Effect of hyperglycemia on endothelial dependent dilatation in the iliac artery of the anaesthetized pig

Noble MIM *, Drake-Holland AJ † Kelly R, Ruane T & Snow HM (introduced by CL Wainwright†) Biological Services Unit and Department of Physiology, University College Cork, *Cardiovascular Medicine, Dept of Medicine and Therapeutics, University of Aberdeen, †School of Pharmacy, Robert Gordon University, Aberdeen.

Clinical hyperglycaemia is known to impair vascular endothelial function, but it is not known whether this involves the dilatation in response to increased wall shear stress in conduit arteries. It has been suggested by Weinbaum et al, 2003 that the glycocalyx and endothelium together form a mechano-chemical transduction system sensing arterial wall shear stress with consequent dilatation of the artery due to nitric oxide (NO) release (Joannides et al, 1995) . Acetylcholine acting on muscarinic receptors on the endothelial cell membrane can also release NO. We measured the response of the iliac artery to both shear stress and acetylcholine before and after exposure to D-glucose. Experiments were carried out in female anaesthetized pigs, weight range 18-30Kg (induction pentobarbitone 30mg/kg i.v., maintenance 6mg/kg/h). The animals were ventilated (air and 40% oxygen) via a tracheostomy. A catheter-tip manometer, sometimes with lumen for infusion of acetylcholine(upstream cannula) was inserted via the right iliac artery or the mesenteric artery into the base of the aorta. The distal end of the left iliac artery was cannulated via the deep femoral artery. The right iliac artery, sacral artery, and all branches of the left iliac and mesenteric artery were ligated. A snare was placed midway down the iliac artery approximately 2cm from the base of the aorta. Occlusion of this snare partitioned the artery into proximal (control) and distal (test) segments. A second snare was placed just above the femoral bifurcation. Temporary occlusion and release of this snare was used to study blood flow increases during reactive hyperemia.Pressure (strain gauge transducer), blood flow (ultrasonic transit time flowmeter) and diameter (sonomicrometry) of the left iliac artery were measured at the control and test segments, and recorded by PowerLab. Systemic infusion (n=7) of D-glucose through the upstream cannula caused arterial dilatation and attenuated the shear stress-dependent dilatation from 35.6±9.9 (mean±SEM) to 10.3±6.2 µm/N/m2, p = 0.0156 (Wilcoxon matched-pairs signed-rank test), with preservation of the responses to acetylcholine. To determine whether luminal or systemic D-glucose was responsible for these effects, d2 was isolated using snares (n=11) and the lumen exposed to blood containing D-glucose (20-40mM) for 20 min. In the control situation, after exposure of the distal section (d2) to normoglycaemia (4mM) glucose, both sections of artery dilated in response to shear stress and acetylcholine. Luminal hyperglycemia (n = 11) attenuated the shear stress dependent dilatation in the distal section only, from 17.2±3.2 to 1.1±2.5 μm/N/m2 p = 0.001, but not the response to acetylcholine. It is concluded that shear stress-induced arterial dilatation, mediated by NO, is attenuated by hyperglycaemia. Zuurbier et al, 2005 have shown that D-glucose affects glycocalyx volume. Therefore we suggest that this inhibitory action is localized to the glycocalyx coating of the luminal surface of the arterial endothelium. These findings indicate that glycocalyx dysfunction may be the primary deleterious effect of D-glucose on blood vessels.