Intrauterine Nitric Oxide Deficiency Weakens Differentiation of Vascular Smooth Muscle in Newborn Rats

Nitric oxide (NO) deficiency during pregnancy is a key reason for preeclampsia development. Besides its important vasomotor role, NO is shown to regulate the cell transcriptome. However, the role of NO in transcriptional regulation of developing smooth muscle has never been studied before. We hypothesized that in early ontogeny, NO is important for the regulation of arterial smooth muscle-specific genes expression. Pregnant rats consumed NO-synthase inhibitor L-NAME (500 mg/L in drinking water) from gestational day 10 till delivery, which led to an increase in blood pressure, a key manifestation of preeclampsia. L-NAME reduced blood concentrations of NO metabolites in dams and their newborn pups, as well as relaxations of pup aortic rings to acetylcholine. Using qPCR, we demonstrated reduced abundances of the smooth muscle-specific myosin heavy chain isoform, α-actin, SM22α, and L-type Ca2+-channel mRNAs in the aorta of newborn pups from the L-NAME group compared to control pups. To conclude, the intrauterine NO deficiency weakens gene expression specific for a contractile phenotype of arterial smooth muscle in newborn offspring.

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Nitric oxide hyperpolarizes and relaxes uterine arterial smooth muscle

European Journal of Pharmacology ◽

10.1016/0014-2999(90)94777-u ◽

1990 ◽

Vol 183 (4) ◽

pp. 1608-1609

Author(s):

M. Tare ◽

H.C. Parkington ◽

H.A. Coleman ◽

T.O. Neild ◽

G.J. Dusting

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Arterial Smooth Muscle

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Hyperpolarization and relaxation of arterial smooth muscle caused by nitric oxide derived from the endothelium

Nature ◽

10.1038/346069a0 ◽

1990 ◽

Vol 346 (6279) ◽

pp. 69-71 ◽

Cited By ~ 294

Author(s):

M. Tare ◽

H. C. Parkington ◽

H. A. Coleman ◽

T. O. Neild ◽

G. J. Dusting

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Arterial Smooth Muscle

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Stimulation of nitric oxide from muscle cells by VIP: prejunctional enhancement of VIP release

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1992.262.4.g774 ◽

1992 ◽

Vol 262 (4) ◽

pp. G774-G778 ◽

Cited By ~ 18

Author(s):

J. R. Grider ◽

K. S. Murthy ◽

J. G. Jin ◽

G. M. Makhlouf

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Muscle Cells ◽

No Synthase ◽

No Production ◽

Field Stimulation ◽

Relaxant Effect ◽

Gastric Muscle ◽

Synthase Inhibitor ◽

Stimulation Of

The source of nitric oxide (NO) and its role in neurally induced relaxation was examined in smooth muscle of the stomach and tenia coli. Field stimulation of gastric muscle strips was accompanied by frequency-dependent relaxation, vasoactive intestinal peptide (VIP) release, and NO production: the NO synthase inhibitor, NG-nitro-L-arginine (L-NNA) completely inhibited NO production and partly inhibited VIP release (52-54%) and relaxation (58-88%); inhibition of all three functions was reversed by L-arginine but not by D-arginine. In isolated gastric muscle cells, VIP caused relaxation and stimulated NO production: L-NNA completely inhibited NO production and partly inhibited relaxation; the inhibition was reversed by L-arginine but not by D-arginine. Abolition of NO production with only partial inhibition of relaxation implied that NO production from muscle cells induced by the action of VIP was partly responsible for relaxation. By contrast, field stimulation of tenia coli was accompanied by relaxation and VIP release but not by NO production. Neither VIP release nor relaxation was affected by L-NNA. In isolated muscle cells of tenia coli, VIP caused relaxation but did not stimulate NO production; relaxation in these cells was not affected by L-NNA. We conclude that 1) VIP is the primary relaxant transmitter in both gastric muscle and tenia coli, 2) the release of VIP in gastric muscle but not in tenia coli stimulates NO production from target muscle cells, and 3) NO amplifies the relaxant effect of VIP in muscle cells and acts presynaptically to enhance the release of VIP.

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Enhancement of myofilament calcium sensitivity by acute hypoxia in rat distal pulmonary arteries

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00068.2011 ◽

2011 ◽

Vol 301 (3) ◽

pp. L380-L387 ◽

Cited By ~ 9

Author(s):

Letitia Weigand ◽

Larissa A. Shimoda ◽

J. T. Sylvester

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Acute Hypoxia ◽

Rho Kinase ◽

Mesenteric Arteries ◽

Arterial Smooth Muscle ◽

Force Relation ◽

Endothelial Denudation ◽

Pulmonary Arterial ◽

Pulmonary Arterial Smooth Muscle

Hypoxic contraction of pulmonary arterial smooth muscle is thought to require increases in both intracellular Ca2+ concentration ([Ca2+]i) and myofilament Ca2+ sensitivity, which may or may not be endothelium-dependent. To examine the effects of hypoxia and endothelium on Ca2+ sensitivity in pulmonary arterial smooth muscle, we measured the relation between [Ca2+]i and isometric force at 37°C during normoxia (21% O2-5% CO2) and after 30 min of hypoxia (1% O2-5% CO2) in endothelium-intact (E+) and -denuded (E−) rat distal intrapulmonary arteries (IPA) permeabilized with staphylococcal α-toxin. Endothelial denudation enhanced Ca2+ sensitivity during normoxia but did not alter the effects of hypoxia, which shifted the [Ca2+]i-force relation to higher force in E+ and E− IPA. Neither hypoxia nor endothelial denudation altered Ca2+ sensitivity in mesenteric arteries. In E+ and E− IPA, hypoxic enhancement of Ca2+ sensitivity was abolished by the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (30 μM), which shifted normoxic [Ca2+]i-force relations to higher force. In E− IPA, the Rho kinase antagonist Y-27632 (10 μM) shifted the normoxic [Ca2+]i-force relation to lower force but did not alter the effects of hypoxia. These results suggest that acute hypoxia enhanced myofilament Ca2+ sensitivity in rat IPA by decreasing nitric oxide production and/or activity in smooth muscle, thereby revealing a high basal level of Ca2+ sensitivity, due in part to Rho kinase, which otherwise did not contribute to Ca2+ sensitization by hypoxia.

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Anticancer Effect of in Vivo Inhibition of Nitric Oxide Synthase in a Rat Model of Breast Cancer

10.21203/rs.3.rs-1180489/v1 ◽

2021 ◽

Author(s):

Nikolay Avtandilyan ◽

Hayarpi Javrushyan ◽

Mikayel Ginovyan ◽

Anna Karapetyan ◽

Armen Trchounian

Keyword(s):

Breast Cancer ◽

Nitric Oxide ◽

Cancer Treatment ◽

No Synthase ◽

Antitumor Effects ◽

Blood Concentrations ◽

Anti Cancer ◽

Cancer Agent ◽

Synthase Inhibitor

Abstract High expression of nitric oxide (NO)-synthase has been found in different cancers like cervical, breast, and central nervous system. NO-synthase activity inhibition has been suggested as a possible tool to prevent breast cancer. The anti-tumor therapeutic effect of L-nitro arginine methyl ester (L-NAME) in vivo remains understudied. Here we hypothesized that NOS inhibition by L-NAME has some antitumor effects on breast cancer development as it inhibits NO levels, which is a pathophysiological modulator of cell proliferation, cell cycle arrest, apoptosis, and angiogenesis. We utilized a novel anti-cancer treatment model by the administration of NO-synthase inhibitor L-NAME (30 mg/kg in a day, intraperitoneal), injected every third day for five weeks (in parallel to tumors evolution) in opposition to high activity of NOS during 7,12-dimethylbenz[a]anthracene-induced breast tumor in rats in vivo. The blood concentrations of nitrite anions, polyamines, malondialdehyde, NH4+ levels, and arginase activity decreased in DMBA+L-NAME-treated rats compared with DMBA rats. The reduction of these compounds also affects the decrease of the mortality rate of rats, tumor number, weight and volume, and the histopathological grade of breast cancer. Treatment with L-NAME showed increases in time of tumor incidence and body weight compared with DMBA-cancer rats. Therefore, the co-administration of L-NAME influences as a potent anti-cancer agent to treat breast cancer and can lead to the development of therapeutic methods for cancers in the future.

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Tnfα-Induced Hypertension in Pregnant Rats Is Associated with Increased [Ca 2+ ] I Signaling in Renal Arterial Smooth Muscle

Hypertension ◽

10.1161/hyp.36.suppl_1.688-e ◽

2000 ◽

Vol 36 (suppl_1) ◽

pp. 688-688

Author(s):

Zohreh N Sirous ◽

Kathy L Cockrell ◽

Barbara T Alexander ◽

Joey P Grnager ◽

Raouf A Khalil

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Resistance ◽

Muscle Cells ◽

Sprague Dawley ◽

Cell Contraction ◽

Arterial Smooth Muscle ◽

Smooth Muscle Contractility ◽

Pregnant Rats ◽

Induced Hypertension

61 Placental ischemia during late pregnancy triggers the release of tumor necrosis factor α (TNFα), which may contribute to the increased vascular resistance associated with pregnancy-induced hypertension (PIH). We have reported that elevation of plasma TNFα 2-fold increases blood pressure and renal vascular resistance in pregnant rats; however, the cellular mechanisms involved are unclear. In this study, we investigated whether TNFα infusion in pregnant rats (10 ng/kg/day for 7 days) is associated with increases in [Ca 2+ ] i and contractility of renal arterial smooth muscle. Pregnant (MAP = 96±3mmHg), TNFα-infused pregnant (123±3mmHg), virgin (108±5mmHg) and TNFα-infused virgin (110±3mmHg) Sprague-Dawley rats were used. Single smooth muscle cells were freshly isolated from the renal interlobular arteries and loaded with fura-2. In cells of pregnant rats incubated in Hank’s solution (1 mM Ca 2+ ), the resting length was 74±6 μm and [Ca 2+ ] i was 82±4 nM. In TNFα-infused pregnant rats, the resting cell length was shorter (54±3 μm) and [Ca 2+ ] i was higher (119±4 nM) than pregnant rats. In pregnant rats, angiotensin II (AII, 10 -7 M) caused a transient increase in [Ca 2+ ] i to 372±9 nM, a maintained increase to 149±8 nM and 21±2% cell contraction. The Ca 2+ channel agonist BAY K8644 (10 -6 M) caused an increase in [Ca 2+ ] i to 249±11 nM and 18±2% cell contraction. In TNFα-infused pregnant rats, the maintained AII- and BAY K8644-induced [Ca 2+ ] i (186±4 and 307±6 nM) and cell contraction (29±3% and 27±3%) were significantly > pregnant rats. AII and BAY K8644-induced contraction and [Ca 2+ ] i were not significantly different between untreated and TNFα-infused virgin rats. In Ca 2+ -free Hank’s, AII and caffeine (10 mM)-induced [Ca 2+ ] i transient and cell contraction were not significantly different in different groups of rats. Thus, TNFα-induced hypertension in pregnant rats is associated with increased [Ca 2+ ] i in renal arterial smooth muscle cells due to enhanced Ca 2+ entry from extracellular space. TNFα, via increasing smooth muscle contractility and [Ca 2+ ] i , may represent a possible mediator of the increased vascular resistance associated with PIH.

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