Nuyt AM. Antenatal antioxidant prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low-protein diet. Am J Physiol Regul Integr Comp Physiol 292: R1236 -R1245, 2007. First published November 30, 2006; doi:10.1152/ajpregu.00227.2006.-Developmental programming of hypertension is associated with vascular dysfunction characterized by impaired vasodilatation to nitric oxide, exaggerated vasoconstriction to ANG II, and microvascular rarefaction appearing in the neonatal period. Hypertensive adults have indices of increased oxidative stress, and newborns that were nutrient depleted during fetal life have decreased antioxidant defenses and increased susceptibility to oxidant injury. To test the hypothesis that oxidative stress participates in early life programming of hypertension, vascular dysfunction, and microvascular rarefaction associated with maternal protein deprivation, pregnant rats were fed a normal, low protein (LP), or LP plus lazaroid (lipid peroxidation inhibitor) isocaloric diet from the day of conception until delivery. Lazaroid administered along with the LP diet prevented blood pressure elevation, enhanced vasomotor response to ANG II, impaired vasodilatation to sodium nitroprusside, and microvascular rarefaction in adult offspring. Liver total glutathione was significantly decreased in LP fetuses, and kidney eight-isoprostaglandin F2␣ (8-isoPGF 2␣) levels were significantly increased in adult LP offspring; these modifications were prevented by lazaroid. Renal nitrotyrosine abundance and blood levels of 1,4-dihydroxynonene and 4-hydroxynonenal-protein adducts were not modified by antenatal diet exposure. This study shows in adult offspring of LP-fed dams prevention of hypertension, vascular dysfunction, microvascular rarefaction, and of an increase in indices of oxidative stress by the administration of lazaroid during gestation. Lazaroid also prevented the decrease in antioxidant glutathione levels in fetuses, suggesting an antenatal mild oxidative stress in offspring of LP-fed dams. These studies support the concept that perinatal oxidative insult can lead to permanent alterations in the cardiovascular system development.hypertension; vascular dysfunction; developmental origin of adult disease; oxidative stress; antioxidants.Cardiovascular diseases represent currently the leading cause of mortality in Western countries. The hypothesis of a developmental origin of these pathologies derives from epidemiological studies, indicating that, independent of genetic or life style factors, the risks of hypertension (HT), stroke, and coronary heart disease in later life are inversely proportional to birth weight. Alteration of the vascular response to ACh, a decreased arterial compliance, and an increased incidence of atherosclerosis are all evidence further illustrating the vascular risk in children and adults born with low birth weight and/or intrauterine growth retardation (3,4,44,47).Experimentally, HT is observed in adults after malnutrit...

Using a video-imaging technique, we characterized the effects of 8-isoprostaglandin F2α(8-iso-PGF2α) on retinal vasculature from piglets. 8-Iso-PGF2α potently contracted (EC50 = 5.9 ± 0.5 nM) retinal vessels. These effects were completely antagonized by the cyclooxygenase inhibitor indomethacin, the thromboxane synthase blocker CGS-12970, the thromboxane receptor antagonist L-670596, and the putative inhibitor of the non-voltage-dependent receptor-operated Ca2+ pathway SKF-96365; constrictor effects of 8-iso-PGF2α were also partly attenuated by the ETA-receptor blocker BQ-123 and an inhibitor of endothelin-converting enzyme, phosphoramidon, but was negligibly affected by the L-type voltage-gated Ca2+ channel blocker nifedipine. Correspondingly, 8-iso-PGF2αelicited endothelin release from retinal preparations, which was markedly reduced by SKF-96365. 8-Iso-PGF2α also increased thromboxane production in the retina and cultured endothelial cells, but not on retinovascular smooth muscle cells; these effects of 8-iso-PGF2α were blocked by indomethacin, CGS-12970, SKF-96365, and EGTA, but not by nifedipine. 8-Iso-PGF2α also increased Ca2+ transients in retinal endothelial cells, which were inhibited by SKF-96365 and EGTA, but not by nifedipine, whereas in smooth muscle cells U-46619, but not 8-iso-PGF2α, stimulated a rise in Ca2+ transients. Finally, H2O2+ FeCl2 (in vitro) and anoxia followed by reoxygenation (in vivo) stimulated formation of 8-iso-PGF2α in the retina. In conclusion, 8-iso-PGF2α-induced retinal vasoconstriction is mediated by cyclooxygenase-generated formation of thromboxane and, to a lesser extent, by endothelin after Ca2+ entry into cells, possibly through receptor-operated channels. Retinal vasoconstriction to 8-isoprostanes might play a role in the genesis of ischemic retinopathies.

Intrauterine programming of hypertension is associated with evidence of increased renin-angiotensin system (RAS) activity. The current study was undertaken to investigate whether arterial baroreflex and blood pressure variability are altered in a model of in utero programming of hypertension secondary to isocaloric protein deprivation and whether activation of the RAS plays a role in this alteration. Pregnant Wistar rats were fed a normalprotein (18%) or low-protein (9%) diet during gestation, which had no effect on litter size, birth weight, or pup survival. Mean arterial blood pressure (MABP; 126 Ϯ 3 mm Hg 9% versus 108 Ϯ 4 mm Hg 18%; p Ͻ 0.05) and blood pressure variability were significantly greater in the adult offspring of the 9% protein-fed mothers. Arterial baroreflex control of heart rate, generated by graded i.v. infusion of phenylephrine and nitroprusside, was significantly shifted toward higher pressure; i.v. angiotensinconverting enzyme inhibitor normalized MABP and shifted the arterial baroreflex curve of the 9% offspring toward lower pressure without affecting the 18% offspring. For examining whether brain RAS is also involved in programming of hypertension, angiotensin-converting enzyme inhibitor and losartan (specific AT 1 receptor antagonist) were administered intracerebroventricularly; both significantly reduced MABP of the 9% but not the 18% offspring. Autoradiographic receptor binding studies demonstrated an increase in brain AT 1 expression in the subfornical organ and the vascular organ of the lamina terminalis in the 9% offspring. These data demonstrate a major tonic role of brain and peripheral RAS on hypertension associated with antenatal nutrient deprivation. Abbreviations ACE-I, angiotensin-converting enzyme inhibitor AngII, angiotensin II AP, area postrema BPV, blood pressure variability HR, heart rate ICV, intracerebroventricular MABP, mean arterial blood pressure MEPO, median preoptic nucleus NTS, nucleus of the solitary tract OVLT, vascular organ of the lamina terminalis PVH, paraventricular nucleus of the hypothalamus RAS, renin-angiotensin system SFO, subfornical organ Chronic cardiovascular diseases of adults can have their origins in fetal life. Epidemiologic studies reveal that hypertension, stroke, and coronary heart disease are inversely related to birth weight (1) and that this relationship is independent of genetic factors (2) and lifestyle (3). It has been suggested that a poor nutrient supply at a critical period of early development leads to permanent alterations in the programming of the developing cardiovascular structures or functions (4). This concept has been supported by animal studies demonstrating an association between nutritional deficit during fetal life and increased blood pressure in adulthood (5, 6).Experimental evidence suggests that activation of the reninangiotensin system (RAS) (7,8) is an important element of hypertension programmed during fetal life. Infants who are born with intrauterine growth restriction have increased plasma renin activity and r...