l-arginine reverses the adverse pregnancy changes induced by nitric oxide synthase inhibition in the rat

Helmbrecht, Gary D.; Farhat, Michel Y.; Lochbaum, L; Brown, Heidi E.; Yadgarova, Klara T.; Eglinton, Gary S.; Ramwell, Peter W.

doi:10.1016/s0002-9378(96)80002-0

Cited by 100 publications

(50 citation statements)

References 17 publications

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“…The decrease in MAP in pregnant rats supplemented with L-arginine was not unexpected, as blockade of NO results in marked elevations in MAP, suggesting a role for this vasodilator in control of arterial pressure during gestation in the rat; [15][16][17][18] an effect that can be reversed by L-arginine. 19 Although L-arginine supplementation resulted in marked decreases in MAP in both pregnant and RUPP subjects, the arterial pressure difference on supplementation with L-arginine was larger in the RUPP rats as compared with pregnant rats. Specifically, a 19 mm Hg difference in arterial pressure was observed between RUPP treated versus RUPP untreated rats as compared with a 12 mm Hg difference in arterial pressure observed between pregnant treated versus pregnant untreated groups.…”

Section: Discussionmentioning

confidence: 93%

“…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%

“…14,16 -18 Furthermore, these NO blockade-mediated effects are reversible by administration of L-arginine. 16,19 We have previously reported that a chronic reduction in uterine perfusion pressure (RUPP) in the pregnant rat results in similar responses, as mid-gestational increases in renal vasodilation and late gestational reductions in blood pressure are attenuated and are associated with variable proteinuria and intrauterine growth restriction. 20 In the RUPP pregnant rat, a significant reduction in renal nNOS protein expression is observed in late gestation as compared with the normal pregnant late-gestational rat.…”

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confidence: 98%

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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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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

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

et al. 2004

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“…Previous research describing blood pressure responses in NO-inhibited animals show hypertension developing 2-3 days following the initiation of L-NAME administration, after which time blood pressures stabilize but then decrease in the last 3-4 days of pregnancy (3,10,23,39,50). We used a higher dose of L-NAME than in previous studies and administered L-NAME via a subcutaneous osmotic pump; mean arterial pressure (MAP) was significantly elevated on day 5 and 10 (days 15 and 20 of pregnancy, respectively) after initiation of L-NAME treatment.…”

Section: Discussionmentioning

confidence: 99%

Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition

Hale

Weger

Mandalà

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Hale SA, Weger L, Mandala M, Osol G. Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition. Am J Physiol Heart Circ Physiol 301: H1266 -H1275, 2011. First published August 19, 2011 doi:10.1152/ajpheart.00519.2011.-Recent findings indicate that endothelial nitric oxide (NO) plays a key role in uterine artery outward circumferential remodeling during pregnancy. Although the underlying mechanisms are not known, they likely involve matrix metalloproteinases (MMPs). The goal of this study was to examine the linkage among NO inhibition, expansive remodeling, and MMP expression within the uterine vascular wall. Adult female rats were treated with N G -nitro-L-arginine methyl ester [L-NAME (LPLN)] beginning on day 10 of pregnancy and until death at day 20 and compared with age-matched controls [late pregnant (LP)]. Mean arterial pressure of LPLN rats was significantly higher than controls. LPLN fetal and placental weights were significantly reduced compared with controls. Main uterine arteries (mUA) were collected to determine dimensional properties (lumen area and wall thickness), collagen and elastin content, and levels of endothelial nitric oxide synthase (eNOS) and MMP expression. Circumferential remodeling was attenuated, as evidenced by significantly smaller lumen diameters. eNOS RNA and protein were significantly (Ͼ90%) decreased in the LPLN mUA compared with LP. Collagen and elastin contents were significantly increased in LPLN rats by ϳ10 and 25%, respectively, compared with LP (P Ͻ 0.05). Both MMP-2 and tissue inhibitors of metalloproteinase-2 as assessed by immunofluorescence were lower in the endothelium (reduction of 60%) and adventitia (reduction of 50%) of LPLN compared with LP mUA. Membrane bound MMP-1 (MT1-MMP) as assessed by immunoblot was significantly decreased in LPLN. These data suggest a novel contribution of MMPs to gestational uterine vascular remodeling and substantiate the linkage between NO signaling and gestational remodeling of the uterine circulation via altered MMP, TIMP-2, and MT1-MMP expression and activity. matrix metalloproteinase; extracellular matrix; hypertension; pregnancy; nitric oxide DURING PREGNANCY, THE UTERINE vasculature undergoes significant expansive remodeling to accommodate the dramatic increase in uteroplacental blood flow that is requisite for normal pregnancy outcome. Studies from our and other laboratories (40,41,44,46,50,61) have established that nitric oxide (NO) is a key molecule involved in vascular remodeling during pregnancy and that expression of endothelial nitric oxide synthase (eNOS) is increased during pregnancy, leading to increased synthesis and release of NO from the endothelium.The importance of NO and NO signaling during pregnancy is underscored by the vascular and reproductive implications evident in mouse knockouts for endothelial NO synthase and in rats treated with the NO inhibitor N G -nitro-L-arginine methyl ester (L-NAME) during pregnancy (50, 64). Tre...

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“…Many subsequent studies confirmed our initial observations. [47][48][49][50][51][52] There was also a report that fetal malformations and IUGR occur in the absence of maternal hypertension during chronic NOS inhibition in the rat. 53 However, these investigators subsequently determined that the fetal malformations (limb reduction) were side effects of the NOS inhibitor used (L-NAME) and that although hypertension was not shown in the acutely prepared state, proteinuria and decreased GFR were consistent with hypertension in conscious, late in pregnancy, NOS-inhibited rats.…”

Section: Chronic Nitric Oxide Synthase Inhibition During Pregnancymentioning

confidence: 99%

Animal models of preeclampsia

Podjarny

Losonczy

Baylis

2004

Seminars in Nephrology

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l-arginine reverses the adverse pregnancy changes induced by nitric oxide synthase inhibition in the rat

Cited by 100 publications

References 17 publications

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

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

Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition

Animal models of preeclampsia

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