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PubMed1994

Transforming growth factor beta 1 inhibits interleukin-1-induced but enhances ionomycin-induced interferon-gamma production in a T cell lymphoma: comparison with the effects of rapamycin.

Transforming growth factor beta 1 (TGF-beta 1) is a multifunctional cytokine whose potent immunomodulatory activity is well documented. To explore the mechanisms of this activity we examined the effect of TGF-beta 1 on the production of IFN-gamma measured at the mRNA and protein levels in the YAC-1 T cell lymphoma. In previous studies, this model proved useful to characterize the mode of action of the immunosuppressant rapamycin (RAP). Here, we found that when induced by IL-1 or IL-1 + PMA, the production of IFN-gamma is suppressed by both TGF-beta 1 (ED50 = 1.9 pM) and RAP (ED50 = 0.2 nM). In contrast, when induced by the calcium ionophore ionomycin, in the absence or in the presence of PMA, this production is enhanced up to 10-fold by TGF-beta 1 (ED50 = 1.8 pM) and 1.5-3-fold by RAP. Therefore, in YAC-1 cells, TGF-beta 1 exerts opposite effects on IFN-gamma production depending on the mode of activation, and these effects parallel those of RAP. To further analyze the mode of action of TGF-beta 1 in this system, we used okadaic acid (OA), an inhibitor of serine/threonine protein phosphatases. Treatment with OA rendered the expression of IFN-gamma mRNA induced by IL-1 insensitive to TGF-beta 1 or RAP, indicating that activation of a phosphatase may play a role in the suppressive effect of both agents. However, OA did not prevent the augmentation of ionomycin-mediated induction of IFN-gamma mRNA by either TGF-beta 1 or RAP. Hence, the up-regulation of IFN-gamma production by TGF-beta 1 and RAP may involve a different biochemical mechanism than that mediating their suppressive action. These observations also favor the hypothesis that the two agents act on the same regulatory pathways. This was further supported by the finding that TGF-beta 1 and RAP modulate IFN-gamma production in an additive rather than synergistic fashion. However, their effects could be dissociated in mutants of YAC-1 cells selected for resistance to the inhibition of IL-1-mediated IFN-gamma induction by RAP. Moreover, the IFN-gamma modulatory action of RAP in YAC-1 cells was accompanied by an antiproliferative effect, whereas TGF-beta 1 failed to alter the growth of these cells. Therefore, the immunomodulatory action of TGF-beta 1 may result from the disruption of biochemical processes related to, although distinct from, those affected by RAP.

Animals↗

PubMed1995

Differential effect of rapamycin and cyclosporin A in proliferation in a murine T cell line expressing either intermediate or high affinity receptor for IL-2.

It has been reported that rapamycin (rap), cyclosporin A (CsA) and FK506 have immunosuppressive effect during the activation process of murine T cells. These drugs were investigated for their suppressive effect on a murine T cell line expressing intermediate (TS1 beta) or high (TS1 alpha beta) affinity IL-2R. Rap and CsA strongly inhibit the IL-2-dependent proliferation of TS1 alpha beta cells while they minimally affect the IL-2-mediated proliferation of TS1 beta cells. FK506 does not have any effect on the IL-2-driven proliferation of either TS1 beta or TS1 alpha beta cells. Simultaneous addition of Rap and CsA or Rap and FK506 inhibit the IL-2-mediated proliferation of TS1 beta and TS1 alpha beta cells and therefore FK506 does not revert the inhibition mediated by Rap in TS1 alpha beta cells. Neither Rap nor CsA affect IL-2R expression and internalization in TS1 alpha beta cells. CsA and Rap strongly inhibit the appearance of DNA binding activity of NF-AT and to a lesser extent NF-kappa B. Rap inhibits IL-2-stimulated phosphatidylinositol 3 (PI3) kinase activity in TS1 alpha beta cells. In TS1 beta cells, Rap activates PI3 kinase on its own, inhibiting the IL-2-stimulated PI3 kinase to a lesser extent. These results suggest that PI3 kinase is a target for Rap action. Our results strongly suggest that we have Rap and CsA sensitive and resistant activation pathways operating in TS1 beta and TS1 alpha beta cells.

Base Sequence↗

PubMed1987

Effect of age, gender, and parity on anal canal pressures. Contribution of impaired anal sphincter function to fecal incontinence.

The contribution of the resting anal canal pressure (RAP) and the maximal squeeze pressure (MSP) to the problem of fecal incontinence was assessed by comparing 143 incontinent patients to a control population of 157 healthy subjects. These parameters were determined using a multilumen continuously perfused catheter and a mechanized rapid pull-through technique. In 10 male volunteers both RAP and MSP were determined using catheters that varied from 3 mm to 18 mm in diameter. In the control population, the RAP was significantly lower in females 40 years of age and over as compared to males. MSP values were significantly lower in females at virtually all ages. In women, parity did not correlate with RAP (coefficient = -0.099, P greater than 0.05) and MSP (coefficient = -0.123, P greater than 0.05) and any decrease in pressures was related to aging. Aging in women was associated with a consistent reduction in RAP (coefficient = -0.614, P less than 0.00005) and MSP (coefficient = -0.372, P = 0.0006). In males, there was a similar but less impressive age-related reduction for the RAP (coefficient = -0.333, P = 0.006) but not for the MSP (coefficient = -0.196, P greater than 0.05). Nine percent of the volunteer population were essentially unable to increase the RAP with maximal squeeze efforts. A linear increase in anal pressures was recorded as catheter diameter increased from 3 to 12 mm. Normative data for the RAP and MSP (mean +/- 2 SD) were constructed for each sex on a decade basis and showed a wide range of pressures for each age grouping. In the group with fecal incontinence (FI) 39% of females and 44% of males fell within the "normal" range for both the RAP and MSP. For all patients with FI, 41% and 17% had impairment of one or both parameters, respectively. It is concluded that: aging affects the RAP in both sexes but to a greater degree in women. The MSP is related to aging in women only; child bearing has no effect upon these parameters; clinical problems of bowel control can occur when sphincter pressure measurements are within the low "normal" range; and recording instrument diameter consistently affects RAP and MSP.

Adult↗

PubMed2004

The low-density lipoprotein receptor-related protein associates with calnexin, calreticulin, and protein disulfide isomerase in receptor-associated-protein-deficient fibroblasts.

The low-density lipoprotein receptor-related protein (LRP) is a large (>600 kDa) multi-ligand-binding cell surface receptor that is now known to participate in a diverse range of cellular events. To accomplish this diverse role, LRP is composed of repetitive amino acid motifs consisting of complement-type and EGF precursor-type repeats. Within these repeats are six conserved cysteine residues that form the core disulfide bond structure of each repeat. To accommodate the intricate folding that such a complex structure dictates, a specialized chaperone is present in the endoplasmic reticulum (ER) called the receptor-associated protein (RAP) that binds to LRP immediately following its biosynthesis and assists in its exocytic transport. Interestingly, RAP -/- mice show reduced LRP expression in certain cell types, but not a more global affect on LRP expression that was expected. Such a tissue-restricted effect by RAP prompted an investigation if other ER chaperones associate with LRP to assist in its complex folding requirements and compensate for the absence of RAP in RAP -/- cells. Fibroblasts obtained from RAP -/- mice demonstrate similar LRP expression levels and subcellular distribution as RAP +/+ fibroblasts. Moreover, RAP -/- cells show an identical exocytic trafficking rate for LRP as RAP +/+ cells and comparable cell surface internalization kinetics. In RAP -/- cells, three well-known ER chaperones, calnexin, calreticulin, and protein disulfide isomerase (PDI), associate with LRP and likely compensate for the absence of RAP.

Animals↗

PubMed2003

Retrograde autologous priming: is it useful in elective on-pump coronary artery bypass surgery?

BACKGROUND: The effect of reduced cardiopulmonary bypass (CPB) prime volume by retrograde autologous priming (RAP) was studied. METHODS: Twenty patients undergoing elective coronary artery bypass grafting were randomized to either standard prime (SP) volume (1,602 +/- 202 mL crystalloid prime, n = 10) or RAP (395 +/- 150 mL). RAP was performed by draining crystalloid prime from the arterial and venous lines into a recirculation bag before CPB. Cardiac index, pulmonary vascular resistance index, systemic vascular resistance index, alveolar-arterial oxygen tension difference, pulmonary shunt fraction, extravascular lung water (EVLW), plasma colloid osmotic pressure (COP), crystalloid fluid balance, body weight, and clinical parameters were evaluated perioperatively. RESULTS: Demographic data and operative parameters were equal for patients in both groups. During CPB, COP was reduced by 55% in the SP group (9.8 +/- 2.0 vs 21.4 +/- 2.1 mm Hg) and by 41% in the RAP group (12.4 +/- 1.1 vs 20.9 +/- 1.8 mm Hg) (p = 0.008, SP vs RAP group). Compared with preoperatively, EVLW was unchanged in the RAP group 2 hours post-CPB, but it was elevated by 21% in the SP group (p = 0.002, SP vs RAP group). End-CPB crystalloid fluid balance was significantly reduced in the RAP group (1,857 +/- 521 vs 2,831 +/- 637 mL). Postoperative (day 2) weight gain in the SP group (1.5 +/- 1.2 kg, p = 0.021) was absent in the RAP group (0.1 +/- 0.9, NS). Postoperative time to full mobilization was shorter in the RAP group. Postpump cardio-respiratory function did not differ among groups. CONCLUSIONS: This small-scale pilot study indicates that by reducing crystalloid fluid administration and fall of COP during CPB, RAP reduces postpump EVLW accumulation and weight gain in uncomplicated coronary artery bypass graft patients with no associated effects on cardio-respiratory function.

Blood Transfusion, Autologous↗

PubMed2006

Perioperative complications of laparoscopic and robotic assisted laparoscopic radical prostatectomy.

PURPOSE: While it remains controversial whether LRP or da Vinci RAP offers any advantages over radical retropubic prostatectomy, LRP and RAP are being used more frequently. We reviewed our experience with these minimally invasive techniques. MATERIALS AND METHODS: We reviewed intraoperative and early postoperative complications of 358 LRPs performed from October 2000 to January 2003 with those of 322 RAPs performed from June 2003 to June 2004. The transperitoneal approach with bilateral pelvic lymph node dissection was performed using each technique. Data acquisition was done independently of the 3 surgeons. RESULTS: The LRP and RAP groups had similar clinical characteristics in terms of patient race, body mass index, prostate specific antigen, risk group, and pathological tumor grade and stage. Median operative time and estimated blood loss for LRP and RAP were 4.1 and 3.1 hours, and 200 and 250 ml, respectively. No blood transfusions were given intraoperatively, although 8 patients with LRP (2.2%) and 5 with RAP (1.6%) were transfused postoperatively. Of the LRP and RAP patients 21 (5.9%) and 3 (0.3%), respectively, experienced intraoperative complications. Postoperatively 48 patients with LRP (13.4%) and 24 with RAP (6.8%) experienced urine leakage, while 19 with LRP (5.3%) and 9 with RAP (2.8%) had ileus. There were no deaths, myocardial infarctions, pulmonary emboli or cerebrovascular accidents. CONCLUSIONS: In our series surgeon experience derived from LRP may contribute to the lower complication rate and operative time of RAP. Dissemination of surgical technique and management of complications may lead to improved perioperative LRP and RAP morbidity. However, the morbidity of these 2 approaches compares favorably with that of radical retropubic prostatectomy.

Adult↗

PubMed2000

Identification, characterization and cDNA cloning of two novel proteins secreted into the external space of the regenerating leg of Periplaneta americana.

We have isolated two proteins (Rap 60 and Rap 40) that were expressed specifically in regenerating legs of the American cockroach (Periplaneta americana). These proteins appear to be derived from a precursor protein with 443 amino acid residues termed regeneration-associated protein (RAP). Rap 60 and Rap 40 corresponded to Glu 223 to Ser 443 and Glu 223 to Glu 366 of RAP, respectively. Hence, Rap 40 is the N-terminal part of Rap 60. These proteins contained 13 repeats of a novel motif, [Glu/Asp-Glu/Asp-Val/Ala-Lys]. The gene encoding RAP was shown to be expressed during embryogenesis and by newly-formed epidermal cells of regenerating legs. Rap 60 and Rap 40 were secreted into the external space of regenerating leg saccules, where they accumulated, suggesting that they are components of extracellular matrix of regenerating leg saccules.

Amino Acid Sequence↗

PubMed1995

The 39-kDa receptor-associated protein modulates lipoprotein catabolism by binding to LDL receptors.

The 39-kDa receptor-associated protein (RAP) is cosynthesized and co-purifies with the low density lipoprotein receptor-related protein (LRP)/alpha 2-macroglobulin receptor and is thought to modulate ligand binding to LRP. In addition to binding LRP, RAP binds two other members of the low density lipoprotein (LDL) receptor family, gp330 and very low density lipoprotein (VLDL) receptors. Here, we show that RAP binds to LDL receptors as well. In normal human foreskin fibroblasts, RAP inhibited LDL receptor-mediated binding and catabolism of LDL and VLDL with Sf 20-60 or 100-400. RAP inhibited 125I-labeled LDL and Sf 100-400 lipoprotein binding at 4 degrees C with KI values of 60 and 45 nM, respectively. The effective concentrations for 50% inhibition (EC50) of cellular degradation of 2.0 nM 125I-labeled LDL, 4.7 nM 125I-labeled Sf 20-60, and 3.6 nM 125I-labeled Sf 100-400 particles were 40, 70, and 51 nM, respectively. Treatment of cells with lovastatin to induce LDL receptors increased cellular binding, internalization, and degradation of RAP by 2.3-, 1.7-, and 2.6-fold, respectively. In solid-phase assays, RAP bound to partially purified LDL receptors in a dose-dependent manner. The dissociation constant (KD) of RAP binding to LDL receptors in the solid-phase assay was 250 nM, which is higher than that for LRP, gp330, or VLDL receptors in similar assays by a factor of 14 to 350. Also, RAP inhibited 125I-labeled LDL and Sf 100-400 VLDL binding to LDL receptors in solid-phase assays with KI values of 140 and 130 nM, respectively. Because LDL bind via apolipoprotein (apo) B100 whereas VLDL bind via apoE, our results show that RAP inhibits LDL receptor interactions with both apoB100 and apoE. These studies establish that RAP is capable of binding to LDL receptors and modulating cellular catabolism of LDL and VLDL by this pathway.

Carrier Proteins↗

PubMed1995

Analysis of ligand binding to the alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein. Evidence that lipoprotein lipase and the carboxyl-terminal domain of the receptor-associated protein bind to the same site.

The endocytic alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2MR/LRP) binds several classes of extracellular ligands at independent sites. In addition, alpha 2MR/LRP can bind multiple copies of the 39-40-kDa receptor-associated protein (RAP). Both amino-terminal and carboxyl-terminal fragments of RAP exhibit affinity, and the fragments apparently bind to different sites on the receptor. RAP completely inhibits the binding of all presently known extracellular ligands, whereas several ligands such as alpha 2-macroglobulin and tissue-type plasminogen activator are poor inhibitors of RAP binding. Since RAP is largely an intracellular molecule that normally does not occupy alpha 2MR/LRP at the cell surface, we hypothesized that an established extracellular ligand might bind to those sites on the receptor capable of binding the RAP fragments. We found complete cross-competition between carboxyl-terminal RAP fragments and fragments of lipoprotein lipase containing the recently identified binding domain for alpha 2MR/LRP (Nykjaer, A., Nielsen, M., Lookene, A., Meyer, N., Røigaard, H., Etzerodt, M., Beisiegel, U., Olivecrona, G., and Gliemann, J. (1994) J. Biol. Chem. 269, 31747-31755). Moreover, the lipoprotein lipase fragment completely inhibited the binding of several alpha 2MR/LRP ligands in a pattern similar to that of carboxyl-terminal RAP fragments. On the other hand, the amino-terminal RAP fragment was a poor competitor of binding of the lipoprotein lipase fragment, whereas it competed effectively with pro-uPA for binding to the receptor. The results provide evidence that lipoprotein lipase binds to the site on alpha2MR/LRP also available for binding of the carboxyl-terminal domain of RAP and suggest that pro-uPA may bind to or overlap the site available for the amino-terminal domain of RAP.

Amino Acid Sequence↗

PubMed1999

The carboxyl-terminal domain of receptor-associated protein facilitates proper folding and trafficking of the very low density lipoprotein receptor by interaction with the three amino-terminal ligand-binding repeats of the receptor.

The 39-kDa receptor-associated protein (RAP) is a specialized antagonist that inhibits all known ligand interactions with receptors that belong to the low density lipoprotein (LDL) receptor gene family. Recent studies have demonstrated a role for RAP as a molecular chaperone for the LDL receptor-related protein during receptor folding and trafficking within the early secretory pathway. In the present study, we investigated a potential role for RAP as a chaperone for the very low density lipoprotein (VLDL) receptor, another member of the LDL receptor gene family. Using intracellular cross-linking techniques, we found that RAP is associated with newly synthesized VLDL receptor. In the absence of RAP co-expression, newly synthesized VLDL receptor exhibited slower trafficking along the early secretory pathway, most likely due to misfolding of the receptor. The role of RAP in the folding of the VLDL receptor was further studied using an anchor-free, soluble VLDL receptor. Metabolic pulse-chase labeling experiments showed that while only 3% of the soluble VLDL receptor was folded and secreted in the absence of RAP co-expression, over 50% of the soluble receptor was secreted in the presence of RAP co-expression. The functions of RAP in VLDL receptor folding and trafficking were mediated by its carboxyl-terminal repeat but not by the amino-terminal and central repeats. Using truncated VLDL receptor constructs, we identified the RAP-binding site within the first three ligand-binding repeats of the VLDL receptor. Thus, our present study demonstrates that RAP serves as a folding and trafficking chaperone for the VLDL receptor via interactions of its carboxyl-terminal repeat with the three amino-terminal ligand-binding repeats of the VLDL receptor.

Binding Sites↗

PubMed2005

Nature and risk of neovascularization in the fellow eye of patients with unilateral retinal angiomatous proliferation.

PURPOSE: To determine the nature and risk of neovascularization in the fellow eyes of patients with unilateral retinal angiomatous proliferation (RAP), a neovascular form of age-related macular degeneration (AMD). METHODS: A consecutive series of 52 patients diagnosed with unilateral RAP were studied retrospectively. Clinical biomicroscopic examination, fluorescein angiography, and indocyanine green angiography were used to evaluate all patients for the development of neovascular manifestations in the fellow eye. RESULTS: Neovascularization developed in the fellow eye in 52 patients over the follow-up period (range, 2-36 months). All patients developed neovascular manifestations of RAP in the fellow eye. Twenty-one patients (40%) developed a RAP lesion within 1 year; 29 (56%), within 2 years; and 52 (100%), within 3 years. At the time of diagnosis of neovascularization in the fellow eye, 8 patients (15%) had a stage I RAP lesion, 36 (70%) had a stage II RAP lesion, and 8 (15%) had a stage III RAP lesion. Other characteristic findings in these patients included the presence of preretinal, intraretinal, and subretinal hemorrhages in 49 patients (94%) and pigment epithelial detachments in 41 patients (79%). CONCLUSIONS: In patients diagnosed with unilateral RAP lesions, the form of neovascularization that develops in the fellow eye is virtually always RAP. The annual and accumulative risk of neovascularization in the fellow eye is higher in patients with RAP than in those with other forms of neovascular AMD. These new findings enhance our understanding of the clinical spectrum of RAP in terms of its natural course and visual prognosis and may possibly offer useful information to establish future treatment options.

Aged↗

PubMed2003

Superior T-cell suppression by rapamycin and FK506 over rapamycin and cyclosporine A because of abrogated cytotoxic T-lymphocyte induction, impaired memory responses, and persistent apoptosis.

Immunosuppressive therapy is best achieved with a combination of agents targeting multiple activation steps of T cells. In transplantation, cyclosporine A (CsA) or tacrolimus (FK506) are successfully combined with rapamycin (Rap). Rap and CsA were first considered for combination therapy because FK506 and Rap target the same intracellular protein and thus may act in an antagonistic way. However, in clinical studies, FK506+Rap proved to be effective. To date, there is no in vitro data supporting these in vivo findings, and it is unclear whether the observed effects are T-cell mediated. In a human polyclonal allogeneic in vitro model, we found that although combined drug treatment markedly reduced expansion of naive T cells, T-cell activation occurred irrespective of the drug combination used. The induction of cytotoxic effector T cells was reduced by CsA+Rap but completely abolished by FK506+Rap. Importantly, combined immunosuppression allowed generation of memory CD4+ and CD8+ T cells and hence did not result in T-cell anergy. However, FK506+Rap treatment resulted in a reduced number of allospecific memory T cells showing a decreased cell-cycle turnover and cytokine producing capacity. In contrast, CsA+Rap treatment led to increased memory T-cell numbers responding with elevated kinetics. The ability of Rap to promote apoptosis, which contributes to T-cell suppression, remained unaffected upon combination with FK506 or CsA. These data support the combined use of FK506+Rap over CsA+Rap for immunosuppressive therapy.

Apoptosis↗

PubMed1985

Angiotensin II natriuresis and antinatriuresis: role of renal artery pressure, renal hemodynamics, and tubular reabsorption.

The aim of this study was to determine the role of changes in renal artery pressure (RAP), renal hemodynamics, and tubular reabsorption in mediating the natriuretic and antinatriuretic actions of angiotensin II (AII). In anesthetized dogs, endogenous AII formation was blocked with SQ-14225 and AII was infused i.v. at rates of 5-1215 ng/kg/min while RAP was either servo-controlled at the normal level or permitted to increase. When RAP was servo-controlled to prevent a rise i RAP, AII infusion at all rates from 5-1215 ng/kg/min decreased urinary sodium excretion (UNaV) and fractional sodium excretion (FENa), while increasing fractional reabsorption of lithium (FRLi), an index of proximal tubule fractional sodium reabsorption and distal fractional sodium reabsorption (FRDNa): When RAP was permitted to increase, AII infusion rates up to 45 ng/kg/min decreased UNaV, and FENa, while increasing FRLi and FRDNa. However, at 135 ng/kg/min and above, UNaV and FENa increased while FRLi and FRDNa decreased when RAP was allowed to rise, even though RBF and FF were not substantially different from the values observed when RAP was servo-controlled. Filtered sodium load was slightly higher when RAP was permitted to increase during AII infusion, compared to the dogs in which RAP was servo-controlled, although the differences were not statistically significant. Thus, even very large doses of AII cause antinatriuresis when RAP was prevented from increasing. The natriuretic effect of high dose of AII is caused by increased RAP which decreases fractional sodium reabsorption in proximal and distal tubules and causes slight increases in sodium delivery to the tubules.

Absorption↗

PubMed1996

Blockade of the alpha 2-macroglobulin receptor/low-density-lipoprotein-receptor-related protein on rat liver parenchymal cells by the 39-kDa receptor-associated protein leaves the interaction of beta-migrating very-low-density lipoprotein with the lipoprotein remnant receptor unaffected.

The nature of the liver binding site which is responsible for the initial recognition and clearance of chylomicron-remnants and beta-migrating very-low-density lipoprotein (beta-VLDL) is under active dispute. We have investigated the effect of the 39-kDa receptor-associated protein (RAP) on the recognition site for activated alpha 2-macroglobulin and beta-VLDL on rat liver parenchymal cells in vivo and in vitro in order to analyze whether both substrates are recognized and internalized by the same receptor system. Radiolabelled trypsin-activated alpha 2-macroglobulin (alpha 2M-T) was cleared rapidly by the liver (maximal uptake of 80.8 +/- 1.0% of the injected dose). Prior injection of 5, 15, or 50 mg gluthathione-S-transferase-linked RAP (GST-RAP)/kg rat reduced the liver uptake to 62.2 +/- 2.3%, 59.3 +/- 1.1%, or 2.9 +/- 0.1% of the injected dose, respectively. Concurrently the serum decay was strongly delayed after injection of 50 mg GST-RAP/kg rat but this did not affect the serum decay and liver uptake of 125I-beta-VLDL. Binding studies with isolated liver parenchymal cells in vitro demonstrated that the binding of 125I-alpha 2M-T was 98% inhibited by GST-RAP with an IC50 of 0.3 microgram/ml (4.2 nM), whereas the binding of 125I-beta-VLDL and 125I-beta-VLDL + recombinant apolipoprotein E (rec-apoE) was unaffected by GST-RAP up to 50 micrograms/ml (700 nM). Also, the cell association and degradation of alpha 2M-T was blocked by RAP, while the association and degradation of beta-VLDL and beta-VLDL + rec-apoE were not influenced. The inhibitory effect of RAP on the cell association and degradation of alpha 2M-T lasted for 1-2 h of incubation at 37 degrees C. The binding of the radioiodinated RAP to isolated liver parenchymal cells was highly efficiently coupled to lysosomal degradation. Upon in vivo injection into rats, 125I-labeled RAP is rapidly cleared from the serum and taken up by the liver, which is also coupled to efficient degradation. Since RAP blocks binding of all known ligands to the alpha 2-macroglobulin receptor/low-density lipoprotein receptor-related protein (the alpha 2Mr/LRP) and at high concentrations the binding to the LDL receptor, we conclude that the initial binding and internalization of beta-VLDL by rat liver parenchymal cells is not mediated by the alpha 2Mr/LRP. The properties of binding of beta-VLDL to rat liver parenchymal cells points to an apoE-specific recognition site for lipoprotein remnants which differs from the alpha 2Mr/LRP, proteoglycans and the LDL receptor and is tentatively called the lipoprotein remnant receptor.

Animals↗

PubMed1969

Studies in clinical shock and hypotension: VI. Relationship between left and right ventricular function.

Left ventricular end diastolic (LVEDP) and mean right atrial (RAP) pressures were recorded simultaneously in 30 patients with shock (14 acute myocardial infarction, 10 acute pulmonary embolism or severe bronchopulmonary disease, and 6 sepsis). Myocardial infarction was characterized by a predominant increase in LVEDP, pulmonary disease by a predominant increase in RAP, and sepsis by a normal relationship between LVEDP and RAP. In all three groups a significant positive correlation was noted between RAP and LVEDP, with the regression line in cor pulmonale deviated significantly toward the RAP axis and the regression line in myocardial infarction exhibiting a zero RAP intercept at an elevated LVEDP.Low cardiac outputs with elevated LVEDP in myocardial infarction indicated severe left ventricular failure. Low outputs with elevated RAP in cor pulmonale were consistent with right ventricular overload. Although cardiac outputs often were normal in sepsis, low outputs with elevated cardiac filling pressures in some patients were consistent with a hemodynamic or humoral-induced generalized depression of cardiac performance.Vasoconstrictor and inotropic drugs often produced a functional disparity between the two ventricles, with the gradient between LVEDP and RAP increasing, apparently because of an increase in left ventricular work or an inadequacy of left ventricular oxygen delivery. Acute plasma volume expansion with dextran in patients with pulmonary vascular disease resulted in a somewhat more rapid rise in RAP than in LVEDP. In septic and myocardial infarction shock, however, LVEDP and RAP usually rose proportionally, with the absolute rise of LVEDP surpassing that of RAP. Although the absolute level of the central venous pressure thus may not be a reliable indicator of left ventricular function in shock, changes in venous pressure during acute plasma volume expansion should serve as a fairly safe guide to changes in LVEDP.

Journal Article↗

PubMed1987

[Mechanism of the renin-angiotensin system and thromboxane A2 on the maintenance of GFR during reduced renal perfusion pressure in dogs].

The interaction between the renin-angiotensin (RA) system and thromboxane A2 (TXA2) was examined in dogs, before and during the renal artery pressure (RAP) was decreased. Intrarenal arterial administration of a small dose of angiotensin II (AII) reduced renal blood flow (RBF) and glomerular filtration rate (GFR) in non-treated dogs when RAP was maintained at the normal level. When mean RAP was decreased to 60 mmHg by means of an aortic clamp, AII reduced RBF, but increased GFR up to 122% of the control value. In dogs pretreated by captopril, GFR decreased when RAP was reduced to 60 mmHg, while RBF was well maintained. However, with the administration of AII, RBF decreased markedly. By indomethacin pretreatment, GFR and RBF decreased during reduced RAP, and their reduction rates were accelerated with the administration of AII into the renal artery. By pretreatment with the thromboxane A2 synthetase inhibitor UK38485, the changes of RBF and GFR following AII infusion were similar to nontreated dogs at normal RAP, but during reduced RAP, AII infusion into the renal artery decreased GFR to 80% of the control value. The thromboxane B2 (TXB2) production by the renal cortex during reduced RAP increased to 2.7-fold that at normal RAP, but TXB2 production did not increase during reduced RAP in captopril pretreated dogs. These results suggest that the RA system and prostanoids, especially TXA2, are important factors for maintaining GFR at low RAP.

Angiotensin II↗

PubMed2005

The epidemiology of recurrent abdominal pain from 2 to 6 years of age: results of a large, population-based study.

OBJECTIVE: Recurrent abdominal pain (RAP) is one of the most common complaints of childhood and is associated with several adverse outcomes in adulthood. Few large, population-based, longitudinal studies have been conducted. The purpose of this study was to investigate the prevalence and epidemiologic features of RAP through early childhood. DESIGN: We report findings from a large, population-based, cohort study of childhood (the Avon Longitudinal Study of Parents And Children). The prevalence and continuity of RAP from 2 to 6 years of age were explored, with associated physical and psychological symptoms among the children and their parents. RESULTS: In a population cohort of 13971 children, RAP was reported for 11.8% of 6-year-old children. It was less common at ages 2 years (3.8%) and 3 years (6.9%). There was a striking degree of continuity of RAP between the ages of 2 and 6 years. RAP was associated with headaches and limb pains among children and with higher rates of anxiety among both children (adjusted odds ratio: 2.12; 95% confidence interval: 1.70-2.65) and their mothers (odds ratio: 1.75; 95% confidence interval: 1.30-2.36). CONCLUSIONS: In a large, population-based, cohort study, RAP was found to be increasingly common up to the age of 6 years. Children with RAP at a young age have a high risk of RAP later in childhood. RAP is associated with other somatic pain symptoms among children and with symptoms of anxiety among children and their mothers. These findings highlight the high prevalence and continuity of RAP through early childhood and the importance of considering psychological symptoms for these children and their families.

Abdominal Pain↗

PubMed2002

Retroauricular pain preceding Bell's palsy: report of three cases and clinical analysis.

A retroauricular pain (RAP) ipsilateral to the side of facial paralysis (FP), often experienced patients with Bell's palsy, usually occurs around the onset of FP. Whether RAP is a risk factor for incomplete recovery from FP is controversial. This paper reports three patients with Bell's palsy in whom acute RAP preceded FP by several days. The intervals between the onset of RAP and FP were 6, 12, and 12 days, and the quality of RAP was dull/tight or neuralgic. All patients received prednisolone and acyclovir orally, and their facial functions recovered within 8 weeks. Based on the serological tests, FP was diagnosed as due to varicella-zoster virus in two patients and as idiopathic in the other. Among 58 consecutive patients with Bell's palsy, including the three patients described, 26 (44.8%) experienced RAP, the onset of which ranged from 12 days before to 2 days after the onset of FP. While the prognosis of FP was not different between patients with and without RAP, FP recovered well in all seven patients in whom RAP preceded the onset of FP by 4 days or more. These findings suggest that RAP preceding by several days may predict the good prognosis of FP. As RAP can be a preceding symptom of acute FP, patients with acute RAP require medical attention for at least 2 weeks.

Adolescent↗