Nitric oxide, superoxide and renal blood flow autoregulation in SHR after perinatal <scp>L</scp>‐arginine and antioxidants

Koeners, Maarten P.; Racasan, Simona; Koomans, Hein A.; Joles, Jaap A.; Braam, Branko

doi:10.1111/j.1748-1761.2007.01702.x

Cited by 27 publications

(44 citation statements)

References 28 publications

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“…Taken together, this is not a proof for but is compatible with increased afferent arteriolar resistance resulting in a partially suppressed FHH adult phenotype with respect to glomerular injury. This is quite the opposite of the response to arginine plus antioxidants that we observed in SHR where RVR was decreased by perinatal treatment (21). It remains unclear how in FHH limited exposure in early life to exogenous NO, a well-known vasodilator, can increase preglomerular resistance in adult life many months later.…”

Section: Discussioncontrasting

confidence: 56%

A perinatal nitric oxide donor increases renal vascular resistance and ameliorates hypertension and glomerular injury in adult fawn-hooded hypertensive rats

Koeners¹,

Braam²,

Giezen³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Koeners MP, Braam B, van der Giezen DM, Goldschmeding R, Joles JA. A perinatal nitric oxide donor increases renal vascular resistance and ameliorates hypertension and glomerular injury in adult fawn-hooded hypertensive rats. Am J Physiol Regul Integr Comp Physiol 294: R1847-R1855, 2008. First published April 16, 2008 doi:10.1152/ajpregu.00073.2008.-Enhancing perinatal nitric oxide (NO) availability persistently reduces blood pressure in spontaneously hypertensive rats. We hypothesize that this approach can be generalized to other models of genetic hypertension, for instance those associated with renal injury. Perinatal exposure to the NO donor molsidomine was studied in fawn-hooded hypertensive (FHH) rats, a model of mild hypertension, impaired preglomerular resistance, and progressive renal injury. Perinatal molsidomine increased urinary NO metabolite excretion at 8 wk of age, i.e., 4 wk after treatment was stopped (P Ͻ 0.05). Systolic blood pressure was persistently reduced after molsidomine (42-wk females: 118 Ϯ 3 vs. 141 Ϯ 5 and 36-wk males: 139 Ϯ 4 vs. 158 Ϯ 4 mmHg; both P Ͻ 0.001). Perinatal treatment decreased glomerular filtration rate (P Ͻ 0.05) and renal blood flow (P Ͻ 0.01) and increased renal vascular resistance (P Ͻ 0.05), without affecting filtration fraction, suggesting persistently increased preglomerular resistance. At 4 wk of age natriuresis was transiently increased by molsidomine (P Ͻ 0.05). Molsidomine decreased glomerulosclerosis (P Ͻ 0.05). Renal blood flow correlated positively with glomerulosclerosis in control (P Ͻ 0.001) but not in perinatally treated FHH rats. NO dependency of renal vascular resistance was increased by perinatal molsidomine. Perinatal enhancement of NO availability can ameliorate development of hypertension and renal injury in FHH rats. Paradoxically, glomerular protection by perinatal exposure to the NO donor molsidomine may be due to persistently increased preglomerular resistance. The mechanisms by which increased perinatal NO availability can persistently reprogram kidney function and ameliorate hypertension deserve further study. proteinuria; renal hemodynamics; glomerulosclerosis A LARGE BODY OF experimental and epidemiological studies supports the concept that the intrauterine and early postnatal environment interacts with early development in that it can program metabolic and cardiovascular disease (5,18,27). Most of these studies focus on how aberrant perinatal factors increase the occurrence of pathologies in later life. When such factors are superimposed on a specific background of inherited disease, developmental programs will also be affected. Hence, programming can also have long-lasting effects against an abnormal genetic background. Accordingly, advantageous perinatal factors can prevent or correct abnormal development. Because hypertension is associated with decreased nitric oxide (NO) availability (52), it is plausible that factors that support NO availability in the perinatal phase can (re)program development beneficially. This might lead to norm...

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Section: Discussioncontrasting

confidence: 56%

A perinatal nitric oxide donor increases renal vascular resistance and ameliorates hypertension and glomerular injury in adult fawn-hooded hypertensive rats

Koeners¹,

Braam²,

Giezen³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…11 Perinatal vitamin C and vitamin E alone had no persistent antihypertensive effects. 20 Our new data suggest that, because reduced expression of the renal cationic amino acid transporter could have limited the effect of L-arginine supplements in our previous study, antioxidative effects of taurine could have contributed substantially to the persistent effects. 11 Offspring of rat dams exposed to food restriction during pregnancy develop mild hypertension, and supplementation of L-arginine after weaning can reduce this blood pressure increase 21 and eventually even protect the kidneys.…”

Section: Discussionmentioning

confidence: 98%

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

et al. 2007

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Abstract-NO deficiency is associated with development of hypertension. Defects in the renal citrulline-arginine pathway or arginine reabsorption potentially reduce renal NO in prehypertensive spontaneously hypertensive rats (SHRs). Hence, we investigated genes related to the citrulline-arginine pathway or arginine reabsorption, amino acid pools, and renal NO in 2-week-old prehypertensive SHRs. In addition, because perinatally supporting NO availability reduces blood pressure in SHRs, we supplemented SHR dams during pregnancy and lactation with citrulline, the rate-limiting amino acid for arginine synthesis. In female offspring, gene expression of argininosuccinate synthase (involved in renal arginine synthesis) and renal cationic amino acid Y-transporter (involved in arginine reabsorption) were both decreased in 2-day and 2-week SHRs compared with normotensive WKY, although no abnormalities in amino acid pools were observed. In addition, 2-week-old female SHRs had much less NO in their kidneys (0.46Ϯ0.01 versus 0.68Ϯ0.05 nmol/g of kidney weight, respectively; PϽ0.001) but not in their heart. Furthermore, perinatal supplementation with citrulline increased renal NO to 0.59Ϯ0.02 nmol/g of kidney weight (PϽ0.001) at 2 weeks and persistently ameliorated the development of hypertension in females and until 20 weeks in male SHR offspring. Defects in both the renal citrulline-arginine pathway and in arginine reabsorption precede hypertension in SHRs. We propose that the reduced cationic amino acid transporter disables the developing SHR kidney to use arginine reabsorption to compensate for reduced arginine synthesis, resulting in organ-specific NO deficiency. This early renal deficiency and its adverse sequels can be corrected by perinatal citrulline supplementation persistently in female and transiently in male SHRs. Key Words: NO Ⅲ amino acids Ⅲ hypertension Ⅲ developmental plasticity Ⅲ electron paramagnetic resonance Ⅲ citrulline H ypertension is associated with oxidative stress, often caused by a self-perpetuating cycle of NO deficiency, increased reactive oxygen species, and a disturbed constrictor-dilator balance in the kidney. 1 Inhibition of NO synthase (NOS) causes marked and persistent hypertension. [2][3][4] Therefore, an impairment of the NO-generating pathway could be involved in the onset of hereditary hypertension. It is even conceivable that a reduction in renal NO precedes hypertension.There are multiple causes of a reduced or deficient NO generation in the prehypertensive kidney. Among others, these are reduced availability of NOS or the NOS substrate L-arginine. In this regard, Vaziri et al 5 reported an abundance of NOS isoforms in kidneys of juvenile spontaneously hypertensive rats (SHRs). Using microarray methodology, we identified a reduction in the expression of argininosuccinate synthase (ASS) and the arginine transporter slc7a7 in kidneys of young SHRs. This led us to investigate the challenging issue of whether NO deficiency precedes hypertension because of reduced arginine availability in SH...

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“…Increased oxidative stress in hypertension promotes inflammation, vascular smooth muscle cell proliferation, and hypertrophy; impairs endothelium-dependent relaxation; and increases constrictive response to vasoactive agents [11,19,31]. Despite its genetic etiology, essential hypertension also results from adverse environmental factors, especially in the perinatal period [7,14,24,25,33]. The "programming hypothesis" proposes that adverse influences acting early in life, in particular in the intrauterine and postnatal period, leads to hypertension in adult life [1,10,17].…”

Section: Discussionmentioning

confidence: 99%

“…Studies of NO production are controversial, but it is generally accepted that NO bioavailability is decreased in SHR, possibly as a result of its inactivation by superoxide anions (O À 2 ) [12,13,27]. Despite the genetic predisposition, this imbalance during pregnancy and lactation also seems to play a role in the development of hypertension in SHR [14,24,25,33]. Racasan et al [24] have demonstrated that SHR offspring from L-arginine-and antioxidantssupplemented SHR dams had persistent lower blood pressure until 12 months of age.…”

Section: Introductionmentioning

confidence: 96%

Perinatal l-arginine and antioxidant supplements reduce adult blood pressure but not ameliorate the altered vascular function in spontaneously hypertensive rats

et al. 2010

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Spontaneously hypertensive rat (SHR) offspring from L-arginine- and antioxidant-supplemented SHR dams had persistent lower blood pressure in adulthood. We investigated the influence of vascular mechanism in this effect. We analyzed response to acetylcholine and phenylephrine in aorta and superior mesenteric arteries from Wistar-Kyoto (WKY), SHR, and SHR perinatally supplemented with L-arginine and 4-hydroxy-2,2,6,6-tetramethylpiperidinoxyl (TEMPOL; SHR-suppl). Supplements reduced blood pressure persistently in SHR. Relaxation to acetylcholine was greater in WKY than SHR and remained unmodified in SHR-suppl compared with SHR. Acute TEMPOL did not alter relaxation to acetylcholine in WKY but increased it similarly in SHR and SHR-suppl. Phenylephrine contraction was increased in SHR compared to WKY. In SHR-suppl, this response was similar to SHR. Endothelium removal or N-nitro-L-arginine methyl ester (L-NAME) increased contraction to phenylephrine more in WKY than SHR. In SHR-suppl, this was similar to SHR. In both SHR and SHR-suppl, TEMPOL similarly reduced phenylephrine response. This effect was prevented by L-NAME. Results exposed reinforce the concept that oxidative stress during perinatal period is a contributing factor to the development of hypertension in SHR. Results also reveal that the beneficial effect of this supplementation does not appear to be related to improved endothelial function, suggesting that other regulatory mechanisms of blood pressure may be involved.

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Nitric oxide, superoxide and renal blood flow autoregulation in SHR after perinatal L‐arginine and antioxidants

Cited by 27 publications

References 28 publications

A perinatal nitric oxide donor increases renal vascular resistance and ameliorates hypertension and glomerular injury in adult fawn-hooded hypertensive rats

A perinatal nitric oxide donor increases renal vascular resistance and ameliorates hypertension and glomerular injury in adult fawn-hooded hypertensive rats

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

Perinatal l-arginine and antioxidant supplements reduce adult blood pressure but not ameliorate the altered vascular function in spontaneously hypertensive rats

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