Abstract-Embryo cross-transplantation and cross-fostering between spontaneously hypertensive rats (SHR) and normotensive rats (WKY) suggest that perinatal environment modulates the genetically determined phenotype. In SHR the balance between NO and reactive oxygen species (ROS) is disturbed. We hypothesized that increasing NO and diminishing ROS in perinatal life would ameliorate hypertension in adult SHR. Pregnant SHR and WKY and their offspring received L-arginine plus antioxidants (vitamin C, vitamin E, and taurine) during the last 2 weeks of pregnancy and then until either 4 or 8 weeks after birth. Systolic blood pressure (SBP) and urinary excretion of protein, nitrates (NO x ), and thiobarbituric acid reactive substances (TBARS) were measured. At 48 weeks of age rats were euthanized for glomerular counts. Perinatal supplements reduced SBP persistently in SHR and prevented the SBP increase observed in aging WKY. Initially NO x excretion was lower and TBARS excretion higher in SHR than WKY. There was a direct effect on NO x excretion in supplemented pregnant SHR and their offspring, but no increase was observed after stopping the supplements. TBARS excretion was only depressed up to 14 weeks by the supplements despite persistent differences in SBP. Consistent effects on nephron number were absent. Mild proteinuria, present in control SHR at 48 weeks, was prevented in all supplemented rats. In animal models there is ample evidence to support this, although a common denominator has not been found. Both embryo cross-transferring and cross-fostering studies between spontaneously hypertensive rats (SHR) and normotensive rats (WKY) resulted in reduced BP in SHR offspring, 3,4 suggesting that either nongenetic causal factors leading to hypertension or consequences of hypertension itself are transmitted to the neonates. Most studies have focused on maneuvers such as restriction of maternal nutrition 5,6 to simulate the Barker proposition that disadvantageous perinatal environmental factors increase BP in the offspring. 1 No studies have addressed whether the reverse holds true (ie, whether advantageous perinatal factors may exist).In this study we focused on the imbalance between NO and reactive oxygen species (ROS) activity, which forms part of a common pathway for endothelial dysfunction and, possibly, hypertension. 7 The SHR is a model for this imbalance; in SHR production of superoxide (O 2 Ϫ ) and other ROS is upregulated in the cardiovascular system and kidney. 8,9 Reports on NO production are conflicting, 10,11 but it is accepted that overall NO availability is decreased in SHR, possibly as a result of its inactivation by O 2 Ϫ . Whether this imbalance also influences development in SHR during pregnancy and lactation is unknown. Hence we first studied whether the imbalance between NO and ROS is already present in young SHR and whether transient perinatal exposure of SHR to dietary supplements that supposedly reduce O 2 Ϫ and support NO formation induce a sustained alteration of this balance after stopping the ...

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...

. NO dependency of RBF and autoregulation in the spontaneously hypertensive rat. Am J Physiol Renal Physiol 285: F105-F112, 2003. First published March 11, 2003 10.1152/ajprenal.00348.2002In the spontaneously hypertensive rat (SHR), renal blood flow (RBF) has been reported to be very dependent on nitric oxide (NO); however, autoregulation is normal, albeit shifted to higher perfusion pressures. To test the hypothesis that in the SHR NO dependency of RBF autoregulation is diminished, we investigated RBF autoregulation in anesthetized young male SHR and normotensive Wistar-Kyoto (WKY) rats before and during acute intravenous NO synthase (NOS) inhibition with N -nitro-L-arginine (L-NNA) and urinary excretion of nitrate plus nitrite (U NOxV) at different renal perfusion pressures (RPP). Under baseline conditions, SHR had higher mean arterial pressure (147 Ϯ 4 mmHg) and renal vascular resistance (16 Ϯ 1 U) than WKY (105 Ϯ 4 mmHg and 10 Ϯ 0.5 U, respectively, P Ͻ 0.05). RBF was similar (9.4 Ϯ 0.5 vs. 10.3 Ϯ 0.1 ml ⅐ min Ϫ1 ⅐ g kidney wt Ϫ1 ). Acute NOS blockade increased mean arterial pressure similarly, but there was significantly more reduction in RBF and hence an enhanced increase in renal vascular resistance in SHR (to 36 Ϯ 3 vs. 17 Ϯ 1 U in WKY, P Ͻ 0.001). The renal vasculature of SHR is thus strongly dependent on NO in maintaining basal RBF. The lower limit of autoregulation was higher in SHR than WKY in the baseline situation (85 Ϯ 3 vs. 71 Ϯ 2 mmHg, P Ͻ 0.05). Acute L-NNA administration did not decrease the lower limit in the SHR (to 81 Ϯ 3 mmHg, not significant) and decreased the lower limit to 63 Ϯ 2 mmHg (P Ͻ 0.05) in the WKY. The degree of compensation as a measure of autoregulatory efficiency attained at spontaneous perfusion pressures was comparable in SHR vs. WKY but with a shift of the curve toward higher perfusion pressures in SHR. Acute NOS blockade only increased the degree of compensation in WKY. Remarkably, UNOxV was significantly lower at spontaneous RPP in SHR. After reduction of RPP, the observed decrease in UNOxV was significantly more pronounced in WKY than in SHR. In conclusion, the renal circulation in SHR is dependent on high levels of NO; however, the capacity to modulate NO in response to RPP-induced changes in shear stress seems to be limited. urinary excretion; renal perfusion pressures THE KIDNEY'S INTRINSIC property to regulate vascular tone so that renal blood flow (RBF) and glomerular filtration rate (GFR) remain relatively constant during perturbations of renal perfusion pressure (RPP) protects the tubular system from rapid changes in filtered load (7,24). On the basis of several observations, it seems likely that nitric oxide (NO) release, depending on perfusion pressure-dependent variations in shear stress, can also dynamically modulate renal vascular tone. Endothelial NO synthase (NOS) is present in the preglomerular vasculature, and the afferent arteriole has been demonstrated to constrict on inhibition of NO synthesis (15). Thus one would anticipate that with a gradual incr...

Perinatal supplements shifted RBF autoregulation characteristics of SHR towards WKY, although capacity of the SHRsuppl kidney to modulate NO production to shear stress still seems impaired. The less strictly controlled RBF as observed in perinatally supplemented SHR could result in an improved long-term blood pressure control. This might partly underlie the beneficial effects of perinatal supplementation.

Despite initial normalization of blood pressure interference with the renin-angiotensin system during a crucial stage of development in SHR can initiate marked smooth muscle cell hyperplasia and disruption of the wall structure of the intrarenal arteries. Subsequent progression of this intrarenal process after cessation of treatment suggests an independent process that eventually results in malignant hypertension and early death.