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]

Neurogenic-nitric oxide interactions affecting brachial artery mechanics in humans: roles of vessel distensibility vs. diameter

2008 ◽  
Vol 295 (4) ◽  
pp. R1181-R1187 ◽  
Author(s):  
Deborah A. Salzer ◽  
Philip J. Medeiros ◽  
Rosemary Craen ◽  
J. Kevin Shoemaker
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Heart Rate ◽  
Brachial Artery ◽  
Lower Body Negative Pressure ◽  
Cold Pressor ◽  
Sympathetic Outflow ◽  
Sympathetic Activation ◽  
Baseline Diameter ◽  
Conduit Vessel

The purpose of this investigation was to assess the interactive influence of sympathetic activation and supplemental nitric oxide (NO) on brachial artery distensibility vs. its diameter. It was hypothesized that 1) sympathetic activation and NO competitively impact muscular conduit artery (brachial artery) mechanics, and 2) neurogenic constrictor input affects conduit vessel stiffness independently of outright changes in conduit vessel diastolic diameter. Lower body negative pressure (LBNP) and a cold pressor stress (CPT) were used to study the changes in conduit vessel mechanics when the increased sympathetic outflow occurred with and without changes in heart rate (LBNP −40 vs. −15 mmHg) and blood pressure (CPT vs. LBNP). These maneuvers were performed in the absence and presence of nitroglycerin. Neither LBNP nor CPT altered brachial artery diastolic diameter; however, distensibility was reduced by 25 to 54% in each reflex (all P < 0.05). This impact of sympathetic activation on brachial artery distensibility was not altered by nitroglycerin supplementation (21–54%; P < 0.05), although baseline diameter was increased by the exogenous NO ( P < 0.05). The results indicate that sympathetic excitation can reduce the distensibility of the brachial artery independently of concurrent changes in diastolic diameter, heart rate, and blood pressure. However, exogenous NO did not minimize or reverse brachial stiffening during sympathetic activation. Therefore, sympathetic outflow appears to impact the stiffness of this conduit vessel rather than its diastolic diameter or, by inference, its local resistance to flow.

REDUCTION OF CIRCULATING INSULIN LEVELS DURING THE INFUSION OF DIFFERENT PROSTAGLANDINS IN THE RAT

1975 ◽  
Vol 79 (1) ◽  
pp. 266-274 ◽  
Author(s):  
L. Saccà ◽  
G. Perez ◽  
F. Rengo ◽  
I. Pascucci ◽  
M. Condorelli
Keyword(s):  
Blood Pressure ◽  
Arterial Blood Pressure ◽  
Insulin Response ◽  
Inhibitory Effect ◽  
Receptor System ◽  
Insulin Levels ◽  
Arterial Blood ◽  
Post Infusion ◽  
Plasma Insulin Levels ◽  
Pre Treatment

ABSTRACT The intravenous infusion of prostaglandin (PG) E1, E2, and A1 into normal rats at a dose of 2 μg/min significantly lowered plasma insulin levels with a tendency to recovery in the post-infusion period. Whereas PGA1 infusion resulted in a moderate but significant hypoglycaemia, the administration of E-series PGs always produced a hyperglycaemic effect. The interference of PGE1 on insulin response to classical insulinogogues (glucagon, aminophylline, and tolbutamide) was also investigated. The results of these experiments demonstrate that PGE1 exerts an inhibitory action on insulin response to all insulin releasing agents investigated. As regards the haemodynamic effects of PGs, PGE1 and PGE2 lowered the arterial blood pressure by about 20%, while PGA1 was almost completely ineffective. On the other hand, the lowering effect of PGE1 on circulating insulin levels remained unchanged in rats treated with reserpine. These findings thus rule out a sympathetic over-activity secondary to the lowered arterial blood pressure as the mechanism of action of PGE1. A possible direct interference with the adrenergic receptor system of the pancreatic islets was also ruled out since the inhibitory effect of PGE1 was not overcome by phentolamine pre-treatment.

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.

scholarly journals Blood Pressure Regulation in Stress: Focus on Nitric Oxide-Dependent Mechanisms

2016 ◽  
pp. S309-S342 ◽  
Author(s):  
A. PUZSEROVA ◽  
I. BERNATOVA
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Vascular Function ◽  
Malignant Tumors ◽  
Current Knowledge ◽  
Cardiovascular Responses ◽  
Special Focus ◽  
Induced Hypertension ◽  
Neuroendocrine Mechanisms ◽  
No Bioavailability

Stress is considered a risk factor associated with the development of various civilization diseases including cardiovascular diseases, malignant tumors and mental disorders. Research investigating mechanisms involved in stress-induced hypertension have attracted much attention of physicians and researchers, however, there are still ambiguous results concerning a causal relationship between stress and long-term elevation of blood pressure (BP). Several studies have observed that mechanisms involved in the development of stress-induced hypertension include increased activity of sympathetic nervous system (SNS), glucocorticoid (GC) overload and altered endothelial function including decreased nitric oxide (NO) bioavailability. Nitric oxide is well known neurotransmitter, neuromodulator and vasodilator involved in regulation of neuroendocrine mechanisms and cardiovascular responses to stressors. Thus NO plays a crucial role in the regulation of the stress systems and thereby in the BP regulation in stress. Elevated NO synthesis, especially in the initial phase of stress, may be considered a stress-limiting mechanism, facilitating the recovery from stress to the resting levels via attenuation of both GC release and SNS activity as well as by increased NO-dependent vasorelaxation. On the other hand, reduced levels of NO were observed in the later phases of stress and in subjects with genetic predisposition to hypertension, irrespectively, in which reduced NO bioavailability may account for disruption of NO-mediated BP regulatory mechanisms and accentuated SNS and GC effects. This review summarizes current knowledge on the role of stress in development of hypertension with a special focus on the interactions among NO and other biological systems affecting blood pressure and vascular function.

Endothelial Function In Tanzanian Children With Sickle Cell Disease: Baseline Results From The Vascular Function Intervention Trial (VFIT)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 984-984
Author(s):  
Sharon E. Cox ◽  
Julie Makani ◽  
Elizabeth Ellins ◽  
Gurishaeli Walter ◽  
Selemani Mtunguja ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Endothelial Function ◽  
Sickle Cell ◽  
Brachial Artery ◽  
Vascular Function ◽  
Full Blood Count ◽  
Intervention Trial ◽  
Brachial Artery Diameter ◽  
Baseline Diameter

Abstract Introduction Endothelial function is impaired in adults with sickle cell anaemia (SCA), but limited data exists in children. Endothelial damage occurs from chronic inflammation, oxidant damage, immune cell activation and ischemia-reperfusion injury. In addition, availability of nitric oxide (NO) as the major vasodilator may be reduced as a result of scavenging by plasma haemoglobin and reduced arginine substrate for endothelial nitric oxide synthase. Methods Tanzanian children (N=119) with SCA (HbSS) aged 8-11.9 years enrolled in the Vascular Function Intervention Trial (ISRCTN74331412/NCT01718054) underwent baseline assessment of endothelium-dependent and -independent vasodilatation. All children were determined clinically well at assessment, hydroxyurea naive, on no long-term medication and not receiving chronic blood transfusions. Blood pressure and vasomotion were assessed after 10 minutes recumbent rest in a temperature controlled room between 08-13:00 hrs. An identical protocol as published in children (Donald & Charakida et al. Eur Heart J; 2010: 31; 1502-10) was used. In brief, brachial arterial endothelium dependent dilatation was assessed by 1 of 3 trained technicians using ultrasound imaging (Ultrasonix SonixTouch with a 12Mz probe & stereotactic holder) to assess flow-mediated dilatation (FMD) in response to reactive hyperaemia induced after release of transient blood pressure cuff occlusion (5 min, 200 mmHg, Hokanson, USA) using an automated air regulator (Logan Research, UK). Automated B-mode image edge detection was used to measure maximum change in arterial diameter (Brachial Tools) expressed as a percentage of resting baseline diameter (FMDmax). Endothelium-independent responses to 2.5µg sub-lingual glyceryl-trinitrate (GTN) were also assessed. All recordings were over-read by an experienced researcher in the UK. Venepuncture for full blood count, clinical chemistry and amino acids was conducted after FMD assessment. Results Patient characteristics are described in Table 1. Mean brachial artery diameter at baseline was 2.61mm (95% CI 2.55 – 2.67mm). Mean FMDmax was 7.70% (95% CI 7.09 – 8.32%). Endothelium-independent vasodilation (GTNmax) was 4.15% (95% CI 3.83 – 4.47%). The FMDmax response was on greater than the GTNmax response (Figure 1). No effect of room or skin temperature on FMDmax or GTNmax was observed. There was a strong inverse association between baseline artery diameter and FMDmax (-3.46, P<0.001) (Figure 2). The time to peak brachial artery diameter in response to hyperaemia was positively skewed (median 55s (IQR: 43-79s)) and was not associated with FMDmax. The only patient characteristic associated with FMDmax was age with a non-significant inverse correlation (-0.52, P=0.06) but was reduced when adjusting for baseline diameter. Baseline heart rate was positively associated with FMDmax and GTNmax (P=0.01 & 0.025). Discussion We have characterised peripheral vascular function in a large cohort of children with SCA. Mean FMDmax was slightly lower than that observed in predominantly Caucasian non-SCA British children of similar age (8.1% [SD3.4]) (Donald & Charakida et al. Eur Heart J 2010: 31; 1502-10), but higher than reported in 21 older French children with SCA (5.6 +/- 0.2) (Montalembert et al. Haematol 2007: 92; 1709-10) which might reflect deterioration of endothelial function with age. There was no apparent association between FMDmax and hemolytic markers or with nutritional status at baseline. Recruitment and assessment of appropriate local non-SCA controls for comparison is planned. Amino acid analyses are ongoing. Disclosures: No relevant conflicts of interest to declare.

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.

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 Tetrahydrobiopterin lowers muscle sympathetic nerve activity and improves augmentation index in patients with chronic kidney disease

2015 ◽  
Vol 308 (3) ◽  
pp. R208-R218 ◽  
Author(s):  
Jeanie Park ◽  
Peizhou Liao ◽  
Salman Sher ◽  
Robert H. Lyles ◽  
Don D. Deveaux ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Folic Acid ◽  
Sympathetic Nerve Activity ◽  
Pulse Wave ◽  
Augmentation Index ◽  
Muscle Sympathetic Nerve Activity ◽  
Nerve Activity ◽  
No Bioavailability

Chronic kidney disease (CKD) is characterized by overactivation of the sympathetic nervous system (SNS) that contributes to cardiovascular risk. Decreased nitric oxide (NO) bioavailability is a major factor contributing to SNS overactivity in CKD, since reduced neuronal NO leads to increased central SNS activity. Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthase that increases NO bioavailability in experimental models of CKD. We conducted a randomized, double-blinded, placebo-controlled trial testing the benefits of oral sapropterin dihydrochloride (6R-BH4, a synthetic form of BH4) in CKD. 36 patients with CKD and hypertension were randomized to 12 wk of 1) 200 mg 6R-BH4 twice daily + 1 mg folic acid once daily; vs. 2) placebo + folic acid. The primary endpoint was a change in resting muscle sympathetic nerve activity (MSNA). Secondary endpoints included arterial stiffness using pulse wave velocity (PWV) and augmentation index (AIx), endothelial function using brachial artery flow-mediated dilation and endothelial progenitor cells, endothelium-independent vasodilatation (EID), microalbuminuria, and blood pressure. We observed a significant reduction in MSNA after 12 wk of 6R-BH4 (−7.5 ± 2.1 bursts/min vs. +3.2 ± 1.3 bursts/min; P = 0.003). We also observed a significant improvement in AIx (by −5.8 ± 2.0% vs. +1.8 ± 1.7 in the placebo group, P = 0.007). EID increased significantly (by +2.0 ± 0.59%; P = 0.004) in the 6R-BH4 group, but there was no change in endothelial function. There was a trend toward a reduction in diastolic blood pressure by −4 ± 3 mmHg at 12 wk with 6R-BH4 ( P = 0.055). 6R-BH4 treatment may have beneficial effects on SNS activity and central pulse wave reflections in hypertensive patients with CKD.

Effects of Neuroactive Amino Acids Derivatives on Cardiac and Cerebral Mitochondria and Endothelial functions in Animals Exposed to Stress

2017 ◽  
Vol 2 (2) ◽  
pp. 34
Author(s):  
TA Popova ◽  
II Prokofiev ◽  
IS Mokrousov ◽  
Valentina Perfilova ◽  
AV Borisov ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Platelet Aggregation ◽  
Atp Synthesis ◽  
Elevated Concentration ◽  
Blood Pressure Monitor ◽  
Pressure Monitor ◽  
Griess Reagent ◽  
Arterial Blood ◽  
Endothelial Functions

Introduction: To study the effects of glufimet, a new derivative of glutamic acid, and phenibut, a derivative of γ-aminobutyric acid (GABA), on cardiac and cerebral mitochondria and endothelial functions in animals following exposure to stress and inducible nitric oxide synthase (iNOS) inhibition. Methods: Rats suspended by their dorsal cervical skin fold for 24 hours served as the immobilization and pain stress model. Arterial blood pressure was determined using a non-invasive blood pressure monitor. Mitochondrial fraction of heart and brain homogenates were isolated by differential centrifugation and analysed for mitochondrial respiration intensity, lipid peroxidation (LPO) and antioxidant enzyme activity using polarographic method. The concentrations of nitric oxide (NO) terminal metabolites were measured using Griess reagent. Hemostasis indices were evaluated. Platelet aggregation was estimated using modified version of the Born method described by Gabbasov et al., 1989. Results: The present study demonstrated that stress leads to an elevated concentration of NO terminal metabolites and LPO products, decreased activity of antioxidant enzymes, reduced mitochondrial respiratory function, and endothelial dysfunction. Inhibition of iNOS by aminoguanidine had a protective effect. Phenibut and glufimet inhibited a rise in stress-induced nitric oxide production. This resulted in enhanced coupling of substrate peroxidation and ATP synthesis. The reduced LPO processes caused by glufimet and phenibut normalized the endothelial function which was proved by the absence of average daily blood pressure (BP) elevation episodes and a significant increase in platelet aggregation level. Conclusion: Glufimet and phenibut restrict the harmful effects of stress on the heart and brain possibly by modulating iNOS activity.

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