Dynamic tail amine interactions drive isoform selectivity for potent human neuronal nitric oxide synthase inhibitors.

1. Epidemiological evidence indicates that low birthweight increases the risk of a number of adult-onset diseases. It is now apparent that many babies with a low birthweight may have been subjected to a combination of reduced growth rates in utero as well as preterm birth. However, the long-term effects of preterm birth following intra-uterine growth restriction (IUGR) are unknown. Thus, our objectives were: (i) to identify prenatal factors associated with preterm birth in IUGR fetuses; and (ii) to characterize postnatal effects of preterm birth following IUGR. 2. We studied pregnant sheep and their offspring, in which fetal growth was restricted by umbilico-placental embolization during late gestation. Some of these animals were born at term (146 +/- 1 days) and some were born prematurely (139 +/- 1 days). In both groups, we have conducted longitudinal studies of postnatal respiratory function, cardiovascular function and learning ability up to 6-8 weeks of age. 3. Before birth, IUGR fetuses born prematurely (P-IUGR) were more hypoxaemic and acidaemic and had higher haemoglobin concentrations than both control fetuses and IUGR fetuses born at term (T-IUGR). In P-IUGR fetuses, plasma cortisol concentrations increased earlier than in the two other groups. The P-IUGR lambs had lower birthweights than T-IUGR lambs and both groups of IUGR lambs remained lighter than controls for 8 weeks. 4. After birth, P-IUGR lambs were hypoxaemic compared with T-IUGR and control lambs. Pulmonary diffusing capacity (adjusted for lung volume) was significantly lower in both groups of IUGR lambs than in controls, with P-IUGR lambs having lower values than T-IUGR lambs. Lung compliance (adjusted for lung volume), was not different between P-IUGR and control lambs, but values were higher in T-IUGR lambs than in control and P-IUGR lambs. Chest wall compliance (adjusted for lung volume) was higher in both groups of IUGR lambs than in controls. 5. During the 8 week postnatal study period, both groups of IUGR lambs had lower mean arterial pressures than control lambs; this relative hypotension was greatest in P-IUGR lambs. 6. In tests of learning ability, P-IUGR lambs took longer to complete a simple maze task at all ages and, in the second postnatal week, made a greater number of errors compared with controls. In an obstacle course, P-IUGR lambs recorded longer trial durations; they also made more errors than control lambs. 7. We conclude that preterm birth in the presence of late- gestational placental insufficiency and IUGR can result in specific effects on respiratory and cardiovascular development after birth, in addition to the effects of IUGR alone.