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Muscle purinergic receptors and endothelial function in patients with type 2 diabetes

 

Pia Thaning

Summary

Background: extracellular nucleotides, ATP (adenosin-tri-phosphat), UTP (uridin-triphosphat)and nucleosides (adenosine) are proposed to be released from red blood cellsand the endothelium in response to a fall in oxygen saturation or shear stress. Activation ofendothelial purinergic receptors results in vasodilation due to release of nitric oxide (NO)and/or prostaglandins (PG). In contracting skeletal muscles, increases in oxygen demandcorrospond with local vasodilation and studies of young healthy subjects have suggestedthat the purinergic system plays a role in exercise-induced hyperemia. Muscle sympathetic nerve activity increases in proportion to exercise intensity and theactive muscle mass. An increase in sympathetic activity during muscle contraction wouldcause vasoconstriction, however this effect is counteracted by locally formed compounds,a phenomenum termed functional sympatholysis. ATP and UTP have been shown tooverride tyramine-induced vasoconstriction in young healthy subjects, suggesting thatpurinergic agonists may be involved in sympatholysis.Hyperglycemia and risk factors associated with diabetes may lead to endothelialdysfunction, which affects vascular reactivity, and an increase in sympathetic activity hasbeen demonstrated in diabetic patients. Both alterations may result in diminishedvasodilation and consequently an insufficient supply of oxygen.The aim of this PhD thesis was to investigate if purinergic vasodilation and functionalsympatholysis in skeletal muscles are impaired in type 2 diabetic patients.Results: leg blood flow in the femoral artery was measured with the ultrasound Dopplermethod during arterial infusions of ATP, UTP and adenosine in type 2 diabetic patientsand age-matched controls. The vasodilatatory potency of nucleotides and nucleosides wasmarkedly reduced in type 2 diabetic patients with endothelial dysfunction expressed asreduced vasodilation during infusion with acetylcholine. In another group of type 2 diabeticpatients, with similar demographic profile and similar antidiabetic and antihypertensivemedication but intact endothelial function, there was no significant difference invasodilatatory potency of ATP and adenosine. This indicates that the vasodilatatory effectof purinergic compounds is reduced in patients with endothelial dysfunction.Ageing per se may affect the vasodilatatory potency and diabetes further aggravates thesechanges, related to the extent of endothelial dysfunction.Functional sympatholysis was found to be intact in diabetic patients with intact endothelialfunction during moderate exercise. This does not preclude that diabetic patients withpronounced endothelial affection might have reduced ability to blunt sympathetic inducedvasoconstriction during exercise.The sympatholytic effect of ATP during alpha-adrenergic activation via tyramine wasreduced in both diabetic and middle-aged subjects compared to previous studies of younghealthy subjects. Yet functional sympatholysis during exercise was intact in both groups,indicating that ATP is not mandatory in elderly to blunt sympathetic inducedvasoconstriction during exercise. Redundancy, where other metabolites compensate, mayensure sufficient oxygen supply. During tyramine infusion, the increase in venous noradrenalin (NA) was identical in thediabetic and the control group. Furthermore, vasoconstictory responses and additionalhemodynamics were similar, indicating that the sensitivity to alpha-adrenergic stimulationwas uniform in the two groups. However, the plasma content of NA was significantly lowerin the diabetic group, both at baseline and consistently during all interventions. This couldreflect a physiological adaptation to habitually increased sympathetic nerve activity, thuspreserving the ability to sufficiently vasodilate during exercise. However, further studieswith precise measurements of sympathetic nerve activity are required to clarify thishypothesis.By immunohistochemical analysis, the presence of purinergic receptors was demonstratedintracellularly and in the surrounding microvessels. There was no difference in distributionor amount of receptors between diabetic and control subjects. This does not excludefunctional differences in purinergic receptors as the cause of the vasodilatatorydifferences. However, diminished purinergic vasodilation may also reflect a reduction inthe activity/availability of the mediators, NO and PG.