The effect of hyperglycaemia on function of rat isolated mesenteric resistance artery.

1. Noradrenaline sensitivity and acetylcholine-induced relaxation were investigated in mesenteric resistance arteries from female Wistar rats (220-250 g) following exposure to isotonic supraphysiological glucose solutions (20 and 45 mM, in physiological buffer, 2 h incubation). 2. Arteries incubated in 20 mM glucose demonstrated enhanced noradrenaline sensitivity compared with those in physiological buffer. 3. Profoundly impaired endothelium-dependent relaxation to acetylcholine was observed in arteries incubated in 20 and 45 mM glucose. 4. Indomethacin (10 microM) normalized noradrenaline sensitivity in 20 mM glucose, but unmasked an enhanced maximum response in 20 and 45 mM glucose relative to controls. 5. Addition of L-arginine (0.1 mM) prevented the abnormality of acetylcholine-induced relaxation in the 20 mM glucose medium and significantly improved relaxation in 45 mM glucose. 6. The aldose reductase inhibitor, ponalrestat (10(-5) M, ZENECA Pharmaceuticals), prevented impaired acetylcholine-mediated relaxation in 20 mM glucose and significantly improved relaxation in 45 mM glucose. 7. Indomethacin (10 microM) improved maximum relaxation but did not alter impaired sensitivity to acetylcholine in the high glucose media (20 and 45 mM). 8. Superoxide dismutase (SOD, 150 u ml-1) also prevented impaired acetylcholine-induced relaxation in 20 mM glucose but not in 45 mM glucose. 9. Endothelium-independent relaxation to sodium nitroprusside (SNP, 10(-9)-10(-5) mM) was normal in 20 mM glucose but was slightly, although significantly impaired by 45 mM glucose. 10. Enhanced responsiveness of rat isolated mesenteric resistance arteries to noradrenaline caused by elevated glucose would appear to be mediated through abnormal cyclo-oxygenase activity and the reduced tonic release of nitric oxide. 11. Hyperglycaemia may lead to abnormal endothelium-dependent relaxation in these arteries through several mechanisms which include a role for increased free radical production, polyol pathway activation and altered L-arginine metabolism.