scholarly journals Placental Ischemia Says “NO” to Proper NOS-Mediated Control of Vascular Tone and Blood Pressure in Preeclampsia

2021 ◽  
Vol 22 (20) ◽  
pp. 11261
Author(s):  
Ana C. Palei ◽  
Joey P. Granger ◽  
Frank T. Spradley
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Animal Studies ◽  
Vascular Dysfunction ◽  
Subsequent Development ◽  
Pressure Control ◽  
Normal Pregnancy ◽  
Ischemic Disease ◽  
No Bioavailability ◽  
Nos Isoforms

In this review, we first provide a brief overview of the nitric oxide synthase (NOS) isoforms and biochemistry. This is followed by describing what is known about NOS-mediated blood pressure control during normal pregnancy. Circulating nitric oxide (NO) bioavailability has been assessed by measuring its metabolites, nitrite (NO2) and/or nitrate (NO3), and shown to rise throughout normal pregnancy in humans and rats and decline postpartum. In contrast, placental malperfusion/ischemia leads to systemic reductions in NO bioavailability leading to maternal endothelial and vascular dysfunction with subsequent development of hypertension in PE. We end this article by describing emergent risk factors for placental malperfusion and ischemic disease and discussing strategies to target the NOS system therapeutically to increase NO bioavailability in preeclamptic patients. Throughout this discussion, we highlight the critical importance that experimental animal studies have played in our current understanding of NOS biology in normal pregnancy and their use in finding novel ways to preserve this signaling pathway to prevent the development, treat symptoms, or reduce the severity of PE.

scholarly journals Mas Receptor Activation Contributes to the Improvement of Nitric Oxide Bioavailability and Vascular Remodeling During Chronic AT1R (Angiotensin Type-1 Receptor) Blockade in Experimental Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (6) ◽  
pp. 1753-1761
Author(s):  
Carmine Savoia ◽  
Emanuele Arrabito ◽  
Rosa Parente ◽  
Carmine Nicoletti ◽  
Luca Madaro ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Blood Pressure Control ◽  
Pressure Control ◽  
Favorable Effect ◽  
Receptor Blockade ◽  
No Bioavailability ◽  
And Function ◽  
Angiotensin Type

Angiotensin (1–7) production increases during AT1R (angiotensin type-1 receptor) blockade. The contribution of Ang (1–7) (angiotensin [1–7]) and its receptor (MasR) to the favorable effect of angiotensin receptor blockers on remodeling and function of resistance arteries remains unclear. We sought to determine whether MasR contributes to the improvement of vascular structure and function during chronic AT1R blockade. Spontaneously hypertensive rats were treated with Ang (1–7) or olmesartan ± MasR antagonist A-779, or vehicle, for 14 days. Blood pressure was measured by tail cuff methodology. Mesenteric arteries were dissected and mounted on a pressurized micromyograph to evaluate media-to-lumen ratio (M/L) and endothelial function. Expression of MasR and eNOS (endothelial nitric oxide synthase) was evaluated by immunoblotting, plasma nitrate by colorimetric assay, and reactive oxygen species production by dihydroethidium staining. Independently of blood pressure, olmesartan significantly reduced M/L and improved NO bioavailability, A-779 prevented these effects. Likewise, Ang (1–7) significantly reduced M/L and NO bioavailability. MasR expression was significantly increased by Ang (1–7) as well as by olmesartan, and it was blunted in the presence of A-779. Both Ang (1–7) and olmesartan increased eNOS expression and plasma nitrite which were reduced by A-779. Superoxide generation was attenuated by olmesartan and Ang (1–7) and was blunted in the presence of A-779. These MasR-mediated actions were independent of AT2R activation since olmesartan and Ang (1–7) increased MasR expression and reduced M/L in Ang II (angiotensin II)–infused AT2R knockout mice, independently of blood pressure control. A-779 prevented these effects. Hence, MasR activation may contribute to the favorable effects of AT1R antagonism on NO bioavailability and microvascular remodeling, independently of AT2R activation and blood pressure control.

Nitric oxide: Its identity and role in blood pressure control

Life Sciences ◽  
1995 ◽  
Vol 57 (17) ◽  
pp. 1547-1556 ◽  
Author(s):  
Shyamal Das ◽  
Keshava N. Kumar
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Blood Pressure Control ◽  
Pressure Control

scholarly journals The Effects of Oral l-Arginine and l-Citrulline Supplementation on Blood Pressure

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1679 ◽  
Author(s):  
David Khalaf ◽  
Marcus Krüger ◽  
Markus Wehland ◽  
Manfred Infanger ◽  
Daniela Grimm
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Animal Studies ◽  
Current Data ◽  
No Production ◽  
First Pass Metabolism ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Antihypertensive Properties ◽  
Pass Metabolism

Nitric oxide (NO) is a well-known vasodilator produced by the vascular endothelium via the enzyme endothelial nitric oxide synthase (eNOS). The inadequate production of NO has been linked to elevated blood pressure (BP) in both human and animal studies, and might be due to substrate inaccessibility. This review aimed to investigate whether oral administration of the amino acids l-arginine (Arg) and l-citrulline (Cit), which are potential substrates for eNOS, could effectively reduce BP by increasing NO production. Both Arg and Cit are effective at increasing plasma Arg. Cit is approximately twice as potent, which is most likely due to a lower first-pass metabolism. The current data suggest that oral Arg supplementation can lower BP by 5.39/2.66 mmHg, which is an effect that is comparable with diet changes and exercise implementation. The antihypertensive properties of Cit are more questionable, but are likely in the range of 4.1/2.08 to 7.54/3.77 mmHg. The exact mechanism by which Cit and Arg exert their effect is not fully understood, as normal plasma Arg concentration greatly exceeds the Michaelis constant (Km) of eNOS. Thus, elevated plasma Arg concentrations would not be expected to increase endogenous NO production significantly, but have nonetheless been observed in other studies. This phenomenon is known as the “l-arginine paradox”.

Vascular dysfunction produced by hyperhomocysteinemia is more severe in the presence of low folate

2006 ◽  
Vol 290 (1) ◽  
pp. H181-H191 ◽  
Author(s):  
J. David Symons ◽  
John C. Rutledge ◽  
U. Simonsen ◽  
Roshny A. Pattathu
Keyword(s):  
Nitric Oxide ◽  
Risk Factors ◽  
Vascular Dysfunction ◽  
Plasma Homocysteine ◽  
No Synthase ◽  
Mesenteric Arteries ◽  
Tension Development ◽  
Dietary Folate ◽  
No Bioavailability ◽  
Liver Folate

Earlier we reported that dietary folate depletion causes hyperhomocysteinemia (HHcy) and arterial dysfunction in rats (Symons JD, Mullick AE, Ensunsa JL, Ma AA, and Rutledge JC. Arterioscler Thromb Vasc Biol 22: 772–780, 2002). Both HHcy and low folate (LF) are risk factors for cardiovascular disease. Therefore, the dysfunction we observed could have resulted from HHcy, LF, and/or their combination (HHcy + LF). We tested the hypothesis that HHcy-induced vascular dysfunction is more severe in the presence of LF. Four groups of rats consumed diets for ∼10 wk that produced plasma homocysteine (μM) and liver folate (μg folate/g liver) concentrations, respectively, of 7 ± 1 and 15 ± 1 (Control; Con; n = 16), 17 ± 2 and 15 ± 2 (HHcy; n = 17), 10 ± 1 and 8 ± 1 (LF; n = 14), and 21 ± 2 and 8 ± 1 (HHcy + LF; n = 18). We observed that maximal ACh-evoked vasorelaxation was greatest in aortas and mesenteric arteries from Con rats vs. all groups. While the extent of dysfunction was similar between LF and HHcy animals, it was less severe compared with arteries from HHcy + LF rats. Maximal ACh-evoked vasorelaxation in coronary arteries was not different between Con and LF rats, but both were greater than HHcy + LF animals. In segments of aortas, 1) ACh-evoked vasorelaxation was similar among groups after incubation with the nonenzymatic intracellular O[Formula: see text] scavenger Tiron, 2) vascular O[Formula: see text] estimated using dihydroethidium staining was greatest in HHcy + LF vs. all groups, and 3) tension development in response to nitric oxide (NO) synthase inhibition was greatest in Con vs. all other groups. We conclude that HHcy + LF evokes greater dysfunction than either HHcy alone (aortas, mesentery) or LF alone (aortas, mesentery, coronary), likely by producing more O[Formula: see text] within the vasculature and thereby reducing NO bioavailability.

Clinical evaluation of nitric oxide responses to anti-VEGF therapy with bevacizumab

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14039-14039 ◽  
Author(s):  
A. Nixon ◽  
J. Allen ◽  
E. Miller ◽  
S. Savage ◽  
N. Kaplan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Brachial Artery ◽  
Exhaled No ◽  
Anti Vegf ◽  
Signed Rank ◽  
Post Infusion ◽  
No Bioavailability ◽  
Pre Treatment ◽  
Hyperemic Flow

14039 Background: Anti-vascular endothelial growth factor (anti-VEGF) therapy has been linked to hypertension (HTN) and arterial thrombo-embolic events that may involve changes in nitric oxide (NO) bioavailability. Methods: 25 patients (pts) with advanced cancer, normal renal function and blood pressure (BP), no increased risks for anti-VEGF toxicities, and not on medications known to confound biomarker studies (including anti-hypertensives) were treated with bevacizumab (BV) 15mg/kg d1, then 10mg/kg q2 week. Prior to biomarker assessment, all patients were placed on a calorie-, nitrate-, and salt-restricted diet for 72 hr. All measures were taken pre-treatment (preRx) and on day 28 of treatment (onRx). Dependant variables included; a) Brachial artery reactivity (BAR) following hyperemic flow stimulus (endothelium-dependent) and sub-lingual nitroglycerine (NTG; endothelium-independent); b) exhaled and plasma/urine total NO2/NO3 using chemiluminescence (Sievers 280NOA) with either KI or VCl3 in HCl as the reductants; c) blood pressure. Additionally, we measured multiple regulators of vascular tone and injury. Comparisons were analyzed using Spearman signed rank tests. Results: Of 25 pts (16 F, 9 M) treated, 21 patients were fully evaluable. Significant changes or strong trends were observed upon comparing preRx vs. onRx for BP (SBP +12.4, DBP +5.6, MAP +7.9 mm Hg), and flow-mediated BAR (-2.0%) with no changes in hyperemic flow/shear stimulus or smooth muscle function (BAR NTG), indicating a decrease in brachial artery endothelial responsiveness. Exhaled NO decreased (-0.8% d1vs d28 and -0.6% pre/post infusion day1). Measurement and data analysis of urinary/plasma NO2/NO3, as well as angiogenic markers, are almost complete and will be reported. Conclusions: After one month of treatment, BV increased BP and decreased endothelium- dependent BAR and exhaled NO, suggesting potentially broad, mechanism-based effects on NO bioavailability in patients. [Table: see text]

scholarly journals Increase in Bioavailability of Nitric Oxide After Renal Denervation Improves Kidney Function in Sheep With Hypertensive Kidney Disease

Hypertension ◽  
2021 ◽  
Vol 77 (4) ◽  
pp. 1299-1310
Author(s):  
Reetu R. Singh ◽  
Zoe M. McArdle ◽  
Lindsea C. Booth ◽  
Clive N. May ◽  
Geoff A. Head ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Glomerular Filtration Rate ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Kidney Function ◽  
Filtration Rate ◽  
Renal Denervation ◽  
Healthy Sheep ◽  
No Bioavailability

Overactivity of renal sympathetic nerves and nitric oxide (NO) deficiency occur in hypertensive chronic kidney disease (CKD). In sheep with hypertensive CKD and NO deficiency, renal denervation (RDN) reduces blood pressure and improves kidney function (glomerular filtration rate). We hypothesized that this improvement in glomerular filtration rate after RDN is associated with increased NO bioavailability. In this study, glomerular filtration rate response to systemic inhibition of NOS (NO synthase) was examined in healthy and CKD sheep at 2 and 30 months after a sham (intact nerves) or RDN procedure. Basal urinary total nitrate (nitrate+nitrite) excretion was examined at 2 and 30 months, and kidney protein expression of endothelial and neuronal NOS was assessed at 30 months. Urinary nitrate+nitrite in CKD-RDN and healthy sheep was ≈50% to 70% greater than in CKD-intact. During NOS inhibition, the fall in glomerular filtration rate in CKD-RDN sheep was ≈20% greater than in CKD-intact. These effects in CKD-RDN sheep were similar to those in healthy sheep. Endothelial NOS protein expression was lower in CKD-intact sheep compared with healthy sheep and compared with CKD-RDN. In summary, RDN normalizes NO bioavailability and restores contribution of NO to renal hemodynamics in CKD. These changes may promote improvements in kidney function and sustained blood pressure lowering after RDN in hypertensive CKD.

NO production by cNOS and iNOS reflects blood pressure changes in LPS-challenged mice

2003 ◽  
Vol 285 (4) ◽  
pp. E871-E875 ◽  
Author(s):  
Marcella M. Hallemeesch ◽  
Ben J. A. Janssen ◽  
Wouter J. de Jonge ◽  
Peter B. Soeters ◽  
Wouter H. Lamers ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Blood Pressure Response ◽  
No Production ◽  
Baseline Conditions ◽  
Pressure Changes ◽  
Oxide Synthase ◽  
Nos Isoforms ◽  
Firm Evidence ◽  
Lps Treatment

Increased nitric oxide (NO) production is the cause of hypotension and shock during sepsis. In the present experiments, we have measured the contribution of endothelial (e) and inducible (i) nitric oxide synthase (NOS) to systemic NO production in mice under baseline conditions and upon LPS treatment (100 μg/10 g ip LPS). NO synthesis was measured by the rate of conversion of l-[ guanidino-15N2]arginine to l-[ ureido-15N]citrulline, and the contribution of the specific NOS isoforms was evaluated by comparing NO production in eNOS-deficient [(–/–)] and iNOS(–/–) mice with that in wild-type (WT) mice. Under baseline conditions, NO production was similar in WT and iNOS(–/–) mice but lower in eNOS(–/–) mice [WT: 1.2 ± 0.2; iNOS(–/–): 1.2 ± 0.2; eNOS(–/–): 0.6 ± 0.3 nmol · 10 g body wt–1· min–1]. In response to the challenge with LPS (5 h), systemic NO production increased in WT and eNOS(–/–) mice but fell in iNOS(–/–) mice [WT: 2.7 ± 0.3; eNOS(–/–): 2.2 ± 0.6; iNOS(–/–): 0.7 ± 0.1 nmol · 10 g body wt–1· min–1]. After 5 h of LPS treatment, blood pressure had dropped 14 mmHg in WT but not in iNOS(–/–) mice. The present findings provide firm evidence that, upon treatment with bacterial LPS, the increase of NO production is solely dependent on iNOS, whereas that mediated by cNOS is reduced. Furthermore, the data show that the LPS-induced blood pressure response is dependent on iNOS.

Effect of systemic nitric oxide synthase inhibition on postexercise hypotension in humans

2000 ◽  
Vol 89 (5) ◽  
pp. 1830-1836 ◽  
Author(s):  
John R. Halliwill ◽  
Christopher T. Minson ◽  
Michael J. Joyner
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Nitric Oxide Synthase ◽  
Arterial Pressure ◽  
Animal Studies ◽  
Adrenergic Blockade ◽  
Regional Hemodynamics ◽  
Postexercise Hypotension ◽  
Peak Aerobic Capacity ◽  
Oxide Synthase

An acute bout of aerobic exercise results in a reduced blood pressure that lasts several hours. Animal studies suggest this response is mediated by increased production of nitric oxide. We tested the extent to which systemic nitric oxide synthase inhibition [ N G-monomethyl-l-arginine (l-NMMA)] can reverse the drop in blood pressure that occurs after exercise in humans. Eight healthy subjects underwent parallel experiments on 2 separate days. The order of the experiments was randomized between sham (60 min of seated upright rest) and exercise (60 min of upright cycling at 60% peak aerobic capacity). After both sham and exercise, subjects received, in sequence, systemic α-adrenergic blockade (phentolamine) and l-NMMA. Phentolamine was given first to isolate the contribution of nitric oxide to postexercise hypotension by preventing reflex changes in sympathetic tone that result from systemic nitric oxide synthase inhibition and to control for alterations in resting sympathetic activity after exercise. During each condition, systemic and regional hemodynamics were measured. Throughout the study, arterial pressure and vascular resistances remained lower postexercise vs. postsham despite nitric oxide synthase inhibition (e.g., mean arterial pressure afterl-NMMA was 108.0 ± 2.4 mmHg postsham vs. 102.1 ± 3.3 mmHg postexercise; P < 0.05). Thus it does not appear that postexercise hypotension is dependent on increased production of nitric oxide in humans.

Abstract 037: Exaggerated Placental Ischemia-induced Hypertension in Endothelin Receptor Type B (ETB)-deficient Pregnant Rats s Independent of Increased sFlt-1 or ROS Levels

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Frank T Spradley
Keyword(s):  
Blood Pressure ◽  
Acute Hypoxia ◽  
Pressure Control ◽  
Normal Pregnancy ◽  
Endothelin Receptor ◽  
Maternal Circulation ◽  
Pregnant Rats ◽  
Uterine Perfusion ◽  
Placental Ischemia ◽  
In Pregnancy

While the pathogenesis of preeclampsia is not fully understood, studies implicate placental ischemia. Reduced uterine perfusion pressure (RUPP)-induced placental ischemia/hypoxia in animal models stimulates release of factors like antiangiogenic sFlt-1 into the maternal circulation increasing vascular-renal ET-1. ET-1 promotes hypertension via reactive oxygen species (ROS). Blockade of vasoconstrictive ETA abolishes RUPP hypertension. Deficiency of vasodilatory ETB in rats leads to increased blood pressure in pregnancy. While ETB deficiency markedly enhances RUPP hypertension, it is unknown if there is exaggerated RUPP-induced sFlt-1, ET-1 or ROS levels in ETB-def rats. The hypothesis was tested that placental ischemia/hypoxia-induced release of sFlt-1 and circulating ET-1 and ROS are greater in ETB-def rats. Eighteen-week-old ETB-def and transgenic (Tg) control pregnant rats were generated with Wistar Hannover males. RUPP or Sham surgeries were on gestational day 14 and assessment of plasmas and placentas at day 19. RUPP increased placental sFlt-1 (pg/mg) similarly in RUPP ETB-def (781±113, N=5) vs Sham ETB-def (573±54, N=12) and RUPP Tg (631±62, N=5) vs Sham Tg (547±31, N=12) (P<0.05). In placental explant cultures, acute hypoxia (48 h 1% O2 vs normoxia 6% O2) stimulated a comparable release of sFlt-1 (pg/mg) in Sham ETB-def (2577±135 vs 2070±78) and Sham Tg (3208±318 vs 2553±107) (P<0.05). Unexpectedly, plasma sFlt-1 (pg/mL) was lower in RUPP ETB-def (153±48) vs Sham ETB-def (476±125) and RUPP Tg (238±32) vs Sham Tg (463±102) (P<0.05). Plasma ET-1 (fmol/L) was exaggerated in RUPP ETB-def (954±70) and greater in Sham ETB-def (735±43) vs RUPP Tg (122±14) or Sham Tg (142±41) (P<0.05). Plasma H2O2 (umol/L) was not exaggerated in RUPP ETB-def (5.4±1.2) or RUPP Tg (4.0±0.5) but was greater (P<0.05) in Sham ETB-def (6.2±0.3) vs Sham Tg (3.6±0.3). In conclusion, these data suggest in 1) normal pregnancy, ETB is crucial for blood pressure control by regulating bioavailable ET-1 to prevent ROS production and 2) placental ischemia, ETB reduces excess ET-1 to buffer hypertension independently of sFlt-1 or ROS. These data support ETB physiology as important in controlling blood pressure in pregnancy and its loss in mediating hypertension in preeclampsia.

Sign in / Sign up

Export Citation Format

Share Document