Prolonged blockade of nitric oxide synthesis in gravid rats produces sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth retardation

Molnár, Miklós; Sütö, Tamás; Tóth, Tibor; Hertelendy, F.

doi:10.1016/s0002-9378(94)70179-2

Cited by 254 publications

(134 citation statements)

References 27 publications

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“…This L-NAME concentration resulted in a daily intake of approximately 1 mg/d. This dose of L-NAME was chosen based on studies of Molnar and coworkers 21 that showed that a dose of approximately 1 mg/d resulted in significant elevation of blood pressure in pregnant rats while having minimal effect in virgin rats. The L-NAME-treated rats were allowed to drink the water containing L-NAME for 4 to 6 days before blood pressure measurements were taken or excision of the aorta.…”

Section: Drugs and Chemicalsmentioning

confidence: 99%

Enhanced Vascular Reactivity During Inhibition of Nitric Oxide Synthesis in Pregnant Rats

et al. 1998

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Abstract-Pregnancy-induced hypertension has been suggested to be mediated by several mechanisms, including reduced nitric oxide (NO) synthesis. In this study, the effects of chronic treatment with the NO synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME) on blood pressure and the underlying changes in vascular reactivity were investigated in virgin and late-pregnancy Sprague-Dawley rats. The systolic blood pressure was 120Ϯ2, 124Ϯ5, 116Ϯ4, and 171Ϯ5 mm Hg in untreated virgin, virgin treated with L-NAME, untreated pregnant, and pregnant treated with L-NAME rats, respectively. The rats were killed, and the thoracic aorta was cut into strips for measurement of active stress in response to ␣ 1 -adrenergic stimulation with phenylephrine and membrane depolarization by high KCl. In pregnant rats, the maximal active stress to phenylephrine (0.31Ϯ0.03ϫ104 N/m 2 ) and the high-KCl-induced active stress (0.55Ϯ0.09ϫ10 4 N/m 2 ) were smaller than those in virgin rats. By contrast, in the L-NAME-treated pregnant rats, the maximal phenylephrine-induced active stress (0. 76Ϯ0.1ϫ10 4 N/m 2 ) was greater than that in virgin rats (0.52Ϯ0.1ϫ10 4 N/m 2 ), whereas the high-KCl-induced active stress (1.08Ϯ0.14ϫ10 4 N/m 2 ) was indistinguishable from that in virgin rats (1. 03Ϯ0.14ϫ10 4 N/m 2 ). Treatment with L-NAME did not affect the phenylephrine-releasable Ca 2ϩ stores in pregnant rats and had minimal effect on active stress in virgin rats. Thus, reduction of NO synthesis during late pregnancy is associated with a significant increase in blood pressure and vascular responsiveness to ␣-adrenergic stimulation, which can possibly be explained in part by enhanced Ca 2ϩ entry from extracellular space. However, other mechanisms such as increased myofilament force sensitivity to Ca 2ϩ and/or activation of a completely Ca 2ϩ -independent mechanism cannot be excluded. (Hypertension. 1998;31:1065-1069.) Key Words: blood pressure Ⅲ calcium Ⅲ muscle, smooth Ⅲ contraction N ormal pregnancy is associated with many hemodynamic changes such as increased heart rate and cardiac output, 1 increased plasma volume, and an increase in uterine 2-4 and renal blood flow.5 Despite the increase in heart rate, blood volume, and cardiac output, normal pregnancy is usually associated with a significant decrease in arterial blood pressure and total peripheral resistance. 6 This normal pregnancyassociated decrease in peripheral resistance has been explained by several mechanisms, including an increase in the metabolic requirements of both maternal and fetoplacental tissues and/or a decrease in vascular reactivity. 7 Several explanations have been proposed for the decrease in vascular reactivity during normal pregnancy, such as decreased pressor response to vasoconstrictors, 8 -10 specific alterations within the vascular wall, 11 and an increase in nitric oxide (NO) synthesis.12,13 Also, Conrad and Vernier 14 have found that the plasma level, metabolic production, and urinary excretion of cGMP, a second messenger of NO and a cellular mediator of va...

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Section: Drugs and Chemicalsmentioning

confidence: 99%

Enhanced Vascular Reactivity During Inhibition of Nitric Oxide Synthesis in Pregnant Rats

et al. 1998

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“…1 Perturbations of the maternal environment that lead to intrauterine growth retardation (IUGR) can have a marked impact on the grown offspring, including increased cardiovascular risk factors (eg, blood pressure and insulin resistance 1,2 ) and reduced adult life span. 3 A wide range of experimental interventions have been used to provoke developmental programming, including disturbances in maternal nutrition (eg, undernutrition and nutritional imbalances 4 ), restriction of uterine blood flow, 5 and the administration of drugs (eg, glucocorticoids 2 and NO synthase inhibitors 6,7 ).…”

mentioning

confidence: 99%

“…Maternal endothelial NO synthase (eNOS) is a potential candidate in this regard, because eNOS has been shown to play an important role in the regulation of uterine blood flow, 8,9 and IUGR has been observed in rats treated with inhibitors of NO synthase 6,7 and in mice with targeted deletion of the eNOS gene (eNOS Ϫ/Ϫ ) 8,10 . In humans, polymorphisms of the eNOS gene are common and are associated with endothelial dysfunction, [11][12][13] increased uterine artery resistance, 14 and poor pregnancy outcomes.…”

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confidence: 99%

Maternal Endothelial Nitric Oxide Synthase Genotype Influences Offspring Blood Pressure and Activity in Mice

Vliet

Chafe

2007

Hypertension

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Abstract-Deficiencies in maternal endothelial NO synthase (eNOS) have been associated with pregnancy complications, intrauterine growth retardation, and altered vascular function in offspring. In the present study, we investigated the influence of the maternal eNOS genotype on offspring's blood pressure, heart rate, and locomotor activity. The effect of maternal eNOS genotype was made by comparing telemetered blood pressure and activity between 2 groups of 13-to 16-week-old male heterozygous eNOS knockout mice, 1 produced by a cross of eNOS knockout (eNOS Ϫ/Ϫ ) mothers and wild-type (eNOS ϩ/ϩ ) fathers (eNOS ϩ/ϪMAT offspring, Nϭ11), the other by a cross of eNOS ϩ/ϩ mothers and eNOS Ϫ/Ϫ fathers (eNOS ϩ/ϪPAT offspring, Nϭ10). Data were also collected for homozygous eNOS Ϫ/Ϫ and eNOS ϩ/ϩ mice (Nϭ15 each). Heterozygous eNOS knockout mice exhibited blood pressures that were intermediate to the eNOS ϩ/ϩ and eNOS Ϫ/Ϫ groups. Relative to eNOS ϩ/ϪPAT mice, eNOS ϩ/ϪMAT mice exhibited significant increases in nocturnal diastolic arterial pressure and diurnal variations (dark-light difference) in systolic, mean, and diastolic arterial pressure. In addition, indices of spontaneous nocturnal locomotor activity, including both the proportion of time spent active and the intensity of activity when active, were also significantly increased. Heart rate did not differ between the groups. Our results suggest that the maternal eNOS genotype influences both blood pressure and behavior of offspring, possibly as a consequence of developmental programming associated with intrauterine growth retardation. Key Words: experimental hypertension Ⅲ pregnancy Ⅲ developmental programming Ⅲ maternal environment Ⅲ hyperactivity Ⅲ knockout mice Ⅲ telemetry Ⅲ nitric oxide T he characteristics of many physiological systems are influenced by the conditions prevailing during development. 1 Perturbations of the maternal environment that lead to intrauterine growth retardation (IUGR) can have a marked impact on the grown offspring, including increased cardiovascular risk factors (eg, blood pressure and insulin resistance 1,2 ) and reduced adult life span. 3 A wide range of experimental interventions have been used to provoke developmental programming, including disturbances in maternal nutrition (eg, undernutrition and nutritional imbalances 4 ), restriction of uterine blood flow, 5 and the administration of drugs (eg, glucocorticoids 2 and NO synthase inhibitors 6,7 ).A relatively unexplored possibility is that developmental programming could also occur as a consequence of maternal genotype. Maternal endothelial NO synthase (eNOS) is a potential candidate in this regard, because eNOS has been shown to play an important role in the regulation of uterine blood flow, 8,9 and IUGR has been observed in rats treated with inhibitors of NO synthase 6,7 and in mice with targeted deletion of the eNOS gene (eNOS Ϫ/Ϫ ) 8,10 . In humans, polymorphisms of the eNOS gene are common and are associated with endothelial dysfunction, 11-13 increased uterine artery resistan...

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“…This procedure mimics in pregnant rats the classical signs of the pre-eclamptic syndrome, i.e., a progressive increase in total peripheral resistance and in blood pressure (Molnar & Hertelendy, 1992;Yallampalli & Garfield, 1993; this study), a reduction in plasma volume expansion (Salas et al, 1995) and, probably because of a vasoconstriction and a relative ischaemia in the foeto-placental unit, a reduction in placental blood flow (Ramsay et al, 1994) with, as a result, intrauterine growth retardation, increase in foetal reabsorptions, and reductions in litter size and in foetal (and maternal) weight (Yallampalli & Garfield, 1993;Molnar et al, 1994;Salas et al, 1995;this study).…”

Section: Discussionmentioning

confidence: 65%

Lack of beneficial effects of the NO‐donor, molsidomine, in the L‐NAME‐induced pre‐eclamptic syndrome in pregnant rats

Richer¹,

Boulanger²,

Es-Slami³

et al. 1996

British J Pharmacology

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1 In pregnant rats, chronic NO-synthase inhibition induces the development of a pre-eclamptic syndrome, characterized by an increase in maternal blood pressure, a loss of vascular refractoriness to pressor stimuli, a reduction in litter size and a decrease in pups (and maternal) weight. We investigated whether a NO-donor, molsidomine, administered during NO synthase inhibition, could restore a normal pregnancy.2 Pregnant rats were given daily, starting from day 14 of gestation, saline (controls), or L-NAME (50 mg kg-' d-'), or molsidomine (15 or 30 mg kg-' d-'), or the L-NAME + molsidomine combinations. Maternal blood pressure and body weight, litter size, pups weight and vascular reactivity to pressor stimuli (angiotensin II, noradrenaline, electrical stimulation of the spinal cord) were investigated. 3 L-NAME alone, as compared to controls, increased maternal blood pressure, reduced litter size (-59%), increased foetal reabsorptions (+ 625%) and decreased foetal weight (-10%). Vascular reactivity to pressor stimuli was enhanced. 4 Molsidomine alone, as compared to controls, dose-dependently decreased maternal blood pressure but had no effect on vascular reactivity and, whatever the dose, on foetal outcome. 5 The L-NAME-molsidomine combinations dose (of molsidomine)-dependently limited the rise in maternal blood pressure induced by L-NAME alone but unexpectedly, dose-dependently and significantly worsened pregnancy evolution, e.g., at 30 mg kg-'d-': litter size (-80%), foetal reabsorptions (+ 1025%), foetal weight (-24%). Vascular reactivity to pressor stimuli was paradoxically further enhanced. 6 Thus, in a chronic NO deprivation-induced model of pre-eclampsia in rats, molsidomine, possibly because of its hypotensive action, worsens the foetal outcome, which questions the usefulness of NOdonors in pre-eclamptic women.

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Prolonged blockade of nitric oxide synthesis in gravid rats produces sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth retardation

Cited by 254 publications

References 27 publications

Enhanced Vascular Reactivity During Inhibition of Nitric Oxide Synthesis in Pregnant Rats

Enhanced Vascular Reactivity During Inhibition of Nitric Oxide Synthesis in Pregnant Rats

Maternal Endothelial Nitric Oxide Synthase Genotype Influences Offspring Blood Pressure and Activity in Mice

Lack of beneficial effects of the NO‐donor, molsidomine, in the L‐NAME‐induced pre‐eclamptic syndrome in pregnant rats

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