, Volume 38, Issue 11, pp 1337–1344 | Cite as

Responses of the skin microcirculation to acetylcholine and sodium nitroprusside in patients with NIDDM

  • S. J. Morris
  • A. C. Shore
  • J. E. Tooke


The mechanisms involved in the pathogenesis of microangiopathy occurring in non-insulin-dependent diabetes mellitus (NIDDM) are unclear. In the present study, blood flow responses to the vasodilators acetylcholine (which acts via the endothelium) and sodium nitroprusside (a smooth muscle relaxant) were evaluated in this patient group. In 14 male patients with NIDDM, treated with either diet alone (n=6) or diet plus insulin, (mean age 59 years) and 14 age-pair-matched control subjects, forearm skin perfusion following multiple doses of iontophoretically applied 1% acetylcholine and 0.01% sodium nitroprusside was recorded by laser Doppler perfusion imaging. Basal skin blood flow was not significantly different in the diabetic group compared with the control group. The following results are expressed as drug-minus-vehicle response. Acetylcholine significantly increased forearm skin perfusion (p<0.001, analysis of variance) in all subjects, but the vasodilatation was attenuated in the patient group compared with control subjects (0.86±0.09 vs 1.36±0.14 arbitrary units of volts (V) respectively, at the fifth measurement point, mean ± SEM, p<0.01). Skin perfusion significantly increased following sodium nitroprusside (p<0.001) but was lower in patients than control subjects (0.12±0.05 vs 0.45±0.11 V, respectively, at the fifth measurement point, p<0.01). These data suggest that endothelial and/or smooth muscle function may be impaired in the skin microcirculation of patients with NIDDM.

Key words

Endothelium microcirculation non-insulin-dependent diabetes mellitus skin vascular smooth muscle 



Insulin-dependent diabetes mellitus


laser Doppler perfusion imager






non-insulin-dependent diabetes mellitus


nitric oxide


analysis of variance


  1. 1.
    Parving HH, Viberti GC, Keen H, Christiansen JS, Lassen NA (1983) Haemodynamic factors in the genesis of diabetic microangiopathy. Metabolism 32: 943–949CrossRefPubMedGoogle Scholar
  2. 2.
    Sandeman DD, Shore AC, Tooke JE (1992) Relation of skin capillary pressure in patients with insulin-dependent diabetes mellitus to complications and metabolic control. N Engl J Med 327: 760–764PubMedGoogle Scholar
  3. 3.
    Jaap AJ, Shore AC, Tooke JE (1994) Capillary filtration coefficient is different in long duration type 1 diabetic patients with and without microvascular complications. Diabetic Med 2[Suppl 1]: S13 (Abstract)Google Scholar
  4. 4.
    Tooke JE (1989) Microcirculation and diabetes. Br Med Bull 45(1): 206–223PubMedGoogle Scholar
  5. 5.
    Shore AC, Jaap AJ, Tooke JE (1994) Capillary pressure in patients with NIDDM. Diabetes 43: 1198–1202PubMedGoogle Scholar
  6. 6.
    Jaap AJ, Shore AC, Gamble J, Gartside IB, Tooke JE (1994) Capillary filtration coefficient in type II (non-insulin-dependent) diabetes. J Diab Comp 8: 111–116CrossRefGoogle Scholar
  7. 7.
    Sandeman DD, Pym CA, Green EM, Seamark C, Shore AC, Tooke JE (1991) Microvascular vasodilatation in feet of newly diagnosed non-insulin-dependent diabetic patients. BMJ 302: 1122–1123PubMedGoogle Scholar
  8. 8.
    Jaap AJ, Hammersley MS, Shore AC, Tooke JE (1994) Reduced microvascular hyperaemia in subjects at risk of developing type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 37: 214–216PubMedGoogle Scholar
  9. 9.
    Kiff RJ, Gardiner SM, Compton AM, Bennett (1991) The effects of endothelin-1 and NG-nitro-l-arginine methyl ester on regional haemodynamics in conscious rats with streptozotocin-induced diabetes mellitus. Br J Pharmacol 103: 1321–1326PubMedGoogle Scholar
  10. 10.
    Taylor PD, Wickenden AD, Mirrlees DJ, Poston L (1994) Endothelial function in the isolated perfused mesentery and aortae of rats with streptozotocin-induced diabetes: effect of treatment with the aldose reductase inhibitor, ponalrestat. Br J Pharmacology 111: 42–48Google Scholar
  11. 11.
    de Tejada IS, Goldstein I, Azadzoi K, Krane RJ, Cohen RA (1989) Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. New Engl J Med 320: 1025–1030PubMedGoogle Scholar
  12. 12.
    Calver A, Collier J, Vallance P (1992) Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest 90: 2548–2554PubMedGoogle Scholar
  13. 13.
    Elliott TG, Cockcroft JR, Groop PH, Viberti GC, Ritter JM (1993) Inhibition of nitric oxide synthesis in the forearm vasculature of insulin-dependent diabetic patients: blunted vasoconstriction in patients with microalbuminuria. Clin Sci 85: 687–693PubMedGoogle Scholar
  14. 14.
    McNally PG, Watt PA, Rimmer T, Burden AC, Hearnshaw JR, Thurston H (1994) Impaired contraction and endothelium-dependent relaxation in isolated resistance vessels from patients with insulin-dependent diabetes mellitus. Clin Sci 87: 31–36PubMedGoogle Scholar
  15. 15.
    Lawrence IG, Watt PAC, McNally PG, Burden AC, Thurston H (1994) Resistance artery structure and function in non-insulin-dependent diabetes mellitus (NIDDM). Diabetologia 37[Suppl 1]: A22 (Abstract)CrossRefGoogle Scholar
  16. 16.
    McVeigh GE, Brennan GM, Johnston GD et al. (1992) Impaired endothelium-dependent and independent vasodilatation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 35: 771–776PubMedGoogle Scholar
  17. 17.
    Vallance P, Collier J (1994) Biology and clinical relevance of nitric oxide. BMJ 309: 453–457PubMedGoogle Scholar
  18. 18.
    Warren JB (1994) Nitric oxide and human skin blood flow responses to acetylcholine and ultraviolet light. FASEB J 8: 247–251PubMedGoogle Scholar
  19. 19.
    Watkins PJ, Grenfell A, Edmonds M (1987) Diabetic complications of non-insulin-dependent diabetes. Diab Med 4: 293–296Google Scholar
  20. 20.
    Tenland T, Salerud EG, Nilsson GE (1983) Spatial and temporal variations in human skin blood flow. Int J Microcirc Clin Exp 2: 81–90PubMedGoogle Scholar
  21. 21.
    Wårdell K, Jakobsson A, Nilsson GE (1993) Laser Doppler perfusion imaging by dynamic light scattering. IEEE Trans Biomed Eng 40 (4): 309–316CrossRefPubMedGoogle Scholar
  22. 22.
    Harris R (1967) Iontophoresis. In: Licht E (ed) Physical medicine library, vol 4. Elizabeth Licht, Connecticut, pp 156–178Google Scholar
  23. 23.
    Rayman G, Williams SA, Spencer PD, Smaje LH, Wise PH, Tooke JE (1986) Impaired microvascular hyperaemic response to minor skin trauma in type I diabetes. BMJ 292: 1295–1298PubMedGoogle Scholar
  24. 24.
    Reynolds NJ, Figueroa CD, Burton JL, Muller-Esterl W, Bhoola KD (1991) Tissue kallikrein and kininogen in human sweat glands and psoriatic skin. Br J Dermatol 124: 236–241PubMedGoogle Scholar
  25. 25.
    Ledger PW (1992) Skin biological issues in electrically enhanced transdermal delivery. Advanced Drug Delivery Reviews 9: 289–307CrossRefGoogle Scholar
  26. 26.
    Westerman RA, Widdop RE, Hogan C, Zimmet P (1987) Non-invasive tests of neurovascular function: reduced responses in diabetes mellitus. Neurosci Lett 81: 177–182CrossRefPubMedGoogle Scholar
  27. 27.
    Rubanyi GM (1991) Endothelium-derived relaxing and contracting factors. J Cell Biochem 46: 27–36PubMedGoogle Scholar
  28. 28.
    Tesfamariam B, Jakubowski JA, Cohen RA (1989) Contraction of diabetic rabbit aorta caused by endothelium-derived PGH2-TxA2. Am J Physiol 257 (Heart Circ Physiol 26): H1327-H1333PubMedGoogle Scholar
  29. 29.
    O'Rouke ST, Vanhoutte PM (1992) Vascular pharmacology. In: Loscalzo J, Creager MA, Dzau VJ (eds) Vascular medicine. A textbook of vascular biology and diseases. Little, Brown & Co., Boston, pp 133–155Google Scholar
  30. 30.
    Tanz RD, Chang KS, Weller TS (1989) Histamine relaxation of aortic rings from diabetic rats. Agents Actions 28: 1–8PubMedGoogle Scholar
  31. 31.
    Vallance P, Collier J, Moncada S (1989) Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet II: 997–1000CrossRefGoogle Scholar
  32. 32.
    Shimzu K, Muramatsu M, Kakegawa Y et al. (1993) Role of prostaglandin H2 as endothelium-derived contracting factor in diabetic state. Diabetes 42: 1246–1252PubMedGoogle Scholar
  33. 33.
    Taylor PD, McCarthy AL, Thomas CR, Poston L (1992) Endothelium-dependent relaxation and noradrenaline sensitivity in mesenteric resistance arteries of streptozotocininduced diabetic rats. Br J Pharmacol 107: 393–399PubMedGoogle Scholar
  34. 34.
    Brownlee M, Cerami A, Vlassara H (1988) Advanced products of nonenzymatic glycosylation and the pathogenesis of diabetic vascular disease. Diabetes Metab Rev 4: 437–451PubMedGoogle Scholar
  35. 35.
    Bucala R, Tracey KJ, Cerami A (1991) Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest 87: 432–438PubMedGoogle Scholar
  36. 36.
    Rodriguez-Mañas L, Arribas S, Girón C, Villamor J, Sánchez-Ferrer CF, Marin J (1993) Interference of glycosylated human hemoglobin with endothelium-dependent responses. Circulation 88(1): 2111–2116PubMedGoogle Scholar
  37. 37.
    Jennings PE, Jones AF, Florkowski CM, Lunec J, Barnett AH (1987) Increased diene conjugates in diabetic subjects with microangiopathy. Diabet Med 4: 452–456PubMedGoogle Scholar
  38. 38.
    Tesfamariam B, Cohen RA (1992) Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol 263 (Heart Circ Physiol 32): H321-H326PubMedGoogle Scholar
  39. 39.
    Bucala R, Makita Z, Koschinsky T, Cerami A, Vlassara H (1993) Lipid advanced glycosylation: pathway for lipid oxidation in vivo. Proc Natl Acad Sci USA 90: 6434–6438PubMedGoogle Scholar
  40. 40.
    Schmidt K, Graier WF, Kostner GM, Mayer B, Böhme E, Kukovetz WR (1991) Stimulation of soluble guanylate cyclase by endothelium-derived relaxing factor is antagonised by oxidised low-density lipoprotein. J Cardiovasc Pharmacol 17(3): S83-S88Google Scholar
  41. 41.
    Hibino T, Takemura T, Sato K (1994) Human eccrine sweat contains tissue kallikrein and kininase II. J Invest Dermatol 102: 214–220CrossRefPubMedGoogle Scholar
  42. 42.
    Garden JW (1966) Plasma and sweat histamine concentrations after heat exposure and physical exercise. J Appl Physiol 21: 631–635PubMedGoogle Scholar
  43. 43.
    Frewin DB, Eakin KE, Downey JA, Bhattachejee P (1973) Prostaglandin-like activity in human eccrine sweat. Aust J Exp Biol Med Sci 51: 701–702PubMedGoogle Scholar
  44. 44.
    Vracko R, Benditt EP (1970) Capillary basal lamina thickening. Its relationship to endothelial cell death and replacement. J Cell Biol 47: 281–285CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • S. J. Morris
    • 1
  • A. C. Shore
    • 1
  • J. E. Tooke
    • 1
  1. 1.Department of Diabetes and Vascular Medicine, Postgraduate Medical SchoolUniversity of ExeterExeterUK

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