Fred C Sander

University of California, Los Angeles, Los Ángeles, California, United States

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Publications (9)30.45 Total impact

  • Fred Sander · Yuansheng Gao · J Usha Raj ·

    Chest 01/2006; 128(6 Suppl):577S-578S. DOI:10.1378/chest.128.6_suppl.577S-a · 7.48 Impact Factor
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    ABSTRACT: Continuous exposure to nitrovasodilators and nitric oxide induces tolerance to their vasodilator effects in vascular smooth muscle. This study was done to determine the role of cGMP-dependent protein kinase (PKG) in the development of tolerance to nitric oxide. Isolated fourth-generation pulmonary veins of newborn lambs were studied. Incubation of veins for 20 h with DETA NONOate (DETA NO; a stable nitric oxide donor) significantly reduced their relaxation response to the nitric oxide donor and to beta-phenyl-1,N2-etheno-8-bromo-cGMP (8-Br-PET-cGMP, a cell-permeable cGMP analog). Incubation with DETA NO significantly reduced PKG activity and protein and mRNA levels in the vessels. These effects were prevented by 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (an inhibitor of soluble guanylyl cyclase) and Rp-8-Br-PET-cGMPS (an inhibitor of PKG). A decrease in PKG protein and mRNA levels was also observed after continuous exposure to cGMP analogs. The PKG inhibitor abrogated these effects. The decrease in cGMP-mediated relaxation and in PKG activity caused by continuous exposure to DETA NO was not affected by KT-5720, an inhibitor of cAMP-dependent protein kinase. Prolonged exposure to 8-Br-cAMP (a cell-permeable cAMP analog) did not affect PKG protein level in the veins. These results suggest that continuous exposure to nitric oxide or cGMP downregulates PKG by a PKG-dependent mechanism. Such a negative feedback mechanism may contribute to the development of tolerance to nitric oxide in pulmonary veins of newborn lambs.
    AJP Lung Cellular and Molecular Physiology 05/2004; 286(4):L786-92. DOI:10.1152/ajplung.00314.2003 · 4.08 Impact Factor
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    ABSTRACT: Cyclic GMP-dependent protein kinase (PKG) plays an important role in regulating pulmonary vasomotor tone in the perinatal period. In this study, we tested the hypothesis that a change in oxygen tension affects PKG-mediated pulmonary vasodilation. Isolated intrapulmonary arteries and veins of near-term fetal lambs were first incubated for 4 h under hypoxic and normoxic conditions (Po2 of 30 and 140 mmHg, respectively) and then contracted with endothelin-1. 8-Bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP), a cell membrane-permeable analog of cGMP, induced a greater relaxation in vessels incubated in normoxia than in hypoxia. beta-Phenyl-1,N2-etheno-8-bromoguanosine-3',5'-cyclic monophosphorothioate, Rp isomer (Rp-8-Br-PET-cGMPS), a selective inhibitor of PKG, attenuated relaxation induced by 8-BrcGMP (10-4 and 3 x 10-4 M). In the presence of Rp-8-Br-PET-cGMPS, the differential responses to 8-BrcGMP between hypoxia and normoxia treatment were abolished in veins but not in arteries. cGMP-stimulated PKG activity was present in arteries but not in veins after 4 h of hypoxia. Both vessel types showed significant increase in cGMP-stimulated PKG activity after 4 h of normoxia. PKG protein (Western blot analysis) and PKG mRNA levels (quantitative RT-PCR) were greater in veins but not in arteries after 4-h exposure to normoxia vs. hypoxia. These results demonstrate that oxygen augments cGMP-mediated vasodilation of fetal pulmonary arteries and veins. Furthermore, the effect of oxygen on response of the veins to cGMP is due to an increase in the activity, protein level, and mRNA of PKG.
    AJP Lung Cellular and Molecular Physiology 10/2003; 285(3):L611-8. DOI:10.1152/ajplung.00411.2002 · 4.08 Impact Factor
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    ABSTRACT: To provide molecular insight into the pathophysiology of Peyronie's disease (PD), a preliminary profile of differential gene expression between the PD plaque and control tunica albuginea was obtained with DNA microarrays. Seven PD plaques and five control tunica albugineas were studied. cDNA specimens were prepared from RNA isolated from one calcified PD plaque and one control tissue and hybridized with the Clontech Atlas 1.2 Array. Another set of plaque and control RNA samples was hybridized with the Affymetrix GeneChip. Relative changes of greater than 2.0 defined up-regulation and down-regulation, respectively. RNA from the remaining tissues was used to determine, by reverse transcriptase-polymerase chain reaction and Western blot analysis, the expression of selected individual genes. Some of up-regulated genes in the PD plaque detected by the Clontech assay were pleiotrophin, monocyte chemotactic protein 1, and early growth response protein, which are involved in osteoblast recruitment, inflammation, and fibroblast proliferation, respectively. Ubiquitin and Id-2, which are involved in tissue remodeling, were down-regulated. The Affymetrix DNA chips identified the up-regulation of elastase (involved in elastic fiber degradation) and the myofibroblast markers alpha and gamma-smooth muscle actin, desmin, and others, as well as the down-regulation of collagenase IV and transforming growth factor-beta modulators. Four of the five genes selected for reverse transcriptase-polymerase chain reaction and Western blotting confirmed the DNA microarray results. In the PD tissue, the genes involved in collagen synthesis, myofibroblast differentiation, tissue remodeling, inflammation, ossification, and proteolysis are up-regulated, and the genes that inhibit some of these processes and collagenase are down-regulated.
    Urology 04/2002; 59(3):451-7. DOI:10.1016/S0090-4295(01)01578-3 · 2.19 Impact Factor
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    ABSTRACT: Atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) are important dilators of the pulmonary circulation during the perinatal period. We compared the responses of pulmonary arteries (PA) and veins (PV) of newborn lambs to these peptides. ANP caused a greater relaxation of PA than of PV, and CNP caused a greater relaxation of PV than of PA. RIA showed that ANP induced a greater increase in cGMP content of PA than CNP. In PV, ANP and CNP caused a similar moderate increase in cGMP content. Receptor binding study showed more specific binding sites for ANP than for CNP in PA and more for CNP than for ANP in PV. Relative quantitative RT-PCR for natriuretic peptide receptor A (NPR-A) and B (NPR-B) mRNAs show that, in PA, NPR-A mRNA is more prevalent than NPR-B mRNA, whereas, in PV, NPR-B mRNA is more prevalent than NPR-A mRNA. In conclusion, in the pulmonary circulation, arteries are the major site of action for ANP, and veins are the major site for CNP. Furthermore, the differences in receptor abundance and the involvement of a cGMP-independent mechanism may contribute to the heterogeneous effects of the natriuretic peptides in PA and PV of newborn lambs.
    AJP Heart and Circulatory Physiology 02/2002; 282(1):H273-80. · 3.84 Impact Factor
  • B O Ibe · F C Sander · J U Raj ·
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    ABSTRACT: Platelet-activating factor (PAF) is a phospholipid with diverse biological functions mediated by a G protein-coupled receptor. We determined PAF receptor binding in lung membranes of four groups of perinatal lambs. Membrane protein (100 microg/ml) was incubated for 60 min at 30 degrees C with 0.5-24 nM of acetyl-[(3)H]PAF in 30 mM Tris buffer, pH 7.2, containing 0.25% BSA, 10 mM MgCl(2), and 125 mM choline chloride. PAF bound to membrane was isolated and quantified by scintillation spectrometry, followed with Scatchard analysis for receptor density (B(max)). The B(max) (means +/- SE, fmol/mg protein) were 445.8 +/- 12.3, 244.2 +/- 3.3, 250.6 +/- 3.6, and 419. 9 +/- 8.6 for the fetal, 90-min-old, <1-day-old, and 6- to 12-day-old lambs, respectively. The B(max) for the 90-min-old and <1-day-old lambs were not different but were significantly lower than those of either the term fetal or 6- to 12-day-old lambs. These data show a significant decrease in PAF binding to its receptor and in PAF B(max) in lung membranes of immediate newborn lambs. The dissociation constants (K(D), nM) were 7.7 +/- 0.52, 11.5 +/- 0.34, 6.9 +/- 0.48, and 5.0 +/- 0.53 for fetal, 90-min-old, <1-day-old, and 6- to 12-day-old newborn lamb lungs, respectively. The K(D) of the 90-min-old lamb was the highest of all. PAF receptor gene measured by RT-PCR showed a significant downregulation of PAF receptor gene mRNA in lungs of lambs <1 day old, suggesting a transcriptional regulation of PAF receptor gene expression in the immediate newborn period. We speculate that decreased PAF receptor binding immediately after birth will facilitate the fall in pulmonary vascular resistance in the immediate newborn period.
    AJP Heart and Circulatory Physiology 04/2000; 278(4):H1168-76. · 3.84 Impact Factor
  • Basil O. Ibe · Fred C. Sander · J.Usha Raj ·
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    ABSTRACT: We recently showed that platelet activating factor (PAF) is an important modulator of pulmonary vasomotor tone in the fetus, with a significant decrease in circulating PAF levels in the immediate newborn period. In this study, we have determined PAF catabolism by PAF acetylhydrolase (PAF-Ah) in lungs of near-term fetal and newborn 2- to 16-h (<1 day) and 6- to 12-day-old lambs. The rate of PAF catabolism by lung homogenate protein from the three groups of lamb lungs was studied at 37 degrees C in 30 mM Tris buffer, pH 7.5, containing 0.01% BSA. Each lung homogenate protein was incubated for 10 min with 50 microM [(3)H]acetyl-PAF at pO(2) <50 Torr (hypoxia) and approximately 100 Torr (normoxia). PAF-Ah activity was quantified as amount of lyso-PAF produced. PAF-Ah activity (means +/- SEM, nmol lyso-PAF/min/mg protein) in fetal lung homogenate was 1.19 +/- 0.14 and 2.46 +/- 0.05 during hypoxia and normoxia, respectively. The corresponding values for the newborns were newborn <1 day, 1.65 +/- 0.26 and 2.95 +/- 0.07 and newborn 6-12 days, 1.25 +/- 0.10 and 2.84 +/- 0.05. In all groups, PAF-Ah activity was higher in normoxia than in hypoxia. During normoxia, PAF-Ah activity in newborn <1 day was significantly higher than the activity in fetus, but similar to the activity in newborn 6- to 12-day-old lamb lungs. These data show a significant up-regulation of PAF-Ah activity in lungs in the immediate newborn period. PAF-Ah gene expression measured by RT-PCR showed a significant up-regulation of the PAF-Ah gene in lungs of lambs <1 day old, suggesting a transcriptional regulation of the PAF-Ah gene in the immediate newborn period. These results suggest that up-regulation of PAF-Ah activity after birth with oxygenation will result in a decrease in circulating PAF levels, thereby facilitating the fall in pulmonary vascular resistance in the immediate newborn period.
    Molecular Genetics and Metabolism 01/2000; 69(1):46-55. DOI:10.1006/mgme.1999.2940 · 2.63 Impact Factor

  • Pediatric Research 04/1998; 43. DOI:10.1203/00006450-199804001-01618 · 2.31 Impact Factor
  • Usha Raj · Yuansheng Gao · Srinivas Dhanakoti · Fred Sander ·
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    ABSTRACT: At birth, the increase in oxygen tension results in upregulation of the nitric oxide-cGMP pathway in the pulmonary vasculature and facilitates vasodilation and a fall in pulmonary vascular resistance. In the perinatal period, both cAMP and cyclic guanosine monophosphate (cGMP) act via cGMP-dependent protein kinase (PKG) in mediating relaxation of the pulmonary circulation, with cGMP working predominantly via PKG. Oxygen exposure results in an increase in PKG activity, PKG protein content, and mRNA expression in fetal pulmonary vascular smooth muscle. The increased production of reactive oxygen species in pulmonary vascular smooth muscle that occurs during hypoxia in the fetus is responsible for downregulation of PKG activity and the PKG protein levels in pulmonary vascular smooth muscle in the fetus, which is reversed on exposure to increased oxygen tension at birth. PKG mRNA expression also appears to be regulated by nitric oxide and cGMP, such that chronic exposure of pulmonary vascular smooth muscle to nitric oxide and cGMP results in downregulation of PKG mRNA levels. This might be one mechanism by which chronic inhalation therapy with nitric oxide in neonates with persistent pulmonary hypertension of the newborn results in development of resistance to nitric oxide-mediated vasodilation in the pulmonary circulation.
    01/1970: pages 35-45;