THE EFFECT OF HYPERGLYCEMIA 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 noradrenalin e sensitivity compared with those in physiological buffer. 3 Profoundl y impaired endothelium-dependent relaxation to acetylcholine was obser ved in arteries incubated in 20 and 45 mM glucose. 4 Indomethacin (10 mu M) normalized noradrenaline sensitivity in 20 mM glucose, but unmas ked an enhanced maximum response in 20 and 45 mM glucose relative to c ontrols. 5 Addition of L-arginine (0.1 mM) prevented the abnormality o f acetylcholine-induced relaxation in the 20 mM glucose medium and sig nificantly improved relaxation in 45 mM glucose. 6 The aldose reductas e inhibitor, ponalrestat (10(-5) M, ZENECA Pharmaceuticals), prevented impaired acetylcholine-mediated relaxation in 20 mM glucose and signi ficantly improved relaxation in 45 mM glucose. 7 Indomethacin (10 mu M ) improved maximum relaxation but did not alter impaired sensitivity t o acetylcholine in the high glucose media (20 and 45 mM). 8 Superoxide dismutase (SOD, 150 u ml(-1)) also prevented impaired acetylcholine-i nduced relaxation in 20 mM glucose but not in 45 mM glucose. 9 Endothe lium-independent relaxation to sodium nitroprusside (SNP, 10(-9)-10(-5 ) mM) was normal in 20 mM glucose but was slightly, although significa ntly impaired by 45 mM glucose. 10 Enhanced responsiveness of rat isol ated mesenteric resistance arteries to noradrenaline caused by elevate d glucose would appear to be mediated through abnormal cyclo-oxygenase activity and the reduced tonic release of nitric oxide.11 Hyperglycae mia may lead to abnormal endothelium-dependent relaxation in these art eries through several mechanisms which include a role for increased fr ee radical production, polyol pathway activation and altered L-arginin e metabolism.