Acute effects of glucose and insulin on vascular endothelium.
OBJECTIVE
Chronic exposure to high concentrations of glucose has consistently been demonstrated to impair endothelium-dependent, nitric oxide (NO)-mediated vasodilation. In contrast, several clinical investigations have reported that acute exposure to high glucose, alone or in combination with insulin, triggers vasodilation. The aim of this study was to examine whether elevated glucose itself stimulates endothelial NO formation or enhances insulin-mediated endothelial NO release.


METHODS
We measured NO release and vessel tone ex vivo in porcine coronary conduit arteries (PCAs). Intracellular Ca(2+) was monitored in porcine aortic endothelial cells (PAECs) by fura-2 fluorescence. Expression of the Na(+)/glucose cotransporter-1 (SGLT-1) was assayed in PAECs and PCA endothelium by RT-PCR.


RESULTS
Stimulation of PCAs with D: -glucose, but not the osmotic control L: -glucose, induced a transient increase in NO release (EC(50) approximately 10 mmol/l), mediated by a rise in intracellular Ca(2+) levels due to an influx from the extracellular space. This effect was abolished by inhibitors of the plasmalemmal Na(+)/Ca(2+) exchanger (dichlorobenzamil) and the SGLT-1 (phlorizin), which was found to be expressed in aortic and coronary endothelium. Alone, D: -glucose did not relax PCA, but did augment the effect of insulin on NO release and vasodilation.


CONCLUSIONS
An increased supply of extracellular D: -glucose appears to enhance the activity of the endothelial isoform of nitric oxide synthase by increasing intracellular Na(+) concentrations via SGLT-1, which in turn stimulates an extracellular Ca(2+) influx through the Na(+)/Ca(2+) exchanger. This mechanism may be responsible for glucose-enhanced, insulin-dependent increases in tissue perfusion (including coronary blood-flow), thus accelerating glucose extraction from the blood circulation to limit the adverse vascular effects of prolonged hyperglycaemia.
Taubert
D
D
Department of Pharmacology, Medical Hospital of the University of Cologne, Gleueler Str. 24, 50931, Cologne, Germany. dirk.taubert@medizin.uni-koeln.de
Rosenkranz
A
A
Berkels
R
R
Roesen
R
R
Schömig
E
E
D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D010695:Phlorhizin / Q000494:pharmacology; D013395:Sucrose / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013552:Swine
D007328:Insulin; D013481:Superoxides; C041470:3',4'-dichlorobenzamil; D009569:Nitric Oxide; D013395:Sucrose; D000584:Amiloride; D010695:Phlorhizin; D005947:Glucose