Valensi P, Sachs R, Dali M, Aptecar E, Attali JR. Impairment of coronary vascular reserve and ACh-induced coronary vasodilation in diabetic patients with angiographically normal coronary arteries and normal left ventricular systolic function. Diabetes. 1993 Jul;42(7):1017–1025. [PubMed]
  • Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 1988 May 19;318(20):1315–1321. [PubMed]
  • Kawamura M, Heinecke JW, Chait A. Pathophysiological concentrations of glucose promote oxidative modification of low density lipoprotein by a superoxide-dependent pathway. J Clin Invest. 1994 Aug;94(2):771–778. [PMC free article] [PubMed]
  • Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes. 1991 Apr;40(4):405–412. [PubMed]
  • Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest. 1996 Jan 1;97(1):22–28. [PMC free article] [PubMed]
  • Rajagopalan S, Harrison DG. Reversing endothelial dysfunction with ACE inhibitors. A new trend. Circulation. 1996 Aug 1;94(3):240–243. [PubMed]
  • 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 Dec;94(6):2511–2515. [PMC free article] [PubMed]
  • Torlone E, Britta M, Rambotti AM, Perriello G, Santeusanio F, Brunetti P, Bolli GB. Improved insulin action and glycemic control after long-term angiotensin-converting enzyme inhibition in subjects with arterial hypertension and type II diabetes. Diabetes Care. 1993 Oct;16(10):1347–1355. [PubMed]
  • Taddei S, Virdis A, Mattei P, Natali A, Ferrannini E, Salvetti A. Effect of insulin on acetylcholine-induced vasodilation in normotensive subjects and patients with essential hypertension. Circulation. 1995 Nov 15;92(10):2911–2918. [PubMed]
  • Petrie JR, Ueda S, Webb DJ, Elliott HL, Connell JM. Endothelial nitric oxide production and insulin sensitivity. A physiological link with implications for pathogenesis of cardiovascular disease. Circulation. 1996 Apr 1;93(7):1331–1333. [PubMed]
  • Rajagopalan S, Kurz S, Münzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest. 1996 Apr 15;97(8):1916–1923. [PMC free article] [PubMed]
  • Andreoli SP. Captopril scavenges hydrogen peroxide and reduces, but does not eliminate, oxidant-induced cell injury. Am J Physiol. 1993 Jan;264(1 Pt 2):F120–F127. [PubMed]
  • Haklar G, Erşahin C, Moini H, Süngün M, Dogan N, Bilsel S, Emerk K, Yalçin AS. Protective effects of cilazapril against free radical injury in myocardial ischaemia-reperfusion. Pharmacol Res. 1995 Jan;31(1):33–36. [PubMed]
  • Kaufman MJ. Comparison of the free radical-scavenging ability of captopril and ascorbic acid in an in-vitro model of lipid oxidation. Implications for reperfusion injury and ACE inhibitor therapy. J Pharm Pharmacol. 1994 Mar;46(3):217–220. [PubMed]
  • Mira ML, Silva MM, Queiroz MJ, Manso CF. Angiotensin converting enzyme inhibitors as oxygen free radical scavengers. Free Radic Res Commun. 1993;19(3):173–181. [PubMed]
  • Vanhoutte PM, Boulanger CM, Mombouli JV. Endothelium-derived relaxing factors and converting enzyme inhibition. Am J Cardiol. 1995 Nov 24;76(15):3E–12E. [PubMed]
  • Auch-Schwelk W, Duske E, Claus M, Graf K, Gräfe M, Fleck E. Endothelium-mediated vasodilation during ACE inhibition. Eur Heart J. 1995 May;16 (Suppl 100):59–65. [PubMed]
  • Clapperton M, McMurray J, Fisher AC, Dargie HJ. The effect of angiotensin-converting enzyme inhibitors on human neutrophil chemotaxis in vitro. Br J Clin Pharmacol. 1994 Jul;38(1):53–56. [PMC free article] [PubMed]
  • Fennessy PA, Campbell JH, Campbell GR. Perindopril inhibits both the development of atherosclerosis in the cholesterol-fed rabbit and lipoprotein binding to smooth muscle cells in culture. Atherosclerosis. 1994 Mar;106(1):29–41. [PubMed]
  • Farhy RD, Ho KL, Carretero OA, Scicli AG. Kinins mediate the antiproliferative effect of ramipril in rat carotid artery. Biochem Biophys Res Commun. 1992 Jan 15;182(1):283–288. [PubMed]

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