IMPAIRED INSULIN-INDUCED ATTENUATION OF NORADRENALINE-MEDIATED VASOCONSTRICTION IN INSULIN-RESISTANT OBESE ZUCKER RATS

1. Insulin resistance is associated with hypertension but the underlyi ng mechanism is unclear, We tested the hypothesis that insulin-induced vasodilatation is impaired in insulin-resistant obese Zucker rats, We studied mesenteric artery (approximate to 220 mu m diameter) function before the development of hypertension in 3-month old obese Zucker ra ts and age-matched lean rats. 2. In vessels from lean rats, insulin at concentrations of 50, 500 and 5000 m-units/l attenuated the constrict ion in response to noradrenaline (50 m-units/l: 8 +/- 3%, P < 0.05; 50 0 m-units/l: 13 +/- 3%, P < 0.02; 5000 m-units/l: 13 +/- 2%, P < 0.02) . 3. Vessels from obese rats failed to show any such response to insul in (2 +/- 6% increase in maximal tension with 5000 m-units/l; not sign ificant), both in the presence and absence of L-arginine (3 mmol/l). 4 . Vessels from obese rats showed slight but significant impairment in the vasodilator response to acetylcholine (5 x 10(-8)-10(-4) mol/l) (o bese: 64.1 +/- 3.7% relaxation; lean: 77.3 +/- 3.7% relaxation; P < 0. 05); however, relaxation in response to A23187 was not significantly d ifferent between the phenotypes (obese: 81.3 +/- 10.6% relaxation; lea n: 79.1 +/- 9.7% relaxation; not significant). 5. Systolic blood press ure was not significantly different in lean (126 +/- 8 mmHg) and obese (127 +/- 7 mmHg) rats at the time of study (not significant). 6. We c onclude that insulin-induced attenuation of noradrenaline-mediated vas oconstriction is impaired in the obese Zucker rat and that this defect precedes and therefore could contribute to the development of hyperte nsion in this insulin-resistant model, The defect in insulin action co uld reside in the endothelial generation of nitric oxide, as endotheli al function is also abnormal.