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. 1994 Jan;111(1):42–48. doi: 10.1111/j.1476-5381.1994.tb14021.x

Endothelial function in the isolated perfused mesentery and aortae of rats with streptozotocin-induced diabetes: effect of treatment with the aldose reductase inhibitor, ponalrestat.

P D Taylor 1, A D Wickenden 1, D J Mirrlees 1, L Poston 1
PMCID: PMC1910054  PMID: 8012723

Abstract

1. Noradrenaline sensitivity and relaxation to acetylcholine were investigated in the isolated perfused mesentery and in aortic rings of control and streptozotocin (STZ)-induced (50 mg kg-1) diabetic Charles River rats. 2. In addition, noradrenaline sensitivity and acetylcholine relaxation were similarly assessed in streptozotocin-induced diabetic rats treated from the time of onset of diabetes with the aldose reductase inhibitor, ponalrestat (100 mg kg-1 day-1). 3. The untreated diabetic rats (2-10 weeks after injection of STZ) demonstrated enhanced vascular sensitivity to noradrenaline in the perfused mesenteric arterial tree, compared with age matched controls (pEC50 [-log concentration (M)]: diabetic 5.62 +/- 0.09, n = 18, versus control 5.23 +/- 0.07, n = 16, P < 0.01). 4. Acetylcholine-induced relaxation was significantly impaired in the perfused mesentery of the diabetic animals compared to controls (pED50 [-log dose (mol)]: diabetic 9.87 +/- 0.10, n = 20, versus controls, 10.29 +/- 0.09, n = 20, P < 0.05). 5. In contrast, the aortic ring preparations demonstrated no significant functional differences between the diabetic and control groups in response to either noradrenaline (pEC50: diabetic 7.66 +/- 0.08, n = 15, versus controls 7.55 +/- 0.06, n = 15, NS), or acetylcholine (pEC50: diabetics 7.30 +/- 0.06, n = 15, versus controls 7.40 +/- 0.09, n = 15, NS). 6. Treatment with the aldose reductase inhibitor, ponalrestat, did not affect the increased vascular reactivity to noradrenaline, or impaired relaxation to acetylcholine in the perfused mesentery.

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Selected References

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  1. Abiru T., Kamata K., Miyata N., Kasuya Y. Differences in vascular responses to vasoactive agents of basilar artery and aorta from rabbits with alloxan-induced diabetes. Can J Physiol Pharmacol. 1990 Jul;68(7):882–888. doi: 10.1139/y90-134. [DOI] [PubMed] [Google Scholar]
  2. Agrawal D. K., McNeill J. H. Effect of diabetes on vascular smooth muscle function in normotensive and spontaneously hypertensive rat mesenteric artery. Can J Physiol Pharmacol. 1987 Nov;65(11):2274–2280. doi: 10.1139/y87-360. [DOI] [PubMed] [Google Scholar]
  3. Arbogast B. W., Berry D. L., Newell C. L. Injury of arterial endothelial cells in diabetic, sucrose-fed and aged rats. Atherosclerosis. 1984 Apr;51(1):31–45. doi: 10.1016/0021-9150(84)90142-4. [DOI] [PubMed] [Google Scholar]
  4. Boulton A. J., Levin S., Comstock J. A multicentre trial of the aldose-reductase inhibitor, tolrestat, in patients with symptomatic diabetic neuropathy. Diabetologia. 1990 Jul;33(7):431–437. doi: 10.1007/BF00404095. [DOI] [PubMed] [Google Scholar]
  5. Brolin S. E., Naeser P. Sorbitol in aortic endothelium of diabetic rats. Diabetes Res. 1988 Jun;8(2):59–61. [PubMed] [Google Scholar]
  6. 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. doi: 10.1056/NEJM198805193182007. [DOI] [PubMed] [Google Scholar]
  7. Bucala R., Tracey K. J., 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. doi: 10.1172/JCI115014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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. doi: 10.1172/JCI116149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cameron N. E., Cotter M. A. Dissociation between biochemical and functional effects of the aldose reductase inhibitor, ponalrestat, on peripheral nerve in diabetic rats. Br J Pharmacol. 1992 Dec;107(4):939–944. doi: 10.1111/j.1476-5381.1992.tb13389.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cameron N. E., Cotter M. A. Impaired contraction and relaxation in aorta from streptozotocin-diabetic rats: role of polyol pathway. Diabetologia. 1992 Nov;35(11):1011–1019. doi: 10.1007/BF02221675. [DOI] [PubMed] [Google Scholar]
  11. Chowienczyk P. J., Watts G. F., Cockcroft J. R., Ritter J. M. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet. 1992 Dec 12;340(8833):1430–1432. doi: 10.1016/0140-6736(92)92621-l. [DOI] [PubMed] [Google Scholar]
  12. Cohen R. A., Tesfamariam B., Weisbrod R. M., Zitnay K. M. Adrenergic denervation in rabbits with diabetes mellitus. Am J Physiol. 1990 Jul;259(1 Pt 2):H55–H61. doi: 10.1152/ajpheart.1990.259.1.H55. [DOI] [PubMed] [Google Scholar]
  13. Corbett J. A., Tilton R. G., Chang K., Hasan K. S., Ido Y., Wang J. L., Sweetland M. A., Lancaster J. R., Jr, Williamson J. R., McDaniel M. L. Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction. Diabetes. 1992 Apr;41(4):552–556. doi: 10.2337/diab.41.4.552. [DOI] [PubMed] [Google Scholar]
  14. Creager M. A., Cooke J. P., Mendelsohn M. E., Gallagher S. J., Coleman S. M., Loscalzo J., Dzau V. J. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990 Jul;86(1):228–234. doi: 10.1172/JCI114688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Durante W., Sen A. K., Sunahara F. A. Impairment of endothelium-dependent relaxation in aortae from spontaneously diabetic rats. Br J Pharmacol. 1988 Jun;94(2):463–468. doi: 10.1111/j.1476-5381.1988.tb11548.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gebremedhin D., Hadházy P., Koltai M. Z., Pogátsa G. Contractile and relaxant responses of diabetic dog femoral arteries. Acta Physiol Hung. 1988;71(2):213–217. [PubMed] [Google Scholar]
  17. Gebremedhin D., Koltai M. Z., Pogátsa G., Magyar K., Hadházy P. Altered responsiveness of diabetic dog renal arteries to acetylcholine and phenylephrine: role of endothelium. Pharmacology. 1989;38(3):177–184. doi: 10.1159/000138535. [DOI] [PubMed] [Google Scholar]
  18. Harris K. H., MacLeod K. M. Influence of the endothelium on contractile responses of arteries from diabetic rats. Eur J Pharmacol. 1988 Aug 9;153(1):55–64. doi: 10.1016/0014-2999(88)90587-0. [DOI] [PubMed] [Google Scholar]
  19. Head R. J., Longhurst P. A., Panek R. L., Stitzel R. E. A contrasting effect of the diabetic state upon the contractile responses of aortic preparations from the rat and rabbit. Br J Pharmacol. 1987 Jun;91(2):275–286. doi: 10.1111/j.1476-5381.1987.tb10282.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hogan M., Cerami A., Bucala R. Advanced glycosylation endproducts block the antiproliferative effect of nitric oxide. Role in the vascular and renal complications of diabetes mellitus. J Clin Invest. 1992 Sep;90(3):1110–1115. doi: 10.1172/JCI115928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hsueh W. A., Anderson P. W. Hypertension, the endothelial cell, and the vascular complications of diabetes mellitus. Hypertension. 1992 Aug;20(2):253–263. doi: 10.1161/01.hyp.20.2.253. [DOI] [PubMed] [Google Scholar]
  22. Kamata K., Miyata N., Kasuya Y. Impairment of endothelium-dependent relaxation and changes in levels of cyclic GMP in aorta from streptozotocin-induced diabetic rats. Br J Pharmacol. 1989 Jun;97(2):614–618. doi: 10.1111/j.1476-5381.1989.tb11993.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kappagoda T., Jayakody L., Rajotte R., Thomson A. B., Senaratne M. P. Endothelium-dependent relaxation to acetylcholine in the aorta of streptozotocin induced diabetic-rat and the BB-diabetic rat. Clin Invest Med. 1989 Jun;12(3):187–193. [PubMed] [Google Scholar]
  24. Lawrence E., Brain S. D. Altered microvascular reactivity to endothelin-1, endothelin-3 and NG-nitro-L-arginine methyl ester in streptozotocin-induced diabetes mellitus. Br J Pharmacol. 1992 Aug;106(4):1035–1040. doi: 10.1111/j.1476-5381.1992.tb14452.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lee T. S., Saltsman K. A., Ohashi H., King G. L. Activation of protein kinase C by elevation of glucose concentration: proposal for a mechanism in the development of diabetic vascular complications. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5141–5145. doi: 10.1073/pnas.86.13.5141. [DOI] [PMC free article] [PubMed] [Google Scholar] [Research Misconduct Found]
  26. Loven D., Schedl H., Wilson H., Daabees T. T., Stegink L. D., Diekus M., Oberley L. Effect of insulin and oral glutathione on glutathione levels and superoxide dismutase activities in organs of rats with streptozocin-induced diabetes. Diabetes. 1986 May;35(5):503–507. doi: 10.2337/diab.35.5.503. [DOI] [PubMed] [Google Scholar]
  27. MCGREGOR D. D. THE EFFECT OF SYMPATHETIC NERVE STIMULATION OF VASOCONSTRICTOR RESPONSES IN PERFUSED MESENTERIC BLOOD VESSELS OF THE RAT. J Physiol. 1965 Mar;177:21–30. doi: 10.1113/jphysiol.1965.sp007572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. MacLeod K. M., McNeill J. H. The influence of chronic experimental diabetes on contractile responses of rat isolated blood vessels. Can J Physiol Pharmacol. 1985 Jan;63(1):52–57. doi: 10.1139/y85-009. [DOI] [PubMed] [Google Scholar]
  29. Mayhan W. G. Impairment of endothelium-dependent dilatation of cerebral arterioles during diabetes mellitus. Am J Physiol. 1989 Mar;256(3 Pt 2):H621–H625. doi: 10.1152/ajpheart.1989.256.3.H621. [DOI] [PubMed] [Google Scholar]
  30. Mayhan W. G., Simmons L. K., Sharpe G. M. Mechanism of impaired responses of cerebral arterioles during diabetes mellitus. Am J Physiol. 1991 Feb;260(2 Pt 2):H319–H326. doi: 10.1152/ajpheart.1991.260.2.H319. [DOI] [PubMed] [Google Scholar]
  31. McVeigh G. E., Brennan G. M., Johnston G. D., McDermott B. J., McGrath L. T., Henry W. R., Andrews J. W., Hayes J. R. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1992 Aug;35(8):771–776. doi: 10.1007/BF00429099. [DOI] [PubMed] [Google Scholar]
  32. Meraji S., Jayakody L., Senaratne M. P., Thomson A. B., Kappagoda T. Endothelium-dependent relaxation in aorta of BB rat. Diabetes. 1987 Aug;36(8):978–981. doi: 10.2337/diab.36.8.978. [DOI] [PubMed] [Google Scholar]
  33. Mulhern M., Docherty J. R. Effects of experimental diabetes on the responsiveness of rat aorta. Br J Pharmacol. 1989 Aug;97(4):1007–1012. doi: 10.1111/j.1476-5381.1989.tb12555.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Oyama Y., Kawasaki H., Hattori Y., Kanno M. Attenuation of endothelium-dependent relaxation in aorta from diabetic rats. Eur J Pharmacol. 1986 Dec 2;132(1):75–78. doi: 10.1016/0014-2999(86)90013-0. [DOI] [PubMed] [Google Scholar]
  35. Pieper G. M., Gross G. J. Oxygen free radicals abolish endothelium-dependent relaxation in diabetic rat aorta. Am J Physiol. 1988 Oct;255(4 Pt 2):H825–H833. doi: 10.1152/ajpheart.1988.255.4.H825. [DOI] [PubMed] [Google Scholar]
  36. Pieper G. M., Mei D. A., Langenstroer P., O'Rourke S. T. Bioassay of endothelium-derived relaxing factor in diabetic rat aorta. Am J Physiol. 1992 Sep;263(3 Pt 2):H676–H680. doi: 10.1152/ajpheart.1992.263.3.H676. [DOI] [PubMed] [Google Scholar]
  37. Porta M., La Selva M., Molinatti P., Molinatti G. M. Endothelial cell function in diabetic microangiopathy. Diabetologia. 1987 Aug;30(8):601–609. doi: 10.1007/BF00277315. [DOI] [PubMed] [Google Scholar]
  38. Saenz de Tejada I., Goldstein I., Azadzoi K., Krane R. J., Cohen R. A. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med. 1989 Apr 20;320(16):1025–1030. doi: 10.1056/NEJM198904203201601. [DOI] [PubMed] [Google Scholar]
  39. Scarborough N. L., Carrier G. O. Increased alpha 2-adrenoreceptor mediated vascular contraction in diabetic rats. J Auton Pharmacol. 1983 Sep;3(3):177–183. doi: 10.1111/j.1474-8673.1983.tb00533.x. [DOI] [PubMed] [Google Scholar]
  40. Sima A. A., Bril V., Nathaniel V., McEwen T. A., Brown M. B., Lattimer S. A., Greene D. A. Regeneration and repair of myelinated fibers in sural-nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil. N Engl J Med. 1988 Sep 1;319(9):548–555. doi: 10.1056/NEJM198809013190905. [DOI] [PubMed] [Google Scholar]
  41. Simmons D. A., Winegrad A. I. Mechanism of glucose-induced (Na+, K+)-ATPase inhibition in aortic wall of rabbits. Diabetologia. 1989 Jul;32(7):402–408. doi: 10.1007/BF00271258. [DOI] [PubMed] [Google Scholar]
  42. Stehouwer C. D., Nauta J. J., Zeldenrust G. C., Hackeng W. H., Donker A. J., den Ottolander G. J. Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet. 1992 Aug 8;340(8815):319–323. doi: 10.1016/0140-6736(92)91401-s. [DOI] [PubMed] [Google Scholar]
  43. Stehouwer C. D., Stroes E. S., Hackeng W. H., Mulder P. G., Den Ottolander G. J. von Willebrand factor and development of diabetic nephropathy in IDDM. Diabetes. 1991 Aug;40(8):971–976. doi: 10.2337/diab.40.8.971. [DOI] [PubMed] [Google Scholar]
  44. Tanz R. D., Chang K. S., Weller T. S. Histamine relaxation of aortic rings from diabetic rats. Agents Actions. 1989 Aug;28(1-2):1–8. doi: 10.1007/BF02022973. [DOI] [PubMed] [Google Scholar]
  45. Taylor P. D., McCarthy A. L., Thomas C. R., Poston L. Endothelium-dependent relaxation and noradrenaline sensitivity in mesenteric resistance arteries of streptozotocin-induced diabetic rats. Br J Pharmacol. 1992 Oct;107(2):393–399. doi: 10.1111/j.1476-5381.1992.tb12757.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Taylor P. D., Oon B. B., Thomas C. R., Poston L. Prevention by insulin treatment of endothelial dysfunction but not enhanced noradrenaline-induced contractility in mesenteric resistance arteries from streptozotocin-induced diabetic rats. Br J Pharmacol. 1994 Jan;111(1):35–41. doi: 10.1111/j.1476-5381.1994.tb14020.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Tesfamariam B., Brown M. L., Cohen R. A. Aldose reductase and myo-inositol in endothelial cell dysfunction caused by elevated glucose. J Pharmacol Exp Ther. 1992 Oct;263(1):153–157. [PubMed] [Google Scholar]
  48. Tesfamariam B., Brown M. L., Cohen R. A. Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J Clin Invest. 1991 May;87(5):1643–1648. doi: 10.1172/JCI115179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Tesfamariam B., Brown M. L., Deykin D., Cohen R. A. Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. J Clin Invest. 1990 Mar;85(3):929–932. doi: 10.1172/JCI114521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Tesfamariam B., Cohen R. A. Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol. 1992 Aug;263(2 Pt 2):H321–H326. doi: 10.1152/ajpheart.1992.263.2.H321. [DOI] [PubMed] [Google Scholar]
  51. Tesfamariam B., Palacino J. J., Weisbrod R. M., Cohen R. A. Aldose reductase inhibition restores endothelial cell function in diabetic rabbit aorta. J Cardiovasc Pharmacol. 1993 Feb;21(2):205–211. doi: 10.1097/00005344-199302000-00004. [DOI] [PubMed] [Google Scholar]
  52. Wakabayashi I., Hatake K., Kimura N., Kakishita E., Nagai K. Modulation of vascular tonus by the endothelium in experimental diabetes. Life Sci. 1987 Feb 16;40(7):643–648. doi: 10.1016/0024-3205(87)90265-7. [DOI] [PubMed] [Google Scholar]
  53. White R. E., Carrier G. O. Enhanced vascular alpha-adrenergic neuroeffector system in diabetes: importance of calcium. Am J Physiol. 1988 Nov;255(5 Pt 2):H1036–H1042. doi: 10.1152/ajpheart.1988.255.5.H1036. [DOI] [PubMed] [Google Scholar]
  54. White R. E., Carrier G. O. Supersensitivity and endothelium dependency of histamine-induced relaxation in mesenteric arteries isolated from diabetic rats. Pharmacology. 1986;33(1):34–38. doi: 10.1159/000138197. [DOI] [PubMed] [Google Scholar]
  55. Williamson J. R., Ostrow E., Eades D., Chang K., Allison W., Kilo C., Sherman W. R. Glucose-induced microvascular functional changes in nondiabetic rats are stereospecific and are prevented by an aldose reductase inhibitor. J Clin Invest. 1990 Apr;85(4):1167–1172. doi: 10.1172/JCI114549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Wong K. K., Tzeng S. F. Norepinephrine-induced contractile responses in isolated rat aortae from different duration of diabetes. Artery. 1992;19(1):1–13. [PubMed] [Google Scholar]
  57. Woolfson R. G., Poston L. Effect of ouabain on endothelium-dependent relaxation of human resistance arteries. Hypertension. 1991 May;17(5):619–625. doi: 10.1161/01.hyp.17.5.619. [DOI] [PubMed] [Google Scholar]
  58. Zeiher A. M., Drexler H., Wollschläger H., Just H. Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation. 1991 Feb;83(2):391–401. doi: 10.1161/01.cir.83.2.391. [DOI] [PubMed] [Google Scholar]

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