Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon

Abstract

Racasan, Simona, Branko Braam, Hein A. Koomans, and Jaap A. Joles. Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon. Am J Physiol Renal Physiol 288: F626 -F636, 2005. First published November 16, 2004 doi:10.1152/ ajprenal.00314.2004.-The "programming hypothesis" proposes that an adverse perinatal milieu leads to adaptation that translates into cardiovascular disease in adulthood. The balance between nitric oxide (NO) and reactive oxygen species (ROS) is disturbed in cardiovascular diseases, including hypertension. Conceivably, this balance is also disturbed in pregnancy, altering the fetal environment; however, effects of perinatal manipulation of NO and ROS on adult blood pressure (BP) are unknown. In spontaneously hypertensive rats (SHR), NO availability is decreased and ROS are increased compared with normotensive Wistar-Kyoto rats, and, despite the genetic predisposition, the perinatal environment can modulate adult BP. Our hypothesis is that a disturbed NO-ROS balance in the SHR dam persistently affects BP in her offspring. Dietary supplements, which support NO formation and scavenge ROS, administered during pregnancy and lactation resulted in persistently lower BP for up to 48 wk in SHR offspring. The NO donor molsidomine and the superoxide dismutase mimic tempol-induced comparable effects. Specific inhibition of inducible nitric oxide synthase (NOS) reduces BP in adult SHR, suggesting that inducible NOS is predominantly a source of ROS in SHR. Indeed, inducible NOS inhibition in SHR dams persistently reduced BP in adult offspring. Persistent reductions in BP were accompanied by prevention of proteinuria in aged SHR. We propose that in SHR the known increase in ANG II type 1 receptor density during development leads to superoxide production, which enhances inducible NOS activity. The relative shortage of substrate and cofactors leads to uncoupling of inducible NOS, resulting in superoxide production, activating transcription factors that subsequently again increase inducible NOS expression. This vicious circle probably is perpetuated into adult life. spontaneously hypertensive rat; nitric oxide; inducible nitric oxide synthase; molsidomine; tempol; proteinuria THERE IS NOW A LARGE BODY of epidemiological data proving that environmental factors acting early in life, in particular in the intrauterine and postnatal period, correlate with chronic cardiovascular diseases. From these observations, Barker (10) developed the "programming hypothesis," which proposes that fetal adaptation to adverse environmental factors in the perinatal period results in permanent structural and physiological changes that manifest as disease in adult life. As such, fetal programming is a form of phenotypic plasticity (10), which has conveyed an evolutionary advantage in the past but now has adverse effects because of relatively rapid changes in the environment in which we live (58). An example of this may be the explosion of hyperten...

Antenatal antioxidant prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low-protein diet

“…More recently, Stewart et al (70) reported enhanced oxidative stress determined by quantitative immunoblotting for nitrotyrosine in the kidneys of 4-wk-old LP offspring; in this study, administration of superoxide dismutase analog before 4 wk of age prevented the increase in nitrotyrosine abundance in the kidney as well as the development of high blood pressure. In spontaneously hypertensive rats, HT is prevented by perinatal administration of L-arginine (essential for NO synthesis) and antioxidant vitamins C and E (61,62).…”

Maternal Supplementation With Citrulline Increases Renal Nitric Oxide in Young Spontaneously Hypertensive Rats and Has Long-Term Antihypertensive Effects

“…Tempol and other superoxide dismutase mimetics have been shown to correct enhanced peripheral vasoconstriction in models of perinatal malnutrition, 25,26 and we have observed that perinatal Tempol can also persistently reduce SBP in SHRs. 12 Judging by the higher body weight, it is possible that perinatal citrulline has long-term stimulatory effects on muscle protein synthesis. Such an effect has been observed previously during refeeding in old malnourished rats.…”

“…Previously we observed that transient perinatal supplementation of SHRs with arginine, taurine, and vitamins C and E had a permanent antihypertensive effect. 11 Accordingly, it is plausible that factors that support NO availability directly or indirectly by increasing arginine availability in the perinatal phase could decrease blood pressure later in life (reprogramming 12 ). Therefore, our secondary hypothesis is that brief perinatal citrulline supplementation in SHRs corrects renal NO in the developing kidney and, hence, has long-term antihypertensive effects in conjunction with a shift of the renal vascular constrictor-dilator balance toward relaxation.…”

Neonatal Oxygen Exposure in Rats Leads to Cardiovascular and Renal Alterations in Adulthood

“…7 In spontaneously hypertensive rats, although considered a model of genetic hypertension, supplementation with antioxidants during gestation and early postnatal weeks resulted in persistent reduction of adult blood pressure. 8 The current studies were undertaken to test the hypothesis that neonatal O 2 injury causes long-term vascular damage and hypertension. Moreover, considering that the kidney plays a role in the development of hypertension and that altered renal development (resulting in lower nephron count) can be triggered by perinatal events, which contribute to adult blood pressure elevation, we also hypothesized that exposure, the dam was alternated every 12 hours with a surrogate mother of a litter maintained in room air (control group NH: pups in normoxia/mother partly in hyperoxia; nϭ12 litters).…”