Sodium Nitrite Increases Regional Blood Flow in Patients with Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2328-2328
Author(s):  
A. Kyle Mack ◽  
Roberto F. Machado ◽  
Vandana Sachdev ◽  
Mark T. Gladwin ◽  
Gregory J. Kato
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Forearm Blood Flow ◽  
Regional Blood Flow ◽  
Cell Disease ◽  
No Donor ◽  
No Donors ◽  
Before And After

Abstract Patients with sickle cell disease have decreased nitric oxide bioavailability, and studies from several groups have confirmed a blunted response to various NO donors in humans and mice with sickle cell disease. Recently published studies show that nitrite induces vasodilation in humans, apparently mediated by conversion of nitrite to NO. This study is designed to determine the potential therapeutic effect of intra-arterial nitrite infusion to restore nitric oxide dependent blood flow in the forearms of patients with sickle cell disease. Venous occlusion strain gauge plethysmography is used to measure the change of forearm blood flow in patients with sickle cell disease, before and after sequential brachial artery infusions of increasing doses of sodium nitrite. In addition, NO responsiveness before and after nitrite infusion is measured by test doses of the NO donor sodium nitroprusside (SNP). Six patients have completed the study and enrollment is continuing. These data indicate that nitrite promotes regional blood flow in patients with sickle cell disease, albeit with a blunted response compared to our healthy control subjects, in whom we previously have found increased blood flow up to 187% with comparable dosing. The significant but blunted response is consistent with the state of nitric oxide resistance to NO donors that has been seen by several groups in patients and mice with SCD. Additionally, we find in these patients that nitrite partially restores SNP responsiveness, with baseline maximal SNP responses more than doubling on average following nitrite infusion, although this finding is preliminary. No adverse effects of nitrite were seen in these six patients. Our early results support a role for nitrite as an NO donor effective in restoring NO-dependent blood flow in patients with sickle cell disease. Additional translational studies are warranted to evaluate the therapeutic effects of systemic nitrite dosing. Table 1. Forearm Blood Flow Response to Nitrite Infusion Nitrite Dose (micromole/min) Sickle Cell Disease Historical Controls P< .0001 (ANOVA) 0.4 5 +/−7.2% N=6 22 +/−3.2% N=10 4 15 +/− 11% N=6 Not infused 40 49 +/− 8.9% N=6 187 +/− 16%N=18 Table 2. Nitrite Effect on Nitroprusside Responsiveness SNP Dose (micrograms/min) Pre-Nitrite Post-Nitrite P= .02 (RM-ANOVA) N=6 0.8 +21 +/− 5.6% +33 +/− 8.3% 1.6 +15 +/− 5.9% +62 +/− 15.1% 3.2 +29 +/− 6.3% +67 +/− 11.5%

scholarly journals Mechanisms of Stroke in Sickle Cell Disease: Sickle Erythrocytes Decrease Cerebral Blood Flow in Rats After Nitric Oxide Synthase Inhibition

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4591-4599 ◽  
Author(s):  
James A. French ◽  
Dermot Kenny ◽  
J. Paul Scott ◽  
Raymond G. Hoffmann ◽  
James D. Wood ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vascular Endothelium ◽  
Cell Disease ◽  
Cerebral Microvessels ◽  
Doppler Flowmetry ◽  
Cranial Window

Abstract The etiology of stroke in sickle cell disease is unclear, but may involve abnormal red blood cell (RBC) adhesion to the vascular endothelium and altered vasomotor tone regulation. Therefore, we examined both the adhesion of sickle (SS)-RBCs to cerebral microvessels and the effect of SS-RBCs on cerebral blood flow when the nitric oxide (NO) pathway was inhibited. The effect of SS-RBCs was studied in the rat cerebral microcirculation using either a cranial window for direct visualization of infused RBCs or laser Doppler flowmetry (LDF ) to measure RBC flow. When fluorescently labeled human RBCs were infused into rats, SS-RBCs had increased adhesion to rat cerebral microvessels compared with control AA-RBCs (P = .01). Next, washed SS-RBCs or AA-RBCs were infused into rats prepared with LDF probes after pretreatment (40 mg/kg intravenously) with the NO synthase inhibitor, N-ω-nitro-L-arginine methyl ester (L-NAME), or the control isomer, D-NAME. In 9 rats treated with systemic L-NAME and SS-RBCs, 5 of 9 experienced a significant decrease in LDF and died within 30 minutes after the RBC infusion (P = .0012). In contrast, all control groups completed the experiment with stable LDF and hemodynamics. Four rats received a localized superfusion of L-NAME (1 mmol/L) through the cranial window followed by infusion of SS-RBCs. Total cessation of flow in all observed cerebral microvessels occurred in 3 of 4 rats within 15 minutes after infusion of SS-RBCs. We conclude that the NO pathway is critical in maintaining cerebral blood flow in the presence of SS-RBCs in this rat model. In addition, the enhanced adhesion of SS-RBCs to rat brain microvessels may contribute to cerebral vaso-occlusion either directly, by disrupting blood flow, or indirectly, by disturbing the vascular endothelium.

Nitric Oxide Effects in Sickle Cell Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-48-sci-48
Author(s):  
Lori Styles
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Oxidant Stress ◽  
Cell Disease ◽  
No Donors ◽  
Skin Ulcers ◽  
No Bioavailability ◽  
Inhaled No

Sickle cell disease (SCD) is a complex hemoglobinopathy characterized by microvascular occlusion and hemolytic anemia. Patients suffer from a myriad of both acute and chronic problems affecting virtually every organ system. Historically, microvascular occlusion has been the focus of scientific investigations into these manifestations and the chronic hemolysis of SCD was overlooked. More recently, however, the importance of the pathophysiology of hemolysis has been appreciated and related to a subset of the clinical manifestations of SCD, including pulmonary hypertension, priapism, skin ulcers, and possibly stroke. This subphenotype of SCD has been convincingly related to impaired nitric oxide (NO) homeostasis due to hemolysis. NO has pleiotropic effects including vaso-dilatory, antioxidative, anti-adhesion, and anti-thrombotic properties, which are all potentially important in the pathophysiology of SCD. Perturbation of NO homeostasis, therefore, could profoundly impact patients with SCD. Animal and human data support a state of “NO resistance” in SCD patients. Human studies have shown that SCD patients have a decreased response to exogenous NO donors and that is likely due to the scavenging of NO by free plasma hemoglobin that results from ongoing hemolysis. “NO resistance” is further augmented by the increased levels of reactive oxygen species (ROS) known to occur in SCD patients. High levels of ROS favor additional hemolysis through increased oxidant stress on the sickle red blood cell and reduce NO bioavailability by inactivation of circulating NO. With the substantial human and animal data to support a role for “NO resistance” in the pathophysiology of SCD, investigation with NO-based therapy have begun. Several approaches to overcoming “NO resistance” can be devised including increasing the precursors to NO, decreasing hemolysis, direct NO donors, and decreasing oxidant stress. To date, studies evaluating arginine (NO precursor), inhaled NO, and sildenafil (NO donor) have been reported. Oral arginine showed no benefit in a large clinical trial, and a preliminary trial of inhaled NO had only minimal benefit. Sildenafil may be more promising and is under further study. Lastly, although impaired NO bioavailability has been related to a subset of patients with pulmonary hypertension, skin ulcers and priapism, it will be important to determine what impact NO has on other manifestations, such as vaso-occlusive pain episodes and whether NO modulation can also be used therapeutically in this setting.

Stimulation of Nitric Oxide Synthase Activity By Plasma Apolipoproteins: a Biomarker of Endothelial Function in Adults with Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4015-4015 ◽  
Author(s):  
Xunde Wang ◽  
Laurel Mendelsohn ◽  
Lita Freeman ◽  
Boris Vaisman ◽  
Alan Remaley ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Sickle Cell Disease ◽  
Endothelial Function ◽  
Human Plasma ◽  
Sickle Cell ◽  
Cell Disease ◽  
Oxide Synthase ◽  
Lines Of Evidence ◽  
Stimulation Of

Abstract Nitric oxide (NO) plays a critical role in maintaining basal vascular tone and regulating blood flow. Many factors, including shear stress and endogenous ligands such as vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF1), stimulate the activity of endothelial nitric oxide synthase (eNOS). We have developed a bioassay that measures stimulation of NOS activity by soluble factors in unfractionated human plasma in cultured human endothelial cells using a sensitive NOS activity assay with radiolabeled substrate. The addition of 1% human plasma to the culture medium stimulates NOS activity 1.5-fold over background, with a linear response up to 10% plasma, which activates NOS 5.5-fold. We have concluded from several lines of evidence that this NOS-inducing activity in human plasma comes from high-density lipoprotein (HDL): The activity is heat-labile and sensitive to reducing agents; it is precipitable by ammonium sulfate and elutes as a broad peak on molecular exclusion and anion exchange columns; by immunoblot, the active fractions have large amounts of apolipoproteins apoA-I, apoE and paroxonase-1. We find that plasma from an apoA-I null mouse shows less stimulation of NOS activity in our bioassay than plasma from a wild type mouse and apoA-I transgenic mouse (p=0.06, Brown-Forsythe test; p=0.04, post-test for linear trend; see figure). Purified HDL fractions stimulate NOS activity four-fold, equivalent to unfractionated plasma, but further subfractionation of HDL components extinguishes its ability to activate NOS. Remarkably, higher than median NOS-stimulating activity in our bioassay was associated with endothelial-dependent blood flow, detected by venous occlusion strain gauge plethysmography measurement of forearm blood flow induced by graded infusions of acetylcholine into the brachial artery in adults with sickle cell anemia (p=0.0013, two-way ANOVA, see figure). The NOS-stimulating activity in patient plasma also correlated with the plasma apoA-I level (Spearman r=0.64, p=0.0012). In summary, our results suggest that circulating functional apoA-I and possibly other apolipoproteins, regulate NO production and endothelial function in adults with sickle cell disease, which is consistent with previous lines of evidence published by other investigators in subjects without sickle cell disease. Most strikingly, our plasma NOS stimulation assay appears to provide a useful research biomarker for endothelial function, applicable to frozen archived plasma biospecimens. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Airway and alveolar nitric oxide production, lung function, and pulmonary blood flow in sickle cell disease

2015 ◽  
Vol 79 (2) ◽  
pp. 313-317 ◽  
Author(s):  
Alan Lunt ◽  
Na'eem Ahmed ◽  
Gerrard F. Rafferty ◽  
Moira Dick ◽  
David Rees ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Sickle Cell Disease ◽  
Lung Function ◽  
Sickle Cell ◽  
Pulmonary Blood Flow ◽  
Nitric Oxide Production ◽  
Cell Disease ◽  
Oxide Production

scholarly journals Sodium nitrite promotes regional blood flow in patients with sickle cell disease: a phase I/II study

2008 ◽  
Vol 142 (6) ◽  
pp. 971-978 ◽  
Author(s):  
A. Kyle Mack ◽  
Vicki R. McGowan II ◽  
Carole K. Tremonti ◽  
Diana Ackah ◽  
Christopher Barnett ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Phase I ◽  
Sickle Cell ◽  
Sodium Nitrite ◽  
Regional Blood Flow ◽  
Cell Disease

scholarly journals Infrared imaging of nitric oxide-mediated blood flow in human sickle cell disease

2012 ◽  
Vol 84 (3) ◽  
pp. 262-269 ◽  
Author(s):  
Alexander M. Gorbach ◽  
Hans C. Ackerman ◽  
Wei-Min Liu ◽  
Joseph M. Meyer ◽  
Patricia L. Littel ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Infrared Imaging ◽  
Cell Disease

scholarly journals Peripheral Blood Flow Responses to Pain Following a Hypnosis Intervention in Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4853-4853
Author(s):  
Ravi Bhatt ◽  
Subhadra Evans ◽  
Lonnie Zeltzer ◽  
Thomas D. Coates ◽  
Jennie Tsao
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Peripheral Blood ◽  
Pain Sensitivity ◽  
Pain Threshold ◽  
Pain Tolerance ◽  
Peripheral Blood Flow ◽  
Cell Disease ◽  
Before And After

Abstract Introduction: Vaso-occlusive pain crises are considered the "hallmark" of sickle cell disease (SCD). Persistent occurrence is thought to lead to changes in the peripheral and central nervous system, which can then in turn lead to changes in pain sensitivity. Imaging studies have shown that hypnotic analgesia can reduce activity in supraspinal areas of the "pain matrix." To date there are no published studies looking at the effectiveness of hypnosis in altering pain perception in patients with SCD. The purpose of this study was to investigate changes in peripheral blood flow in response to a 30-minute hypnosis intervention and its relationship to pain sensitivity. Methods: To assess the effectiveness of increasing vasodilation, a laboratory based, single session hypnosis protocol was administered to a sample of 14 SCD patients and 14 healthy controls. Continuous readings for SpO2, pulse rate and pulse waveform was monitored using a pulse oximetry transducer placed on the left thumb. Bio-behavioral pain measures were collected during a standardized pain protocol before and after a hypnosis session, performed by a trained therapist. The protocol consisted of assessing pain tolerance and threshold via a heat probe (˚C) for "pain task 1", preceded by an anticipation period. "Pain task 2" consisted of assessing pain intensity via the same heat probe (˚C) on a 1-100 visual analog scale (VAS), preceded by another anticipation period. Results: To investigate blood-flow responses to their respective baseline (baseline vs. hypnosis), all recorded signal following these two periods was normalized respectively. Independent sample t-tests between both normalized anticipation and pain responses periods revealed controls showed no response to hypnosis for anticipation period 1(t(23.42) = .184, p = .855, d = .072), but SCD patients showed a large increase in blood flow (t(16.99) = 4.189, p = .0006, d = 1.79). Neither controls (t(21.05) = .00, p = .994, d = .003) or SCD patients (t(19.99) =.718, p = .481, d = .305) showed an effect of hypnosis in response to pain task 1. Neither controls (t(23.96) = -.139, p = .890, d = -.05) or SCD patients (t(18.82) = 1.035, p = .313, d = .441) showed a response to anticipation period 2, but the effect size reveals that this may be due to a lack of power. Neither controls (t(16.52) = .258, p = .799, d = .101) or SCD patients (t(19.63) = p = .5375, d = .268) showed no changes in response to hypnosis for pain task 2. Independent sample t-tests revealed no significant difference in pain threshold (t(13) = 0.941, p = .364, d = .251) or tolerance (t(13) = 0.937, p = 0.366, d = 0.250) in SCD patients before and after hypnosis. Differences in pain ratings were marginal but showed a decrease with medium effect (t(13) = -1.5315, p = 0.150, d = 0.409). The same tests revealed significant decreases in controls for pain threshold (t(13) = 2.825, p = 0.01, d = .755), pain tolerance (t(13) = 2.482, p = 0.02, d = 0.664), and pain rating (t(13) = 2.950, p = 0.01, d = .789). Conclusion: Results revealed that hypnosis may be an effective treatment in helping manage vasoconstriction in SCD as a response to cognitive appraisals about pain, as well as reducing pain sensitivity. The data presented provide preliminary clinical evidence of the use of hypnosis as a treatment method to improve vasodilation in SCD patients and decreasing pain crises, thus increasing overall quality of life. Disclosures No relevant conflicts of interest to declare.

Atorvastatin Therapy Restores Nitric Oxide-Dependent Vascular Responsiveness in Patients with Sickle Cell Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 239-239 ◽  
Author(s):  
Gregory J. Kato ◽  
Christian Hunter ◽  
Lori Hunter ◽  
Andre Dejam ◽  
Roberto Machado ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cell Adhesion ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Oxidant Stress ◽  
Cell Disease ◽  
Atorvastatin Therapy ◽  
Vascular Responsiveness ◽  
No Bioavailability

Abstract We and others have published biochemical and physiological evidence supporting a model in which intravascular hemolysis and oxidant stress in patients with sickle cell disease (SCD) results in impaired nitric oxide (NO) bioavailability, with an associated reduction in NO-dependent blood flow. This reduced bioavailability is characterized by NO destruction and thus a resistance to both endogenous and exogenous (nitroprusside, nitroglycerin, NONOates) NO. A crucial regulator of endothelial cell homeostasis, NO regulates basal vasodilation, inhibits platelet aggregation, and tonically inhibits expression of cell adhesion molecules by endothelial cells, including vascular cell adhesion molecule (VCAM-1). Statins have been reported to both improve NO-dependent blood flow and reduce oxidant stress in patients with hypercholesterolemia and in normal subjects. We therefore investigated whether atorvastatin has similar effects in patients with SCD. Five patients have completed the study (targeted enrollment will be 15 patients); patients were selected for suspected NO-dependent vascular dysfunction as determined by higher than median plasma levels of soluble VCAM-1 or pulmonary hypertension (tricuspid regurgitant jet velocity > 2.4 meters/second). Baseline vascular reactivity to arterial infusions of sodium nitroprusside (SNP), acetylcholine (ACh), and the inhibitor of endothelial NO synthesis, L-NG-monomethyl-L-arginine (L-NMMA) at increasing doses was assessed by forearm venous occlusion plethysmography. Patients took atorvastatin 10 mg daily for two weeks, then 20 mg daily for another two weeks, and forearm studies were repeated. All patients tolerated the drug without adverse effects. Plasma total cholesterol levels decreased in all patients, (baseline 115 ± 5 mg/dL, post-treatment 93 ± 5 mg/dL (mean ± SEM), p=0.002). Serum creatine kinase increased slightly, but remained in the normal range (55 ± 9 vs. 73 ± 18 IU/L, p=0.15). All patients had markedly impaired responses at baseline to SNP, ACh and L-NMMA compared to healthy control subjects, validating our screening methodology to identify subjects with NO resistance. After four weeks of oral atorvastatin therapy, responsiveness to both SNP and ACh significantly improved in each group compared to baseline by ANOVA with repeated measures (p < 0.05). Response to L-NMMA was not significantly affected. These data provide a non-invasive strategy for identifying patients with NO-resistance (endothelial dysfunction) by screening soluble VCAM-1 levels and tricuspid regurgitant jet velocities, and further suggest that high pulmonary artery systolic pressures in this population are associated with reduced NO bioavailability. Additionally, we show that short term use of the FDA approved medication atorvastatin, is safe in this population. Our data are consistent with statin-mediated improvement in vascular responsiveness to NO that is independent of improved endothelial NO production, and support consideration of statins in clinical trials to reduce vascular occlusion in patients with SCD. Figure Figure

scholarly journals Is there a role for selective vasodilation in the management of sickle cell disease?

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 597-602 ◽  
Author(s):  
GP Rodgers ◽  
MS Roy ◽  
CT Noguchi ◽  
AN Schechter
Keyword(s):  
Blood Flow ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Microvascular Obstruction ◽  
Controlled Study ◽  
Control Group ◽  
Cell Disease ◽  
Retinal Arteriolar

Abstract To test the hypothesis that microvascular obstruction to blood flow at the level of the arteriole may be significant in individuals with sickle cell anemia, the ophthalmologic effects of orally administered nifedipine were monitored in 11 steady-state patients. Three patients with evidence of acute peripheral retinal arteriolar occlusion displayed a prompt reperfusion of the involved segment. Two other patients showed fading of retroequatorial red retinal lesions. Color vision performance was improved in six of the nine patients tested. The majority of patients also demonstrated a significant decrease in the amount of blanching of the conjunctiva which reflects improved blood flow to this frequently involved area. Such improvements were not observable in a control group of untreated stable sickle cell subjects. These findings support the hypothesis that inappropriate vasoconstriction or frank vasospasm may be a significant factor in the pathogenesis of the microvascular lesions of sickle cell disease and, further, that selective microvascular entrapment inhibition may offer an additional strategy to the management of this disorder. We believe a larger, placebo-controlled study with nifedipine and similar agents is warranted.

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