(Circulation. 1997;95:560-561.)
© 1997 American Heart Association, Inc.
Articles |
Insulin-Dependent Diabetes Mellitus and Nitrovasodilation
Important and Complex Interactions
the Indiana University Medical Center (H.O.S., A.D.B.) and the Richard L. Roudebush VA Medical Center, Indianapolis, Ind.
Correspondence to Alain D. Baron, MD, Department of Medicine, Indiana University Medical Center, 541 N Clinical Dr, CL459, Indianapolis, IN 46202-5111.
Key Words: Editorials • acetylcholine • nervous system, autonomic • regional blood flow • vasodilation
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Introduction |
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 Top Introduction References |
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Endothelial dysfunction in IDDM patients could contribute to their higher rates of macrovascular disease. The study of endothelial function in IDDM has yielded conflicting results,1 2 3 4 which is not surprising given the complexity of the IDDM state. First, endothelium-dependent vasodilation is modulated by insulin,5 6 and insulin levels fluctuate greatly in these subjects. Second, increased glucose levels, a hallmark of IDDM, have been shown to impair endothelium-dependent vasodilation in vitro7 8 and may contribute to endothelial dysfunction in vivo. Third, long-standing hyperglycemia with advanced glycosylated end-product formation causes dysregulation of the endothelium-derived NO system9 ; and fourth, autonomic nervous system function that regulates vascular tone and reactivity is often impaired early in the course of IDDM even in subjects who do not have clinically evident neuropathy.10 11 12 13
The article by Makimattila and colleagues14 in this issue sheds some light on this complex problem. The authors assessed changes in forearm blood flow to the endothelium-dependent vasodilator ACh, the endothelium-independent vasodilator SNP, and the inhibitor of NO synthase L-NMMA in controls and in IDDM subjects. IDDM subjects were characterized by either normal or massively elevated albumin excretion (macroalbuminuria), which is a marker for increased risk of cardiovascular mortality and has been reported to be associated with severe endothelial dysfunction.15 It is important to note that, unlike previous studies, this study14 controlled for blood glucose and insulin levels while studying vascular responsiveness, thus removing important potential confounding factors. The authors also measured autonomic responses to a host of stimuli with the use of sophisticated techniques to uncover subtle autonomic dysfunction. The relationship between blood flow responses and indices of autonomic function were then evaluated by simple correlation and multiple linear regression analyses. The novel and unexpected findings are that subjects with macroalbuminuria exhibit higher blood flow responses to ACh and SNP and that the magnitude of response in IDDM subjects is directly related to the severity of autonomic dysfunction. While the study design is sound, some caveats are noteworthy: (1) the studies are performed at the high end of the dose-response curve for ACh. Thus, differences that may have occurred at lower concentrations could have been missed. (2) The maximal response to ACh in the controls was twofold, while it has been reported to be greater than fourfold1 3 4 at a similar ACh dose, ie, comparable to the response in macroalbuminuric patients. This discrepancy should not affect the relative difference in vascular responses to ACh between groups. However, if responses in the control group were uniquely low (for whatever reason) differences between normal and macroalbuminuric IDDM may have been overestimated. In other words, the vascular response to ACh in normal and macroalbuminuric IDDM subjects may actually be comparable, but the normoalbuminuric IDDM may have decreased response to ACh.
These caveats notwithstanding, the interpretation of the current results is not straightforward because NO-dependent vasodilation is determined by both the magnitude of NO release by the endothelium and the sensitivity and responsiveness of the VSMC to NO. Thus, increased vasodilatory responses could be due to (1) higher rates of NO production or reduced NO clearance, (2) increased sensitivity of the vascular smooth muscle, and/or (3) decreased sympathetic vasoconstrictor tone. Scenario 1 cannot account for the enhanced response to SNP, which would be expected to be normal or decreased. Scenario 2 is much more likely. If the sensitivity of VSMC to NO is increased, even subnormal amounts of NO could elicit a higher blood flow response. Increased sensitivity of the VSMC would also explain the higher response to SNP. As suggested by Moncada et al,16 hypersensitivity to nitrovasodilators could be secondary to chronically reduced basal rates of NO production in the IDDM, leading to upregulation of the NO response system. Calver et al1 reported decreased response to L-NMMA in IDDM, which suggests reduced basal rates of NO production. Makimattila et al14 report normal responses to L-NMMA in IDDM, which is compatible with reduced NO production combined with increased NO sensitivity. Scenario 3 is also possible. Impaired sympathetic nervous system function could potentially lead to enhanced responses to NO or SNP. In support of this notion, Sartori and coworkers17 recently reported that insulin-mediated, endothelium-dependent vasodilation is enhanced in patients who have undergone sympathectomy. Also, local 
-adrenergic blockade may increase blood flow in response to ACh.18
How does one explain the strong correlation between indices of autonomic dysfunction and blood flow responses? The hyperglycemic state could have independent effects of similar magnitude on the autonomic nervous system and the vasculature, and the correlation may just reflect the association with the IDDM. On the other hand, the strong relationship between autonomic dysfunction and the nitrosovasodilator response could reflect the progressive withdrawal of sympathetic pressor tone with long-standing diabetic neuropathy. This would change the balance between the endothelial vasodilator system and sympathetic pressor tone in favor of augmented vasodilation. Thus, taken together, increased reactivity to nitrovasodilators in IDDM patients with macroalbuminuria could be explained by hypersensitivity at the level of the VSMC and/or decreased sympathetic vasoconstrictor tone.
Clearly, these provocative data beg further study into the interaction between the autonomic nervous system and endothelial/VSMC function. Moreover, it is clear that the measurement of in vivo NO production rates in conjunction with functional measures of vascular responsiveness is required for a full understanding of the status of endothelium-dependent vasodilation in disease states.
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Selected Abbreviations and Acronyms |
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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1. 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;90:2548-2554.
2. Elliott TG, Cockroft JR, Groop P-H, 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.. 1993;85:687-693.[Medline] [Order article via Infotrieve]
3. Smits P, Kapma J-A, Jacobs M-C, Lutterman J, Thien T. Endothelium-dependent vascular relaxation in patients with type 1 diabetes. Diabetes.. 1993;42:148-153.[Abstract]
4.
Johnstone MT, Craeger SJ, Scales KM, Cusco JA, Lee BK, Craeger MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation.. 1993;88:2510-2516.
5. 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;94:2511-2515.
6. Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. J Clin Invest.. 1994;94:1172-1179.
7.
Tesfamariam B, Cohen RA. Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol.. 1992;263:H321-H326.
8.
Bohlen G, Lash JM. Topical hyperglycemia rapidly suppresses EDRF-mediated vasodilation of normal rat arterioles. Am J Physiol.. 1993;265:H219-H225.
9. Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilation in experimental diabetes. J Clin Invest.. 1991;87:432-438.
10. Bodmer CW, Patrick AW, How TV, Williams G. Exaggerated sensitivity to NE-induced vasoconstriction in IDDM patients with macroalbuminuria: possible etiology and diagnostic implications. Diabetes.. 1992;41:209-214.[Abstract]
11. Eckberg DL, Harkins SW, Fritsch JM, Musgrave GE, Gardner DF. Baroreflex control of plasma norepinephrine and heart period in healthy subjects and diabetic patients. J Clin Invest.. 1986;78:366-375.
12. Hoffman RP, Sinkey CA, Kienzle MG, Anderson EA. Muscle sympathetic nerve activity is reduced in IDDM before overt autonomic neuropathy. Diabetes.. 1993;42:375-380.[Abstract]
13.
Miller JA. Sympathetic vasoconstrictive responses to high- and low sodium diets in diabetic and normal subjects. Am J Physiol.. 1995;269:R380-R388.
14.
Makimattila S, Mantysaari M, Groop P-H, Summanen P, Virkamaki A, Schlenzka A, Fagerudd J, Yki-Jarvinen H. Hyperreactivity to nitrovasodilators in forearm vasculature is related to autonomic dysfunction in insulin-dependent diabetes mellitus. Circulation.. 1997;95:618-625.
15. Stehouwer CDA, Nauta JJP, Zeldenrust GC, Hackeng WHL, Donker AJM, Ottolander GJH. Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet.. 1992;340:319-323.[Medline] [Order article via Infotrieve]
16.
Moncada S, Rees DD, Schulz R, Palmer RMJ. Development and mechanism of a specific supersensitivity to nitrovasodilators after inhibition of vascular nitric oxide synthesis in vivo. Proc Natl Acad Sci U S A.. 1991;88:2166-2170.
17. Sartori C, Trueb L, Scherrer U. Insulin's direct vasodilator action in humans is masked by sympathetic vasoconstrictor tone. Diabetes. 1996;45(suppl 2):85A. Abstract.
18.
Linder L, Kiowski W, Buehler FR, Luescher TF. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Circulation.. 1990;81:1762-1767.
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