Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs

Exposure to chronic hypoxia during gestation predisposes infants to neonatal pulmonary hypertension, but the underlying mechanisms remain unclear. Here, we test the hypothesis that moderate continuous hypoxia during gestation causes changes in the rho-kinase pathway that persist in the newborn period, altering vessel tone and responsiveness. Lambs kept at 3,801 m above sea level during gestation and the first 2 wk of life were compared with those with gestation at low altitude. In vitro studies of isolated pulmonary arterial rings found a more forceful contraction in response to KCl and 5-HT in high-altitude compared with low-altitude lambs. There was no difference between the effects of blockers of various pathways of extracellular Ca2+ entry in low- and high-altitude arteries. In contrast, inhibition of rho-kinase resulted in significantly greater attenuation of 5-HT constriction in high-altitude compared with low-altitude arteries. High-altitude lambs had higher baseline pulmonary artery pressures and greater elevations in pulmonary artery pressure during 15 min of acute hypoxia compared with low-altitude lambs. Despite evidence for an increased role for rho-kinase in high-altitude arteries, in vivo studies found no significant difference between the effects of rho-kinase inhibition on hypoxic pulmonary vasoconstriction in intact high-altitude and low-altitude lambs. We conclude that chronic hypoxia in utero results in increased vasopressor response to both acute hypoxia and serotonin, but that rho-kinase is involved only in the increased response to serotonin.

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Pulmonary hypertension and pulmonary vascular reactivity in beagles at high altitude

Journal of Applied Physiology ◽

10.1152/jappl.1988.65.6.2632 ◽

1988 ◽

Vol 65 (6) ◽

pp. 2632-2640 ◽

Cited By ~ 28

Author(s):

R. F. Grover ◽

R. L. Johnson ◽

R. G. McCullough ◽

R. E. McCullough ◽

S. E. Hofmeister ◽

...

Keyword(s):

Pulmonary Hypertension ◽

High Altitude ◽

Sea Level ◽

Vascular Reactivity ◽

Chronic Hypoxia ◽

Acute Hypoxia ◽

Prostaglandin Synthesis ◽

Inhibition Of Prostaglandin Synthesis ◽

Pulmonary Arterial ◽

Low Altitude

It is unclear whether dogs develop pulmonary hypertension (PH) at high altitude. Beagles from sea level were exposed to an altitude of 3,100 m (PB 525 Torr) for 12-19 mo and compared with age-matched controls remaining at low altitude of 130 m (PB 750 Torr). In beagles taken to high altitude as adults, pulmonary arterial pressures (PAP) at 3,100 m were 21.6 +/- 2.6 vs. 13.2 +/- 1.2 Torr in controls. Likewise, in beagles taken to 3,100 m as puppies 2.5 mo old, PAP was 23.2 +/- 2.1 vs. 13.8 +/- 0.4 Torr in controls. This PH reflected a doubling of pulmonary vascular resistance and showed no progression with time at altitude. Pulmonary vascular reactivity to acute hypoxia was also enhanced at 3,100 m. Inhibition of prostaglandin synthesis did not attenuate the PH or the enhanced reactivity. Once established, the PH was only partially reversed by acute relief of chronic hypoxia, but reversal was virtually complete after return to low altitude. Hence, beagles do develop PH at 3,100 m of a severity comparable to that observed in humans at the same or even higher altitudes.

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Store-operated channels in the pulmonary circulation of high- and low-altitude neonatal lambs

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00024.2012 ◽

2013 ◽

Vol 304 (8) ◽

pp. L540-L548 ◽

Cited By ~ 22

Author(s):

Daniela Parrau ◽

Germán Ebensperger ◽

Emilio A. Herrera ◽

Fernando Moraga ◽

Raquel A. Riquelme ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Vascular Resistance ◽

Vascular Reactivity ◽

Chronic Hypoxia ◽

Hypoxic Pulmonary Vasoconstriction ◽

Acute Hypoxia ◽

Pulmonary Arteries ◽

Arterial Blood ◽

Low Altitude

We determined whether store-operated channels (SOC) are involved in neonatal pulmonary artery function under conditions of acute and chronic hypoxia, using newborn sheep gestated and born either at high altitude (HA, 3,600 m) or low altitude (LA, 520 m). Cardiopulmonary variables were recorded in vivo, with and without SOC blockade by 2-aminoethyldiphenylborinate (2-APB), during basal or acute hypoxic conditions. 2-APB did not have effects on basal mean pulmonary arterial pressure (mPAP), cardiac output, systemic arterial blood pressure, or systemic vascular resistance in both groups of neonates. During acute hypoxia 2-APB reduced mPAP and pulmonary vascular resistance in LA and HA, but this reduction was greater in HA. In addition, isolated pulmonary arteries mounted in a wire myograph were assessed for vascular reactivity. HA arteries showed a greater relaxation and sensitivity to SOC blockers than LA arteries. The pulmonary expression of two SOC-forming subunits, TRPC4 and STIM1, was upregulated in HA. Taken together, our results show that SOC contribute to hypoxic pulmonary vasoconstriction in newborn sheep and that SOC are upregulated by chronic hypoxia. Therefore, SOC may contribute to the development of neonatal pulmonary hypertension. We propose SOC channels could be potential targets to treat neonatal pulmonary hypertension.

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Acute in vitro hypoxia and high-altitude (4,559 m) exposure decreases leukocyte oxygen consumption

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00413.2010 ◽

2011 ◽

Vol 300 (1) ◽

pp. R32-R39 ◽

Cited By ~ 7

Author(s):

Vitalie Faoro ◽

Bruno Fink ◽

Sarah Taudorf ◽

Christoph Dehnert ◽

Marc M. Berger ◽

...

Keyword(s):

Oxygen Consumption ◽

High Altitude ◽

Respiratory Burst ◽

Acute Hypoxia ◽

Resonance Spectroscopy ◽

Metabolic Functions ◽

Spin Resonance ◽

Ros Formation ◽

Low Altitude

Hypoxia impairs metabolic functions by decreasing activity and expression of ATP-consuming processes. To separate hypoxia from systemic effects, we tested whether hypoxia at high altitude affects basal and PMA-stimulated leukocyte metabolism and how this compares to acute (15 min) and 24 h of in vitro hypoxia. Leukocytes were prepared at low altitude and ∼24 h after arrival at 4559 m. Mitochondrial oxygen consumption (JO2) was measured by respirometry, oxygen radicals by electron spin resonance spectroscopy, both at a Po2= 100 mmHg (JO2,100) and 20 mmHg (JO2,20). Acute hypoxia of leukocytes decreased JO2at low altitude. Exposure to high altitude decreased JO2,100, whereas JO2,20was not affected. Acute hypoxia of low-altitude samples decreased the activity of complexes I, II, and III. At high altitude, activity of complexes I and III were decreased when measured in normoxia. Stimulation of leukocytes with PMA increased JO2,100at low (twofold) and high altitude (five-fold). At both locations, PMA-stimulated JO2was decreased by acute hypoxia. Basal and PMA-stimulated reactive oxygen species (ROS) production were unchanged at high altitude. Separate in vitro experiments performed at low altitude show that ∼75% of PMA-induced increase in JO2was due to increased extra-mitochondrial JO2(JO2,res; in the presence of rotenone and antimycin A). JO2,reswas doubled by PMA. Acute hypoxia decreased basal JO2,resby ∼70% and PMA-stimulated JO2,resby about 50% in cells cultured in normoxia and hypoxia (1.5% O2; 24 h). Conversely, 24 h in vitro hypoxia decreased mitochondrial JO2,100and JO2,20, extra-mitochondrial, basal, and PMA-stimulated JO2were not affected. These results show that 24 h of high altitude but not 24 h in vitro hypoxia decreased basal leukocyte metabolism, whereas PMA-induced JO2and ROS formation were not affected, indicating that prolonged high-altitude hypoxia impairs mitochondrial metabolism but does not impair respiratory burst. In contrast, acute hypoxia impairs respiratory burst at either altitude.

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Tropical tropospheric ozone derived using Clear-Cloudy Pairs (CCP) of TOMS measurements

Atmospheric Chemistry and Physics Discussions ◽

10.5194/acpd-3-225-2003 ◽

2003 ◽

Vol 3 (1) ◽

pp. 225-252 ◽

Cited By ~ 1

Author(s):

M. J. Newchurch ◽

D. Sun ◽

J. H. Kim ◽

X. Liu

Keyword(s):

High Altitude ◽

Tropospheric Ozone ◽

Total Ozone ◽

Stratospheric Ozone ◽

Lower Troposphere ◽

Total Ozone Mapping Spectrometer ◽

Significant Difference ◽

Retrieval Efficiency ◽

Retrieval Errors ◽

Low Altitude

Abstract. Using TOMS total-ozone measurements over high-altitude cloud locations and nearby paired clear locations, we describe the Clear-Cloudy Pairs (CCP) method for deriving tropical tropospheric ozone. The high-altitude clouds are identified by measured 380 nm reflectivities greater than 80% and Temperature Humidity InfraRed (THIR) measured cloud-top pressures less than 200 hPa. To account for locations without high-altitude clouds, we apply a zonal sine fitting to the stratospheric ozone derived from available cloudy points, resulting in a wave-one amplitude of about 4 DU. THIR data is unavailable after November 1984, so we extend the CCP method by using a reflectivity threshold of 90% to identify high-altitude clouds and remove the influence of high-reflectivity-but-low-altitude clouds with a lowpass frequency filter. We correct ozone retrieval errors associated with clouds, and ozone retrieval errors due to sun glint and aerosols. Comparing CCP results with Southern Hemisphere ADditional OZonesondes (SHADOZ) tropospheric ozone indicates that CCP tropospheric ozone and ozonesonde measurements are highly consistent. The most significant difference between CCP and ozonesonde tropospheric ozone can be explained by the low Total Ozone Mapping Spectrometer (TOMS) retrieval efficiency of ozone in the lower troposphere.

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Use of Medium Potency Statins Is Associated with Improved Outcomes after Frontline RCHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽

10.1182/blood-2020-136010 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 45-45

Author(s):

Sushanth Gouni ◽

Paolo Strati ◽

Jason Westin ◽

Loretta J. Nastoupil ◽

Raphael E Steiner ◽

...

Keyword(s):

Cell Lines ◽

Research Funding ◽

Response Assessment ◽

Cholesterol Content ◽

In Vivo Studies ◽

High Cholesterol ◽

Improved Outcomes ◽

Significant Difference

Background: Pre-clinical studies show that statins may improve the efficacy of chemoimmunotherapy in patients with DLBCL, through interference with cell membrane-initiated signaling pathways. Clinical retrospective studies, however, yield conflicting data, due to heterogeneous properties of statins, including potency and hydrophilicity. Methods: This is a retrospective analysis of patients with previously untreated, advanced stage DLBCL, non-double hit, treated with frontline R-CHOP between 01/01/2000 and 09/01/2019 (data cut-off 04/15/2020) at MD Anderson Cancer Center, and for whom data regarding statin use at time of initiation of treatment were available. Lugano 2014 response criteria were applied retrospectively for response assessment. Cellular cholesterol levels were analyzed in 6 DLBCL cell lines using an Amplex red fluorometric assay. A doxorubicin (DXR)-resistant cell line was generated exposing SUDHL4 cells to escalating doses of DXR; a DXR-resistant DLBCL patient-derived xenograft (PDX) model was established through serial transplantation and exposure to DXR. Results: 271 patients were included in the analysis, 182 (67%) were older than 60 years, 134 (49%) were male, 212 (72%) had stage IV disease, and 217 (80%) had an IPI score > 3; upon pathological review, 38 (36%) cases were non-GCB type, and 18 (28%) were double-expressors; 214 (79%) were able to complete all planned 6 cycles of RCHOP. Seventy-nine (29%) patients received statins at time of initiation of chemoimmunotherapy: 15 patients received low potency statin, 51 medium and 13 high; 18 patients received hydrophilic statins and 61 lipophilic. Patients receiving statins were significantly older as compared to patients who did not (p<0.001); no other significant difference in baseline characteristics was observed when comparing the 2 groups. Overall, 265 out of 271 patients were evaluable for response, as 6 stopped treatment because of toxicity before first response assessment. Among these, ORR was 95% (252/265) and CR rate was 62% (165/265). ORR rate was identical in patients who were treated with statin and those who did not (95% both, p=1). After a median follow-up of 77 months (95% CI, 70-84 months), 119 patients progressed/died, median PFS was not reached and 6-year PFS was 57%. 6-year PFS rate according to statin intensity was: 48% (low), 72% (medium), 57% (high). PFS. 6-year PFS rate was 64% for hydrophilic and 72% for lipophilic statins. Patients treated with statins had a trend for longer PFS (p=0.06), significantly longer for patients receiving medium potency statins (p=0.04). No significant difference in PFS was observed when comparing patients treated with lipophilic statins to all others (not reached vs 84 months, p=0.22). To confirm these clinical data, in-vitro and in-vivo studies were performed. Six cell lines were tested: 4 with high cholesterol content (SUDHL4, HBL1, HT, and U2932; 5.0-8.0 µg/mg protein), and 2 with low cholesterol content (DOHH2 and OCI-LY19; 1.5-2.0 µg/mg protein); the latter showed the highest sensitivity to DXR-mediated killing. The combination of lovastatin and DXR (10nM) was tested in all 4 cell lines with high cholesterol content, resulting in more cell death than either treatment alone. Lovastatin (at the nanomolar range) resensitized DXR-resistant SUDHL4 cells to DXR. Finally, in a DXR-resistant PDX model, the combination of lovastatin and DXR resulted in delayed tumor growth as compared to chemotherapy alone. Conclusions: Use of medium potency statins is associated with improved outcomes after frontline RCHOP in patients with DLBCL. This was further confirmed in functional in-vitro and in-vivo studies. Future interventional studies, aimed at improving outcomes in these patients using this novel combination, are warranted. Disclosures Westin: Amgen: Consultancy; 47: Research Funding; Kite: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding. Nastoupil:Gamida Cell: Honoraria; Merck: Research Funding; TG Therapeutics: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Novartis: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Gilead/KITE: Honoraria. Neelapu:Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Karus Therapeutics: Research Funding; N/A: Other; Takeda Pharmaceuticals: Patents & Royalties; Acerta: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Precision Biosciences: Other: personal fees, Research Funding; Legend Biotech: Other; Adicet Bio: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Calibr: Other; Incyte: Other: personal fees; Unum Therapeutics: Other, Research Funding. Landgraf:NCI/NIH: Research Funding. Vega:NCI: Research Funding.

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Preparation and preclinical evaluation of aceclofenac loaded pectinate mucoadhesive microspheres

Drugs and Therapy Studies ◽

10.4081/dts.2012.e8 ◽

2012 ◽

Vol 2 (1) ◽

pp. 8 ◽

Cited By ~ 1

Author(s):

Santanu Chakraborty ◽

Priyanka Nayak ◽

Bala Murali Krishna ◽

Madhusmruti Khandai ◽

Ashoke Kumar Ghosh

Keyword(s):

Particle Size ◽

Drug Release ◽

Polymer Concentration ◽

Research Work ◽

In Vivo Studies ◽

Systemic Absorption ◽

Cross Linking ◽

Significant Difference

The aim of the present research work was to fabricate aceclofenac loaded pectinate microspheres by ionic gelation method and evaluate the effect of different cross-linking agents and polymer concentration on particle size, encapsulation efficacy and drug release behavior. It was also investigated that whether this pectinate dosage form was able to target the drug release in intestinal region and prevent the different side effect associated with the drug in stomach or not. It was observed that particle size, encapsulation efficacy and in vitro drug release were largely depended on polymer concentration and cross-linking agents. It was also observed that pectinate microspheres showed excellent pH depended mucoadhesive properties and they were able to restrict the drug release in stomach. <em>In vitro</em> drug release study showed that alminium-pectinate microspheres have more sustaining property as compared to barium-pectinate microspheres. Holm-Sidak multiple comparison analysis suggested a significant difference in measured t<sub>50%</sub> values among all the formulations with same cross-linking agent. In vivo studies revealed that the anti inflammatory and analgesic effects induced by pectinate microspheres were significantly high and prolonged as compared to pure drug. So, pectinate microspheres can be an excellent carrier for targeting the delivery of aceclofenac as well as help in improving the patient compliance by prolonging the systemic absorption.

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Effects of Short-Term Inhibition of Rho Kinase on Dromedary Camel Oocyte In Vitro Maturation

Animals ◽

10.3390/ani10050750 ◽

2020 ◽

Vol 10 (5) ◽

pp. 750

Author(s):

Hammed A. Tukur ◽

Riyadh S. Aljumaah ◽

Ayman Abdel-Aziz Swelum ◽

Abdullah N. Alowaimer ◽

Mutassim Abdelrahman ◽

...

Keyword(s):

In Vitro Maturation ◽

Rho Kinase ◽

Positive Outcome ◽

Dromedary Camel ◽

Second Phase ◽

Short Term ◽

Rock Inhibitor ◽

Nuclear Maturation ◽

Significant Difference

This is the first report on a biphasic in vitro maturation (IVM) approach with a meiotic inhibitor to improve dromedary camel IVM. Spontaneous meiotic resumption poses a major setback for in vitro matured oocytes. The overall objective of this study was to improve in vitro maturation of dromedary camel oocytes using ROCK inhibitor (Y-27632) in a biphasic IVM to prevent spontaneous meiotic resumption. In the first experiment, we cultured immature cumulus–oocyte complexes (COCs, n = 375) in a prematuration medium supplemented with ROCK inhibitor (RI) for 2 h, 4 h, 6 h, and 24 h before submission to normal in vitro maturation to complete 28 h. The control was cultured for 28 h in the absence of RI. In the first phase of experiment two, we cultured COCs (n = 480) in the presence or absence (control) of RI for 2 h, 4 h, 6 h, and 24 h, and conducted real-time relative quantitative PCR (qPCR) on selected mRNA transcripts. The same was done in the second phase, but qPCR was done after completion of normal IVM. Assessment of nuclear maturation showed that pre-IVM for 4 h yielded an increase in MII oocyte (54.67% vs. 26.6% of control; p < 0.05). As expected, the same group showed the highest degree (2) of cumulus expansion. In experiment 2, qPCR results showed significantly higher expression of ACTB and BCL2 in the RI group treated for 4 h when compared with the other groups. However, their relative quantification after biphasic IVM did not reveal any significant difference, except for the positive response of BCL2 and BAX/BCL2 ratio after 4 and 6 h biphasic IVM. In conclusion, RI prevents premature oocyte maturation and gave a significantly positive outcome during the 4 h treatment. This finding is a paradigm for future investigation on dromedary camel biphasic IVM and for improving the outcome of IVM in this species.

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Heterogeneity of hypoxia-mediated decrease in IK(V) and increase in [Ca2+]cyt in pulmonary artery smooth muscle cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00391.2006 ◽

2007 ◽

Vol 293 (2) ◽

pp. L402-L416 ◽

Cited By ~ 21

Author(s):

Oleksandr Platoshyn ◽

Ying Yu ◽

Eun A Ko ◽

Carmelle V. Remillard ◽

Jason X.-J. Yuan

Keyword(s):

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Hypoxic Pulmonary Vasoconstriction ◽

Acute Hypoxia ◽

Muscle Cells ◽

Expression Level ◽

Kv Channels ◽

Pulmonary Artery Smooth Muscle ◽

High Level

Hypoxic pulmonary vasoconstriction is caused by a rise in cytosolic Ca2+ ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) via multiple mechanisms. PASMC consist of heterogeneous phenotypes defined by contractility, proliferation, and apoptosis as well as by differences in expression and function of various genes. In rat PASMC, hypoxia-mediated decrease in voltage-gated K+ (Kv) currents ( IK(V)) and increase in [Ca2+]cyt were not uniformly distributed in all PASMC tested. Acute hypoxia decreased IK(V) and increased [Ca2+]cyt in ∼46% and ∼53% of PASMC, respectively. Using combined techniques of single-cell RT-PCR and patch clamp, we show here that mRNA expression level of Kv1.5 in hypoxia-sensitive PASMC (in which hypoxia reduced IK(V)) was much greater than in hypoxia-insensitive cells (in which hypoxia negligibly affected IK(V)). These results demonstrate that 1) different PASMC express different Kv channel α- and β-subunits, and 2) the sensitivity of a PASMC to acute hypoxia partially depends on the expression level of Kv1.5 channels; hypoxia reduces whole-cell IK(V) only in PASMC that express high level of Kv1.5. In addition, the acute hypoxia-mediated changes in [Ca2+]cyt also vary in different PASMC. Hypoxia increases [Ca2+]cyt only in 34% of cells tested, and the different sensitivity of [Ca2+]cyt to hypoxia was not related to the resting [Ca2+]cyt. An intrinsic mechanism within each individual cell may be involved in the heterogeneity of hypoxia-mediated effect on [Ca2+]cyt in PASMC. These data suggest that the heterogeneity of PASMC may partially be related to different expression levels and functional sensitivity of Kv channels to hypoxia and to differences in intrinsic mechanisms involved in regulating [Ca2+]cyt.

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Pulmonary artery pressure and arterial oxygen saturation in people living at high or low altitude: systematic review and meta-analysis

Journal of Applied Physiology ◽

10.1152/japplphysiol.00394.2016 ◽

2016 ◽

Vol 121 (5) ◽

pp. 1151-1159 ◽

Cited By ~ 25

Author(s):

Rodrigo Soria ◽

Matthias Egger ◽

Urs Scherrer ◽

Nicole Bender ◽

Stefano F. Rimoldi

Keyword(s):

Systematic Review ◽

Pulmonary Artery ◽

Oxygen Saturation ◽

High Altitude ◽

Pulmonary Artery Pressure ◽

Meta Analysis ◽

Arterial Oxygen Saturation ◽

Arterial Oxygen ◽

Low Altitude ◽

Apparently Healthy

More than 140 million people are living at high altitude worldwide. An increase of pulmonary artery pressure (PAP) is a hallmark of high-altitude exposure and, if pronounced, may be associated with important morbidity and mortality. Surprisingly, there is little information on the usual PAP in high-altitude populations. We, therefore, conducted a systematic review (MEDLINE and EMBASE) and meta-analysis of studies published (in English or Spanish) between 2000 and 2015 on echocardiographic estimations of PAP and measurements of arterial oxygen saturation in apparently healthy participants from general populations of high-altitude dwellers (>2,500 m). For comparison, we similarly analyzed data published on these variables during the same period for populations living at low altitude. Twelve high-altitude studies comprising 834 participants and 18 low-altitude studies (710 participants) fulfilled the inclusion criteria. All but one high-altitude studies were performed between 3,600 and 4,350 m. The combined mean systolic PAP (right ventricular-to-right atrial pressure gradient) at high altitude [25.3 mmHg, 95% confidence interval (CI) 24.0, 26.7], as expected was significantly (P < 0.001) higher than at low altitude (18.4 mmHg, 95% CI 17.1,19.7), and arterial oxygen saturation was significantly lower (90.4%, 95% CI 89.3, 91.5) than at low altitude (98.1%; 95% CI 97.7, 98.4). These findings indicate that at an altitude where the very large majority of high-altitude populations are living, pulmonary hypertension appears to be rare. The reference values and distributions for PAP and arterial oxygen saturation in apparently healthy high-altitude dwellers provided by this meta-analysis will be useful to future studies on the adjustments to high altitude in humans.

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Effect of Single Dose In Vivo Propranolol Therapy on In Vitro Adhesion of Human SS RBC.

Blood ◽

10.1182/blood.v108.11.1234.1234 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1234-1234 ◽

Cited By ~ 1

Author(s):

Laura M. De Castro ◽

Jude C. Jonassaint ◽

Jennifer G. Johnson ◽

Milena Batchvarova ◽

Marilyn J. Telen

Keyword(s):

Safety Data ◽

Study Drug ◽

Flow Chamber ◽

In Vivo Studies ◽

Dependent Manner ◽

Number Of Patients ◽

Significant Difference ◽

Before And After

Abstract Sickle red blood cells (SS RBC) are abnormally adhesive to both endothelial cells (ECs) and components of the extracellular matrix (ECM). Epinephrine (epi) has been shown to elevate cAMP in SS RBC and increase adhesion of SS RBC to ECs in a protein kinase A-dependent manner. In vitro and in vivo studies performed in our lab have led to the hypothesis that adrenergic stimuli such as epi may initiate or exacerbate vaso-occlusion and thus contribute to the association of vaso-occlusive events with physiologic stress. We are conducting a prospective, dose-escalation pilot clinical study to investigate whether in vivo administration of one dose of propranolol either down-regulates baseline SS RBC adhesion in vitro or prevents its upregulation by epi. In addition, this study will provide additional safety data regarding the use of propranolol in normotensive patients with sickle cell disease (SCD). Figure Figure To date, we have completed the first two dose cohorts. 11 subjects (9 SS and 1 Sβ° thalassemia; 7 females, 3 males) have participated. No severe adverse events were noted. Cohorts 1 and 2 had mean pre-propranolol blood pressure (BP) of 116 (5.9 SD)/ 60.4 (3.98 SD) and 106.8 (4.68 SD)/ 58 (3.9 SD), respectively; this difference was not statistically significant. Minimal and asymptomatic changes in BP were noted in both cohorts after drug administration, with biphasic systolic and diastolic BP nadirs at 45 and 240 minutes. No clinically significant changes in heart rate were observed. Adhesion studies were performed using a graduated height flow chamber on the day of RBC collection. RBC adhesion to ECs was studied before and after epi stimulation and was measured at sheer stresses ranging from 1 to 3 dyne/cm2. Baseline adhesion measurements were validated by comparing percent (%) adhesion assayed at 2 different times within 7 days—at screening and before propranolol dose on the study drug day. We observed no significant difference in adhesion at the 2 different time points without propranolol. Comparison of % adhesion of epi-stimulated RBC to ECs before and 1 hour after propranolol showed that propranolol given in vivo significantly inhibited both non-stimulated and epi-stimulated SS RBC adhesion (p=0.04 and p=0.001, respectively). Lastly, comparison of SS RBC adhesion at both drug doses confirmed the drug-related inhibition of adhesion (p<0.004). We conclude that propranolol administered in vivo decreases SS RBC baseline adhesion to ECs and substantially abrogates epi-stimulated adhesion to ECs, as measured in vitro. Although we have thus far studied only a small number of patients and low propranolol doses, we expect to confirm these results with the 3rd cohort, in which a higher dose of propranolol will be used. If our findings continue to show that propranolol can decrease both SS RBC baseline and epi-stimulated adhesion to ECs, study of propranolol on a larger scale would be warranted in order to ascertain its safety and efficacy as an anti-adhesive therapy in SCD.

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