Systemic Hemodynamics and Regional Blood Flow During Chronic Nitric Oxide Synthesis Inhibition in Pregnant Rats

Kassab, Salah; Miller, M. Todd; Hester, Robert L.; Novak, Jacqueline; Granger, J. P.

doi:10.1161/01.hyp.31.1.315

Cited by 68 publications

(53 citation statements)

References 27 publications

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“…The growth inhibition of L-NAME in the renal sub-capsular assay may be partially due to a decrease in renal blood flow. Kassab et al (1998) previously demonstrated a decreased renal blood flow after administration of NO inhibitors, which is confirmed in our study by elevated creatinine and urea levels. Therefore, conclusions concerning anti-tumour effect of NO inhibitors from the data obtained in the renal sub-capsular assay cannot be drawn, but these data strongly suggest a growth inhibitory effect on the tumour by NO inhibitors.…”

Section: Discussionsupporting

confidence: 91%

Nitric oxide synthase inhibition results in synergistic anti-tumour activity with melphalan and tumour necrosis factor alpha-based isolated limb perfusions

et al. 2000

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Nitric oxide (NO) is an important molecule in regulating tumour blood flow and stimulating tumour angiogenesis. Inhibition of NO synthase by L-NAME might induce an anti-tumour effect by limiting nutrients and oxygen to reach tumour tissue or affecting vascular growth. The anti-tumour effect of L-NAME after systemic administration was studied in a renal subcapsular CC531 adenocarcinoma model in rats. Moreover, regional administration of L-NAME, in combination with TNF and melphalan, was studied in an isolated limb perfusion (ILP) model using BN175 soft-tissue sarcomas. Systemic treatment with L-NAME inhibited growth of adenocarcinoma significantly but was accompanied by impaired renal function. In ILP, reduced tumour growth was observed when L-NAME was used alone. In combination with TNF or melphalan, L-NAME increased response rates significantly compared to perfusions without L-NAME (0–64% and 0–63% respectively). An additional anti-tumour effect was demonstrated when L-NAME was added to the synergistic combination of melphalan and TNF (responses increased from 70 to 100%). Inhibition of NO synthase reduces tumour growth both after systemic and regional (ILP) treatment. A synergistic anti-tumour effect of L-NAME is observed in combination with melphalan and/or TNF using ILP. These results indicate a possible role of L-NAME for the treatment of solid tumours in a systemic or regional setting. © 2000 Cancer Research Campaign

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Section: Discussionsupporting

confidence: 91%

Nitric oxide synthase inhibition results in synergistic anti-tumour activity with melphalan and tumour necrosis factor alpha-based isolated limb perfusions

et al. 2000

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“…[32][33][34] Numerous studies have shown that inhibition of NO production by inhibitors specific for nitric oxide synthase (NOS) during pregnancy in the rat results in marked elevations in arterial pressure, proteinuria, intrauterine growth restriction, and attenuation of the mid-gestational increases in renal vasodilation, all features characteristic of women with preeclampsia. 14,17,18 In addition, reversal of NO-blockade mediated effects in the pregnant rat occur in treatment with L-arginine, the precursor for NO. 16,19 Thus, impairment of the NO pathway may play a role in mediating the pathophysiology of preeclampsia.…”

Section: Discussionmentioning

confidence: 99%

l -Arginine Attenuates Hypertension in Pregnant Rats With Reduced Uterine Perfusion Pressure

et al. 2004

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Abstract-A chronic reduction in uterine perfusion pressure in the pregnant rat is associated with significant elevations in mean arterial pressure, proteinuria, and reductions in kidney function as is chronic nitric oxide blockade, suggesting that nitric oxide deficiency may contribute to the clinical manifestations of preeclampsia. The purpose of this study was to determine whether supplementation with L-arginine, the precursor for nitric oxide, attenuates the hypertension produced in response to a chronic reduction in uterine perfusion pressure in the pregnant rat. Reduced uterine perfusion was initiated at day 14 of gestation with arterial pressure determined at day 19 of gestation in conscious, chronically instrumented rats. Arterial pressure was significantly elevated in pregnant rats with chronic reductions in uterine perfusion as compared with pregnant control rats (132Ϯ2 versus 109Ϯ2 mm Hg, PϽ0.01, respectively). Treatment with L-arginine (2%) in the drinking water was initiated at day 10 of gestation. L-arginine supplementation resulted in a significant decrease in arterial pressure in both pregnant rats with reduced uterine perfusion pressure (113Ϯ2 Key Words: arginine Ⅲ arterial pressure Ⅲ hypertension, pregnancy Ⅲ nitric oxide Ⅲ preeclampsia P reeclampsia, a major cause of maternal and fetal morbidity and mortality, is estimated to affect 5% to 10% of all pregnancies in the United States. 1,2 Symptoms generally associated with preeclampsia include increased responsiveness to vasoconstrictors, elevations in arterial pressure, proteinuria, reduced glomerular filtration rate (GFR), and intrauterine growth restriction. 1,2 The initiating event in preeclampsia is suggested to involve reduced placental perfusion leading to maternal endothelial cell dysfunction. 1,3-5 A role for endothelial dysfunction in the pathophysiology of preeclampsia is implicated, as this pregnancy-specific disorder is associated with reduced synthesis of vasodilators and increased production of vasoconstrictors. [5][6][7][8][9] Numerous studies indicate that nitric oxide (NO) production is elevated in normal pregnancy. 6,10 In the rat, plasma and urinary levels of cGMP, a second messenger of NO, and levels of urinary nitrite/nitrate, metabolites of NO and indicators of whole body NO production, are increased during pregnancy. 10 -12 In addition, renal protein expression of inducible and neuronal nitric oxide synthase (iNOS and nNOS, respectively) are increased by 31% and 25%, respectively, in the rat at mid-gestation. 11 Further studies have demonstrated that NO plays an important role in mediating systemic hemodynamics and renal vasodilation during pregnancy. 6,10 -15 Chronic NO synthesis inhibition in the pregnant rat is associated with marked elevations in arterial pressure, reductions in GFR, proteinuria, and intrauterine growth restriction, many of the features observed in women with preeclampsia. 14,16 -18 Furthermore, these NO blockade-mediated effects are reversible by administration of L-arginine. 16,19 We have previo...

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“…All dams in both groups littered spontaneously between day 22 and day 23 of gestation; mean duration of pregnancy was similar in the two groups [ 8 -18) in the L-NAME group and 15 Ϯ 1.5 (range, [12][13][14][15][16][17] in the control group; p Ͼ 0.05]. The day of birth was defined as postnatal day 0.…”

Section: Methodsmentioning

confidence: 99%

Effect of Nω-Nitro-l-Arginine Methyl Ester–Induced Intrauterine Growth Restriction on Postnatal Lung Growth in Rats

2005

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Infants with intrauterine growth restriction (IUGR) are at high risk for morbidity and mortality. Preeclampsia, one of the leading causes of IUGR, begins during the canalicular phase of lung development. The aim of our study was to determine whether induced IUGR was responsible for abnormal lung development in rat pups. We randomized pregnant Sprague-Dawley rats to daily gavage with either the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME; n ϭ 5, 50 mg · kg Ϫ1 · dϪ1 ) or pure water (n ϭ 6). The pups were weighed at birth and on postnatal days 7 and 14. At each of these time points, pups were killed and their lung growth was assessed on the basis of lung volume and light-microscopy morphometric data. At birth, body weight, total alveolar surface area, and alveolar surface density were significantly decreased and alveolar size was significantly increased in the L-NAME group, compared with the control group. On day 7, body weight was similar in the two groups, and the only significant difference was smaller total alveolar surface area in the L-NAME group. On day 14, neither body weight nor lung morphometric parameters were significantly different between the L-NAME group and the controls. These results suggest that postnatal catch-up growth may completely correct the lung development disorders present at birth in IUGR pups, in parallel with the catch-up body weight gain. Studies have established that intrauterine growth restriction (IUGR) is correlated with increased morbidity and mortality (1-3). Despite the huge strides made in neonatal medicine over the past 15 y, the risk for respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis, as well as length of stay and hospital costs, remain higher in growth-restricted newborns (3). Importantly, the adverse effects of IUGR are long lasting, one of the most common long-term consequences being respiratory disease (4 -7).Preeclampsia is among the leading causes of IUGR. The placental vascular abnormalities associated with preeclampsia impair maternofetal exchanges, thereby restricting fetal growth (8). Impairments in maternofetal exchanges begin during the third trimester of pregnancy, during which lung development is at the canalicular phase, characterized by formation of the distal airways, blood vessels, and alveolar-capillary barrier (9).Although the pathophysiology of preeclampsia remains unclear, experimental evidence points to a key role for nitric oxide (NO) (10 -13). NO synthase (NOS) inhibition during the last third of pregnancy in rats was followed by hypertension and proteinuria in the dams and by IUGR and high fetal mortality in the offspring, a combination that replicated preeclampsia in humans (14 -16). In rats, IUGR induced by NOS inhibition was associated with hindlimb necrosis at birth (17). To our knowledge, the long-term development of the offspring was not documented. These data prompted us to assess whether lung development was impaired in rat pups with IUGR induced by NOS inhibition in the ...

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Systemic Hemodynamics and Regional Blood Flow During Chronic Nitric Oxide Synthesis Inhibition in Pregnant Rats

Cited by 68 publications

References 27 publications

Nitric oxide synthase inhibition results in synergistic anti-tumour activity with melphalan and tumour necrosis factor alpha-based isolated limb perfusions

Nitric oxide synthase inhibition results in synergistic anti-tumour activity with melphalan and tumour necrosis factor alpha-based isolated limb perfusions

l -Arginine Attenuates Hypertension in Pregnant Rats With Reduced Uterine Perfusion Pressure

Effect of Nω-Nitro-l-Arginine Methyl Ester–Induced Intrauterine Growth Restriction on Postnatal Lung Growth in Rats

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