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Objective: The aim was to examine the effects of diabetes mellitus on adrenergic neurotransmission and smooth muscle responsiveness in the densely innervated carotid artery from six-week alloxan diabetic rabbits., Methods: Rings of carotid arteries were isolated from normal and diabetic rabbits and isometric tension was measured in response to stimulation of adrenergic nerves, alpha adrenoceptors, and activation by calcium., Results: Basal content and stimulated overflow of endogenous noradrenaline were reduced by approximately 25% in arteries from diabetic as compared to normal rabbits. In contrast, responses to endogenous noradrenaline released from adrenergic nerves by electrical stimulation or tyramine displacement were not different between arteries from normal and diabetic groups. Neuronal uptake blockade using cocaine caused a significantly smaller leftward shift in the contractions produced by electrical stimulation and exogenously applied noradrenaline in arteries from diabetic rabbits. The tonic, but not phasic, contractions caused by phenylephrine were larger in arteries from diabetic rabbits. Calcium-induced contractions caused by readdition of calcium to a calcium-free medium containing potassium (15 mmol.litre-1) were also significantly larger in arteries from diabetic rabbits. BAY K 8644, a calcium channel activator, caused an increase in calcium induced contractions and abolished the difference between the two groups., Conclusions: Although neurogenic contractions of diabetic carotid artery are normal, there is inefficient or reduced neuronal uptake as well as increased activity of calcium channels in the smooth muscle which increase contractions to alpha adrenoceptor agonists.

Diabetes is characterized by hyperglycemia, a relative lack of insulin, and an inclination to vascular disease and neuropathy. The link between diabetes and vascular disease is not understood, but autonomic dysfunction could partly account for alterations in reactivity of diabetic blood vessels to neurotransmitters and circulating hormones. Changes in local control of vascular tone, such as imbalance in production of relaxing and contracting factors by the endothelium, may be related to the initiation and maintenance of abnormal vascular reactivity characteristically seen in diabetic vascular complications. The emphasis is to discuss functional changes of blood vessel adrenergic neuroeffector mechanisms and endothelial cell dysfunction, together with the complex interrelationship of cyclooxygenase catalysis, protein kinase C activity, sodium-potassium ATPase activity, and flux through the polyol pathway. This review focuses on the common mechanisms by which hyperglycemia causes changes in vascular function.

Transmural electrical stimulation of isolated ring segments of the rabbit carotid artery caused frequency-dependent contractions; these were blocked by tetrodotoxin or prazosin. Mechanical or chemical removal of the endothelium markedly augmented responses to electrical stimulation. Inhibition of norepinephrine uptake and metabolism with cocaine, hydrocortisone, and pargyline increased contractions in rings with endothelium more than those without endothelium, but responses remained greater in rings denuded of endothelium. Methylene blue, an inhibitor of guanylate cyclase, enhanced responses to electrical stimulation of rings with intact endothelium only. Combined inhibition of guanylate cyclase and norepinephrine disposition increased the contractions and abolished the difference between the responses of rings with and without endothelium. In a perfusion-cascade system, the perfusate of donor segments with endothelium relaxed a bioassay ring without endothelium. Electrical stimulation of the segment caused no further relaxation of the bioassay ring. However, contractions caused by electrically stimulating the bioassay ring were depressed during superfusion with the perfusate of segments with, but not without, endothelium, indicating that vasodilators spontaneously released from the endothelium inhibit responses to nerve stimulation. These observations suggest that inhibition by the endothelium of the response to adrenergic nerve stimulation results from 1) spontaneous release of endothelium-derived vasodilators and 2) disposition of norepinephrine by the endothelial cells.

Transmural electrical stimulation was used to elicit frequency-dependent adrenergic neurogenic contractions in isolated carotid arteries from cholesterol-fed and control rabbits. In rings with endothelium, responses to adrenergic nerve stimulation were significantly greater in arteries from cholesterol-fed as compared with those from control rabbits. Responses to adrenergic nerve stimulation of rings without endothelium were not different between the two groups. Methylene blue, a guanylate cyclase inhibitor, increased contractions of rings with endothelium and abolished the difference between the responses of arteries from cholesterol-fed and control rabbits. Methylene blue had no significant effect on arteries without endothelium. The overflow of endogenous norepinephrine (NE) caused by transmural electrical stimulation was not different between segments of arteries from cholesterol-fed and control rabbits. In control rabbits, exogenously applied NE contracted arteries with endothelium less than arteries without endothelium, whereas in cholesterol-fed rabbits the contractions caused by NE were not different between arteries with and without endothelium. Acetylcholine-induced relaxations were not different between rings with endothelium from cholesterol-fed and control rabbits. These results suggest that hypercholesterolemia selectively impairs the inhibitory influence of the endothelium on adrenergic contractions.

Isolated perfused rabbit carotid arteries were used to determine the effects of endothelial cell shear stress on the response to adrenergic nerve stimulation. Arterial segments with and without endothelium were cannulated and perfused with physiological salt solution. Adrenergic nerves were activated by transmural electrical field stimulation. Neurogenic vasoconstriction was significantly greater in segments without endothelium when compared with that of segments with endothelium. In segments with endothelium only, vasoconstriction was depressed when shear stress was increased by increasing the viscosity of the perfusate with dextran. Perfusion with methylene blue (2 X 10(-6) M), a guanylate cyclase inhibitor, increased vasoconstriction in segments with endothelium only. In the presence of methylene blue, vasoconstriction was no longer different between segments with and without endothelium, and perfusion with dextran had no effect. In a perfusion-cascade system, perfusion with dextran of donor segments with but not without endothelium caused further relaxation of a contracted bioassay ring. These results suggest that shear stress on endothelial cells modulates adrenergic vasoconstriction by augmenting release of endothelial cell-derived vasodilators.