Hyperreactivity to Nitrovasodilators in Forearm Vasculature Is Related to Autonomic Dysfunction in Insulin-Dependent Diabetes Mellitus

BACKGROUND: The link between diabetes and vascular disease is poorly understood. Data regarding endothelial function in vivo in patients with insulin-dependent diabetes mellitus (IDDM) have been inconsistent with in vitro studies demonstrating hyperglycemia-induced impairments in endothelium-dependent vasodilation. METHODS AND RESULTS: We determined whether alterations in neural control of the vascular tone might contribute to blood flow responses to intrabrachial infusions of acetylcholine (ACh), sodium nitroprusside (SNP), and L-N-monomethyl-arginine (L-NMMA) in 22 men with IDDM (12 with normoalbuminuria. HbA1c = 8.6 +/- 0.3%; 10 with macroalbuminuria, HbA1c = 8.6 +/- 0.3%) and 11 matched normal men. Autonomic function was assessed from reflex vasoconstriction to cold, the blood pressure response to standing and hand grip, and heart rate variation, including spectral analysis, during controlled breathing, and the Valsalva maneuver. IDDM with macroalbuminuria exhibited hyperresponsiveness to both ACh and SNP compared with the patients with normoalbuminuria or normal subjects. Reflex sympathetic vasoconstriction to cold was severely impaired in the IDDM patients with macroalbuminuria (-19 +/- 6%) compared with normoalbuminuric patients (-39 +/- 5%, P < .05) and normal subjects (-54 +/- 7%, P < .001). The macroalbuminuric patients also had evidence of autonomic dysfunction during controlled and deep breathing tests and during the Valsalva maneuver. Within the group of IDDM patients, neither the urinary albumin excretion rate nor other parameters such as HbA1c or serum cholesterol correlated with forearm blood flow during the vasoactive drug infusions. There were, however, significant inverse correlations between several measures of both sympathetic and parasympathetic autonomic functions and vascular hyperresponsiveness to SNP and ACh. For example, the Valsalva ratio was inversely correlated with the increase in blood flow in response to infusion of 3 (r = -.74, P < .001) and 10 (r = -.73, P < .001) micrograms/min SNP and 7.5 (r = -.73, P < .001) and 15 (r = -.75, P < .001) micrograms/min ACh. CONCLUSIONS: These data are consistent with idea that altered neurotransmission is an important determinant of vascular reactivity of diabetic blood vessels to nitrovasodilators in vivo.