396 Early Endothelium-Dependent Vasodilatory Dysfunction Innormotensive, Intra-Uterine Growth Restricted Rats is Restored by L-Arginine and Inhibition of Arginases

Abstract

Increasing clinical and experimental evidence demonstrates that fetalprogrammed hypertension in adulthood is associated with altered endotheliumdependent vasodilation. However, it is debated whether decreased endothelium-dependent vasodilation precedes or is a consequence of elevated arterial pressure. We studied endotheliumdependent vasodilating capacity and the L-argininenitric oxide pathway in intra-uterine growthrestricted (IUGR), 5-week-old, male rats, before the development of elevated arterial pressure. We furthermore tested the hypothesis that alteration in endothelial vasodilation may be due to a reduction in L-arginine bioavailability. Methods- Pregnant rats were fed either a control or protein restricted diet during gestation. Endothelium-intact aortic rings of 5-week-old male offspring of the control and IUGR groups were isolated and preconstricted with phenylephrine (PE) to test vascularreactivity to acetylcholine (Ach) and sodium nitroprusside (SNP), respectively endothelium-dependent and -independent vasodilators. Other experiments were conducted with L-arginine supplementation or with S-(2-boronoethyl)-L-cysteine (BEC), a specific endothelial arginase inhibitor. Arginase enzymatic activity was measured in aorta. Results- Systolic blood pressure was not different between groups, and increased later in IUGR rats. While the vasodilatory response to SNP was similar in the two groups, a decreased vasodilatory response to Ach (- 20 %, p< 0.05) was observed in the IUGR group. Moreover, L-arginine supplementation and arginases inhibition restored the altered vasodilating capacity of aortic rings of IUGR animals. Arginase activity is enhanced in aorta of young IUGR rats. Conclusions- Reduced endothelium-dependent vascular relaxation precedes the developmentof fetal programmed hypertension in IUGR rats and involves the L-arginine-NO pathway. L-arginine supplementation and inhibition of arginases restore endothelium-dependent vasodilation in IUGR, prehypertensive rats.