Comparison of outcomes between endovascular treatment and bypass surgery in Takayasu arteritis.

OBJECTIVES: There is currently a lack of evidence regarding the optimal revascularization method for Takayasu arteritis (TA). This study compares outcomes between endovascular treatment and surgical therapy in TA patients requiring revascularization. METHOD: From September 1994 to January 2011, 235 patients were diagnosed with TA according to the diagnostic criteria of the 1990 American College of Rheumatology, and of these, arterial revascularizations were performed in 65 (27.7%). Symptomatic or angiographic recurrence and peri-operative use of immunosuppressive drugs were investigated by retrospectively reviewing medical records. RESULTS: A total of 111 arterial lesions in the 65 (27.7%) patients were revascularized during the follow-up period (median 3.2 years, range 0.01-12.7 years). At the 2-year follow-up, the symptomatic recurrence rate was significantly higher in the endovascular treatment group (32.3% vs. 11.5%, p = 0.016), as was the incidence of angiographic recurrence (32.1% vs. 11.1%, p = 0.026). The symptomatic recurrence rate was not influenced by the need for peri-operative immunosuppressive drugs (20% vs. 34.1%, p = 0.34). CONCLUSIONS: In TA patients, surgical revascularization seems to be superior to endovascular treatment with regard to patency. Further investigation to identify novel and optimal arterial revascularization methods for TA patients should be undertaken.

First Report of Stolbur Phytoplasma Infection in Commercial Freesia hybrida Cultivars.

In January 2012, disease symptoms including chlorosis, leaf crinkle, leaf curving and stunting of whole plants, virescence, and curving and necrosis of flower stalks were observed in Freesia hybrida cvs. Evone, Honey Moon, Golden Gem, and Pallas in Icheon and Suwon (Gyeonggi Province in Korea). To determine a possible phytoplasma infection, the symptomatic freesia plants were examined for the presence of phytoplasma 16S rDNA fragment by PCR with the primer pair P1/P6 (2) and R16F1/R16R1 (in nested PCR), which amplifies phytoplasma 16S rDNA regions (4). An expected PCR product of ~1,096 bp was obtained from the symptomatic freesia plants, and they were designated as FreLN, Fre-phy-Ev4, Fre-phy-Ev6, Fre-phy-GG, Fre-phy-HM, and Fre-phy-Pal. The PCR products were sequenced and registered as GenkBank accessions AB695174 and AB709951-55. The sequence corresponding to symptomatic freesia had 98.8 to 99.4% identity with Stolbur phytoplasma strains in the 16S rDNA region, and it had only 95.7 to 96.3% identity with AY phytoplasma strains. In the ultra-thin sections of the leaf midribs, globous phytoplasmal bodies 54 to 214 nm in size were observed in sieve tube elements of phloem tissue. Fre-Phy-Ev6 and Fre-Phy-HM were doube-infected with Stolbur phytoplasma and Freesia mosaic virus (FreMV). Fre-Phy-Ev6 and Fre-Phy-HM revealed necrosis of flower stalks and flower color breaking besides curving of flower stalks. Therefore, flower color breaking and flower stalk necrosis were assumed to be caused by FreMV (1). Symptoms of chlorosis and stunting of whole plants shown in FreLN and virescence of Fre-phy-GG were typical symptoms of phytoplasmal diseases, while leaf crinkle, leaf curving, and curving of flower stalks appeared to be unique symptoms in F. hybrida. Stolbur phytoplasma was abundant in commercial freesia cultivation fields. Some of the cultivars, such as cv. Pallas, showed only curving of leaf and flower stalks without any typical symptom of phytoplasmal diseases. A phytoplasmal disease was reported in Poland in 2001 from F. hybrida exhibiting leaf chlorotic and necrotic spots, and classified as AY I-B based on RFLP analysis of PCR products (3). To our knowledge, this is the first report of Stolbur phytoplasma in F. hybrida. This result is significant because F. hybrida could be the infection source of Stolbur phytoplasma disease in floricultural crops. Interestingly, we found a prevalence of Stolbur phytoplasma in Petunia hybrida cultivars (GenBank Accession Nos. AB713757 to AB713758). High nucleotide sequence identity of 99.8% in the 16S rDNA region of Stolbur phytoplasma isolates from petunia and freesia support the inference that those Stolbur phytoplasma isolates could infect both floricultural crops. References: (1) A. A. Brunt. Freesia. Page 274 in: Virus and virus-like Diseases of Bulb and Flower Crops, John Wiley & Sons, Chichester, 1995. (2) S. Deng and C. Hiruki. J. Microbiol. Methods. 14:53, 1991. (3) M. Kaminska and H. Sliwa. Plant Dis. 85:336, 2001. (4) I. M. Lee et al. Phytopathology 84:559, 1994.

Changes in pulmonary artery pressures during ethanol sclerotherapy for arteriovenous malformations: identifying the most vulnerable period.

AIM: To evaluate the changes in pulmonary artery pressure (PAP) during ethanol embolization and to identify the most vulnerable period associated with cardiovascular collapse in patients with arteriovenous malformations (AVMs). MATERIALS AND METHODS: Twenty-three patients (30 sessions) with AVMs were enrolled. PAP was measured at the following times: baseline (T(baseline)); immediately before (T(pre)), and after (T(post)) bolus injection of absolute ethanol; at the time of maximum mean PAP value during a session (T(highest-ethanol)); 10 min after final injection (T(final)); after restoration of spontaneous breathing (T(resp)); at extubation (T(extubation)); 30 min after extubation (T(extubation-30)(min)); and at the time of maximum mean PAP after patient resumed spontaneous respiration (T(highest-resp)). Nitroglycerin was infused (range 0.5-3 µg/kg/min) in all patients to attenuate the effect of ethanol on pulmonary vasoconstriction. RESULTS: The PAPs of T(highest-ethanol), T(resp), T(extubation), and T(highest-resp) were significantly higher than the corresponding values for T(baseline) and T(final) (all p<0.05). The systolic and mean PAPs of T(highest-resp) were significantly higher than those at T(highest-ethanol) (both p<0.05). In 24 sessions (80%), the highest mean PAP was detected during the recovery period. CONCLUSION: The greatest rise in PAP was noted during the recovery period in patients undergoing ethanol embolotherapy. Therefore, PAP monitoring and nitroglycerin infusions are recommended during the recovery period because early detection of an increase in PAP and prompt management may prevent detrimental complications.

Saccharomyces cerevisiae produces a yeast substance that exhibits estrogenic activity in mammalian systems.

Partially purified lipid extracts of Saccharomyces cerevisiae contain a substance that displaces tritiated estradiol from rat uterine cytosol estrogen receptors. The yeast product induces estrogenic bioresponses in mammalian systems as measured by induction of progesterone receptors in cultured MCF-7 human breast cancer cells and by a uterotrophic response and progesterone receptor induction after administration to ovariectomized mice. The findings raise the possibility that bakers' yeast may be a source of environmental estrogens.

Clinical and angiographic follow-up of spontaneous isolated superior mesenteric artery dissection.

OBJECTIVES: To observe the clinical features and angiographic findings in patients with a spontaneous isolated superior mesenteric artery dissection (SISMAD) and to identify any correlation between them. METHODS: From a single institution, 32 patients (22 symptomatic patients at presentation; mean age 54years; men 97%) with SISMAD were retrospectively reviewed. All patients were available for clinical follow-up after treatment (conservative, n=28, 88%, open or endovascular superior mesenteric artery (SMA) reconstruction, n=4, 12%), and follow-up CT scans were available in 28 patients (mean 22months, range 1-80months). RESULTS: We found a positive correlation between pain severity and dissection length (p=0.03, rho=0.50, Spearman's partial correlation analysis). After conservative treatment, only one patient (3%) required bowel resection, and there was no difference in outcome between patients who were treated with anticoagulation or anti-platelet therapy and those who were not (p=1.00, Fisher's exact test). No patients had progression of their lesion on the follow-up CT angiography. CONCLUSIONS: In SISMAD patients, dissection length is positively associated with more severe clinical symptoms. After conservative treatment, we observed a benign clinical course and no CT progression of the dissection, even without anticoagulation or anti-platelet therapy. Based on our observation, patients with SISMAD can be treated conservatively without anticoagulation therapy.

Characterization of congenital vascular malformation in the extremities using whole body blood pool scintigraphy and lymphscintigraphy.

The purpose of this study was to investigate the clinical usefulness of combined whole body blood pool scintigraphy (WBBPS) and lymphscintigraphy (LS) in the characterization of patients with congenital vascular malformations (CVMs) of the extremities. Subjects included 134 patients who underwent Tc-99m RBC WBBPS and Tc-99m filtered tin colloid (or antimony sulfur colloid) LS on initial diagnosis. Scintigraphic results were interpreted as arteriovenous malformations (AVMs), venolymphatic malformations (VLMs), lymphatic malformations (LMs), and venous malformations (VMs). Final diagnosis of the type of vascular malformation was determined by physical examination, magnetic resonance imaging (MRI), angiography, duplex ultrasonography, and/or biopsy results. The final diagnosis demonstrated that 14 of the study subjects had an AVM, 29 had a HLM, 20 had a LM, and 71 had a VM. The sensitivity of WBBPS and LS in the characterization of CVM was 85.7% (12/14) for AVMs, 96.6% (28/29) for VLMs, 95.0% (19/20) for LMs, and 88.7% (63/71) for VMs. The specificity was 100% for AVMs (120/120), 91.4% for VLMs (96/105), 99.1% for LMs (113/114), and 98.4% for VMs (62/63). The overall accuracy of WBBPS and LS was 91.0% (122/134). Our results show that combination of WBBPS with LS can characterize extremity CVMs in patients with high diagnostic accuracy, and may thus be useful for making optimal treatment decisions.

Effect of proximal arterial occlusion on the progression of the distal arterial disease.

PURPOSE: To test the hypothesis that a proximal arterial occlusion has a protective effect on the progression of distal arterial disease, assessed by distal runoff resistance score (DRRS). MATERIALS AND METHODS: One hundred and nineteen patients (median age 64 y, male 96%) with a unilateral iliac and/or femoral arterial occlusion caused by atherosclerosis were analyzed retrospectively. DRRS was assessed on arteriograms of the test limb (with proximal arterial occlusion) and control limb (contralateral limb). Multivariate analysis was performed to determine if a proximal arterial occlusion was an independent risk factor for the development of a difference in the DRRS between the test and control limbs. RESULTS: The clinical features of the subjects were claudication in 85%, ankle brachial index 0.52 (median), diabetes in 30% and smoker in 76%. The upper leg DRRS of the test limb was significantly lower in the iliac occlusion group than in the control limb (1.87+/-1.69 vs 2.85+/-2.75, p=0.032). However, multivariate analysis failed to identify any risk factors associated with the difference in DRRS in both limbs. CONCLUSION: There was no evidence that a proximal arterial occlusion was associated with a slower progression of distal arterial disease.

Synthesis and secretion of corticosteroid-binding globulin by rat liver. A source of heterogeneity of hepatic corticosteroid-binders.

Classical glucocorticoid receptors (type II) have a high affinity for synthetic and natural glucocorticoids. We have previously demonstrated an additional binding site in kidney cytosol (type III) which has a high affinity for corticosterone but a low affinity for dexamethasone. In many ways, this binder resembles plasma corticosteroid-binding globulin (CBG). The first goal of this study was to determine the organ distribution of the type III binding sites. Cytosol was prepared from isolated cells to avoid plasma contamination. Of the tissues examined, type III sites were found only in liver and kidney; sites were absent from thymocytes, IM-9 lymphocytes, adipocytes, and bone cells. The second goal of this study was to ascertain whether CBG is synthesized in liver and kidney. Liver and kidney slices were incubated in vitro and the concentration of type III sites was seen to rise in hepatic cytosol and incubating medium but not kidney. To verify the impression that liver was synthesizing and secreting CBG, the following experiments were performed: (a) To demonstrate that type III sites were CBG, steroid-binding profiles and migration on polyacrylamide gel electrophoresis were shown to be identical for hepatic type III sites and serum. (b) To indicate that the rise in type III sites was dependent on protein synthesis, it was shown that cycloheximide blocked the appearance of new type III sites. (c) To establish that the type III sites were being secreted, in situ liver perfusion experiments showed time-dependent release of new sites into the perfusate. In conclusion, liver synthesizes and secretes type III sites, a finding previously suspected but never proved. The presence of type III sites in kidney remains to be explained.

Human decidua is a major source of renin.

Plasma prorenin levels are elevated in normal pregnant women. Current evidence suggests renin production by tissues of the uteroplacental unit contribute to this elevation. The purpose of this investigation was to define the source of renin biosynthesis within the human uteroplacental unit and to characterize the renin produced. RNA extraction and Northern blot analysis consistently demonstrated renin mRNA expression in uterine lining both in the pregnant (decidua) and nonpregnant states (endometrium) and in fetal chorion laeve, which is inseparable from the decidua. In contrast, renin mRNA expression was not detected in basal plate and intertwin chorion (which is separate from decidua), amnion, myometrium, or placental villi. The total renin content in decidual homogenates was two- to threefold greater than in endometrial homogenates, and cultured human decidual cells produced significantly more total renin than cultured human endometrial cells, suggesting that pregnancy enhanced renin production by the cells lining the uterus. Immunoblot analysis and [3H]leucine incorporation identified 47,000-mol wt prorenin as the major form of renin produced by cultured human decidual cells. These studies indicate that maternal decidua is the major source of prorenin in the uteroplacental unit.

Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction.

Angiotensin II (AII) is a critical factor in cardiac remodeling which involves hypertrophy, fibroblast proliferation, and extracellular matrix production. However, little is known about the mechanism by which AII accelerates these responses. Osteopontin is an acidic phosphoprotein with RGD (arginine-glycine-aspartate) sequences that are involved in the vascular smooth muscle cell remodeling process. We identified the presence of osteopontin mRNA and protein in cultured rat cardiac fibroblasts and its prominent regulation by AII (10(-11) M). Osteopontin message levels were increased fourfold (P < 0.01) and protein fivefold (P < 0.05) at 24 h after addition of AII (10(-7) M). This response was inhibited by the AT1 receptor blocker, losartan. Osteopontin mRNA levels were increased in hypertrophied ventricles from animals with renovascular hypertension (1.6-fold, P < 0.05) and aortic banding (2.9-fold, P < 0.05). To examine the function of osteopontin, we determined its effects on (a) the ability of cardiac fibroblasts to contract three-dimensional collagen gels and (b) cardiac fibroblast growth. A monoclonal antibody against osteopontin partially blocked AII-induced three-dimensional collagen gel contraction by cardiac fibroblasts (64+/-4 vs. 86+/-5% in the presence of antibody, P < 0.05), while osteopontin itself promoted contraction of the gels by fibroblasts (71+/-5%, P < 0.05 compared with control). Either a monoclonal antibody against beta3 integrin which is a ligand for osteopontin or the RGD peptide blocked both AII and osteopontin-induced collagen gel contraction. Thus, the osteopontin RGD sequence binds to beta3 integrins on the fibroblast to promote fibroblast binding to collagen. All induced a threefold increase in DNA synthesis of cardiac fibroblasts, which was completely blocked by antibodies against osteopontin and beta3 integrin, or by RGD peptide, but not by controls. Thus, All-induced growth of cardiac fibroblasts also requires osteopontin engagement of the beta3 integrin. Taken together, these results provide the first evidence that osteopontin is a potentially important mediator of AII regulation of cardiac fibroblast behavior in the cardiac remodeling process.

Proximal 2.6 kb of 5'-flanking DNA is insufficient for human renin promoter activity in renin-synthesizing chorio-decidual cells.

In order to determine the influence of proximal 5'-flanking DNA of the human renin gene (REN) in cells that express human renin, transient expression analyses were carried out in chorio-decidual cells. Constructs containing different lengths of REN promoter DNA, extending as far as 2595 bp upstream of the transcription start site, were unable to drive transcription of a chloramphenicol acetyl transferase reporter gene in chorio-decidual cells, nor in noncognate 293 or JEG-3 cells. The tk promoter was similarly inactive in constructs containing -2595 to -453 fragments of REN 5'-flanking DNA. In each cell type, the -2595 to -1300 DNA exerted a negative influence. Additional promoter- and cell type-dependent negative influences were noted for other regions of REN 5'-flanking DNA and the -453 to -145 DNA increased tk promoter activity 2.5-fold in chorio-decidual cells. By introducing the SV40 enhancer into constructs, a weak stimulation of the REN promoter was observed in chorio-decidual cells, but not in noncognate, JEG-3 cells, although the -2595 to -1300 DNA retained its negative influence in the cognate cell type. These results show that the proximal 2.6 kb of REN 5'-flanking DNA is unable to drive reporter gene activity in renin-synthesizing, chorio-decidual cells under basal conditions and suggest that trans-acting factors unique to at least this cell type, together with enhancer(s) located outside of the proximal 2.6 kb of REN promoter DNA tested, could be required for human renin promoter activity.

Angiotensin II has multiple profibrotic effects in human cardiac fibroblasts.

BACKGROUND: Angiotensin II (Ang II) is implicated in cardiac remodeling and is increasingly recognized for its profibrotic activity. METHODS AND RESULTS: Because little is known about the direct cellular effects of Ang II on human cardiac fibroblasts, we isolated fibroblasts from ventricles of explanted human hearts and added Ang II (100 nmol/L) to determine its role in growth, extracellular matrix accumulation, and adhesion. To assess which Ang II receptor is involved, Ang II was added in the presence of irbesartan (10 micromol/L), a specific AT(1) receptor antagonist; PD 123319 (10 micromol/L), a specific AT(2) receptor antagonist, or divalinil (100 nmol/L), an AT(4) receptor inhibitor. In human ventricles (n=13), message levels of atrial natriuretic peptide and AT(1) receptor were inversely correlated, which suggests a decrease in AT(1) receptor expression with progressive heart failure. Northern analysis and fluorescence-activated cell sorting demonstrated AT(1) receptor in cultured human cardiac fibroblasts. Ang II increased mitogen-activated protein kinase activity and in DNA synthesis (5-fold, P<0.01) stimulated a 2-fold increase in transforming growth factor-beta(1) (P<0.05) mRNA levels at 2 hours and a 2-fold increase in laminin (P<0.05) and fibronectin (P<0.05) mRNA levels at 24 hours. Ang II also enhanced plasminogen activator inhibitor-1 expression, which inhibits metalloproteinases that degrade the extracellular matrix. All of these effects were inhibited by irbesartan but not PD 123319 or divalinil. In addition, Ang II increased cardiac fibroblast attachment to collagens I and III, which was associated with an increase in focal adhesion kinase activity. CONCLUSIONS: Activation of the AT(1) receptor in human heart promotes fibrosis. Ang II plays a novel role in stimulation of plasminogen activator inhibitor-1 expression and adhesion of cardiac fibroblasts to collagen.

Current concepts in lymphatic malformation.

A lymphatic malformation (LM) is the most common form of congenital vascular malformation (CVM). The new Hamburg classification of CVM distinguishes the truncular (T) form from the extratruncular (ET) form of LMs. Both are consequences of a developmental arrest at the different stages of lymphangiogenesis as a result of defective genes. The purpose of this review was to evaluate the current management results of both forms of LMs. A retrospective review of the clinical data of 315 patients with a diagnosis of LMs treated between September 1994 and December 2001 was performed. Lymphoscintigraphy was the most frequent diagnostic test. The patients with the ET form were treated with sclerotherapy with OK-432 and/or ethanol. Combinations of CDP (complex decongestive physiotherapy) and/or compressotherapy were used to treat all the T-form patients. In addition, surgery, either reconstructive or ablative, was offered to patients with the T form who failed to respond to the proper CDP. A multidisciplinary team performed the management of LM, and the results were evaluated every 6 months. Among 797 patients with CVM, 315 were confirmed to have LMs, either as the T form (226) or the ET form (89). Another 66 LMs were diagnosed with hemolymphatic malformations (HLM). Most of the ET forms (89/315) were the cystic type (70/89), while the T forms included aplasia and/or an obstruction (204/226). The ET form was most frequent in the head, neck, and thorax (69/89). The T form was located most frequently to the extremities (202/226), mostly to the lower limb (180/202). Two hundred and twenty-six T forms belonged to the various clinical stages: stages I-32, II-104, III-48, IV-18, and an unclear stage-24. The ET form was treated with sclerotherapy using OK-432 (108/120) and absolute ethanol (12/120). Among the 11 patients with the multiple ET form, 7 patients underwent perioperative sclerotherapy with OK-432 and a subsequent surgical excision. The clinical response of the T form at the extremity to CDP was excellent to good in a majority of clinical stages I to II (121/136) but decreased to a good to fair degree in stages III to IV (31/66). The additional surgical therapy, either reconstructive (10/19) or ablative (9/19), provided limited success in improving CDP efficacy, owing mainly to poor compliance. The long-term outcome of the initial success through self-motivated home-maintenance care during the follow-up period of up to 48 months was totally dependent on patient compliance. OK-432 sclerotherapy to 51 ET forms has shown excellent results on 88.9% of the cystic type (40/45) and 50% (3/6) of the cavernous type (minimum follow-up for 24 months). Seventeen ET forms in 7 patients were treated with a preoperative OK-432 sclerotherapy and a subsequent surgical excision, which provided good to excellent results in 14 for a minimum of 24 months. Primary lymphedema, which is the T form of LMs, can be managed safely by a combination of CDP with compressotherapy. Patients with good compliance can benefit from additional surgical therapy, either reconstructive or ablative. The ET form, particularly the cystic type, can be treated with various scleroagents that are preferably less toxic as the primary therapy. A surgical excision with or without perioperative sclerotherapy provides good results for patients with the localized cavernous type of the ET form. A multidisciplinary team approach is essential for the proper care of LM.

Mechanisms of hyperkalemia in systemic lupus erythematosus.

We found that nearly 10% of 142 patients with systemic lupus erythematosus (SLE) had persistent, unexplained hyperkalemia. Renal mineralocorticoid resistance has been suggested to account for the hyperkalemia in SLE. We studied the renin-aldosterone response to intravenous furosemide (60 mg) and upright posture and the renin response to converting enzyme inhibition (captopril, 50 mg) and upright posture in five patients with SLE and hyperkalemia (group 1) and five normokalemic patients with SLE (group 2). Renal function was comparable. Plasma chloride level was higher and bicarbonate level slightly lower in group 1 than in group 2. Plasma cortisol level was normal in all patients. None of the patients was receiving nonsteroidal anti-inflammatory drugs or corticosteroids at the time of study. Basal plasma renin concentration and plasma aldosterone level were not significantly different between the two groups, although both tended to be higher in group 2. However, four of the five patients in group 1 had significantly blunted renin response to captopril compared with group 2. The same four patients also had blunted renin and aldosterone responses to furosemide. Thus, the majority of hyperkalemic patients with SLE had an impaired renin and aldosterone response to stimulation. We conclude that hyporeninemic hypoaldosteronism plays a key role in the pathogenesis of hyperkalemia in SLE.

Demonstration of glucocorticoid receptors in the adrenal cortex: evidence for a direct dexamethasone suppressive effect on the rat adrenal gland.

The adrenal cortex was evaluated for the presence of glucocorticoid receptors and functions. Substantial binding of [3H]dexamethasone was observed in aminoglutethimide-treated, hypophysectomized, and intact rats. Further studies demonstrated binding in cultured bovine adrenocortical cells and in Y-1 cells, a cloned murine cell line of adrenal cortical origin. Scatchard analysis of specific binding data in cytosol from hypophysectomized rats revealed an apparent Kd of approximately 15 nM and a receptor content (Nmax) of 123 fmol/mg cytosol protein. Analysis of Y-1 cell cytosol showed a Kd of approximately 17 nM and Nmax of 190 fmol/mg protein. The binding site in hypophysectomized rats had the following steroid specificities: high affinity for dexamethasone, corticosterone, and progesterone; moderate affinity for 11 beta-cortisol, and low affinity for testosterone, estradiol, pregnenolone, and 11 alpha-cortisol. Sedimentation in sucrose density gradients revealed 8S binding peaks in cytosols prepared from intact rat adrenal glands, Y-1 cells, and cultured bovine adrenocortical cells. Time- and temperature-dependent nuclear uptake of [3H]dexamethasone in Y-1 cells was demonstrated. In vivo treatment of hypophysectomized rats with dexamethasone significantly enhanced the rate of adrenal atrophy. ACTH stimulation tests in hypophysectomized rats showed a decreased corticosterone response in dexamethasone-treated rats compared to that in control animals. However, in vitro, there was no evidence for an effect of dexamethasone on ACTH-stimulated corticosterone production. The data indicate that the adrenal cortex possesses a high affinity binding site that fulfills the criteria for a glucocorticoid receptor. Glucocorticoid administration enhances adrenal atrophy and impairs adrenal function. We speculate that this action contributes to the suppressive effect of glucocorticoids on the pituitary-adrenal axis.

Angiotensin II causes mesangial cell hypertrophy.

Angiotensin II, a potent vasoconstrictor and known growth factor for vascular smooth muscle cells, has been implicated in the development of glomerulosclerosis. Because mesangial cell growth plays a critical role in the glomerulosclerotic process, the objective of this study was to determine the direct effect of long-term (48-hour) angiotensin II treatment on the growth of cultured murine mesangial cells. Subconfluent, quiescent adult murine mesangial cells were treated for 48 hours with media containing angiotensin II with and without its specific inhibitor losartan. In comparison to cells treated with serum-free medium, cells treated with serum plus insulin demonstrated a significant increase in cell number (1.93 +/- 0.1 times control, p < 0.05), [3H]thymidine incorporation per 10(5) cells (2.29 +/- 0.12 times control, p < 0.05), [3H]leucine incorporation per 10(5) cells (1.81 +/- 0.18 times control, p < 0.05), and total protein content per 10(5) cells (1.65 +/- 0.07 times control, p < 0.05). In contrast, cells treated with angiotensin II (10(-6) M) had no significant increase in cell number (0.84 +/- 0.01 times control) or [3H]thymidine incorporation per 10(5) cells (1.23 +/- 0.12 times control) but demonstrated a significant increase in [3H]leucine incorporation per 10(5) cells (1.61 +/- 0.09 times control) and total protein content per 10(5) cells (1.38 +/- 0.04 times control). Pretreatment with losartan blocked 56% of the angiotensin II-induced increase in [3H]leucine incorporation and 84% of the angiotensin II-induced increase in total protein content.(ABSTRACT TRUNCATED AT 250 WORDS)

Integrins, adhesion, and cardiac remodeling.

Integrins are heterodimeric cell surface receptors that mediate a cell's ability to perceive its environment, respond to changed in its environment, and alter its environment. When activated, these receptors form focal adhesions, which are areas of close attachment of the cells to extracellular matrix proteins in which colocalization of cytoskeletal proteins, intracellular signaling molecules, and growth factor receptors occurs. In cardiac fibroblasts, integrins mediate cell growth and adhesion. Growth factors such as angiotensin II regulate DNA synthesis, protooncogene expression, extracellular matrix production, adhesion, and other actions of cardiac fibroblasts, many of which require integrin activation. In addition to controlling growth factor and hemodynamic effects, regulation ofintegrin activity may be useful to affect cardiac fibrosis and the remodeling process.

Biochemical similarity of expressed human prorenin and native inactive renin.

Prorenin is secreted by mammalian cells transfected with a human preprorenin expression construct. The purpose of this investigation was to compare the physicochemical properties of expressed prorenin in culture medium with the known characteristics of human inactive renin, which accounts for nearly half the renin in plasma and kidney. We found that expressed human prorenin strongly resembles human renal and plasma inactive renin. The expressed prorenin was inactive and could be equally activated by acid (dialysis to pH 3.3) or trypsin. Acid activation was completely reversible; reexposure to acid could reactivate the expressed inactive renin. Exposure to cold (-5 degrees C for 3 days) could also activate expressed renin. The Michaelis-Menten constant of acid-activated expressed renin with sheep substrate was 0.29 microM, and the pH optimum was 7.8. Expressed inactive renin bound to a cibacron-blue affinity column and could be eluted with 0.5M NaCl. All the above characteristics resemble those of human renal and plasma inactive renin. In addition, the molecular weight of expressed prorenin and human chorionic renin was 47,000, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and 46,000, as measured by high-performance liquid chromatography. These data, taken together with the published observation that native human inactive renin cross-reacts with antibodies generated against amino acid sequences in the prosegment of renin, provide strong support for the hypothesis that human inactive renin is prorenin.

Plasma cyclic guanosine monophosphate in chronic heart failure: hemodynamic and neurohormonal correlations and response to nitrate therapy.

This study evaluated the relation between plasma cyclic guanosine monophosphate (cGMP) and hemodynamic and neurohormonal parameters in patients with chronic congestive heart failure and assessed the effect of organic nitrate on plasma cGMP levels. Plasma cGMP was fourfold higher in 18 patients with congestive heart failure compared with 15 control subjects (16.7 +/- 9.7 versus 4.0 +/- 1.0 pmol/ml; p < 0.0001) but did not correlate with plasma levels of catecholamines, renin, atrial natriuretic peptide, or with baseline hemodynamic values. The administration of a hemodynamically effective dose of oral isosorbide dinitrate (40 mg) resulted in a transient reduction in plasma cGMP from 16.7 +/- 9.7 pmol/ml at baseline to 13.0 +/- 6.6 pmol/ml at 1 hour (p < 0.05). This change was associated with small and statistically insignificant changes in neurohormonal values and had no relation to any of the hemodynamic changes. We concluded that (1) elevated plasma cGMP in congestive heart failure does not correlate with other neurohormonal or hemodynamic parameters and may be an independent parameter of heart failure, (2) in contrast to previously documented nitrate-mediated increases in intracellular cGMP, nitrate therapy results in a reduction in plasma cGMP, and (3) changes in plasma cGMP cannot serve as a surrogate measurement of changes in intracellular cGMP.

Extrarenal renin-secreting tumors: insights into hypertension and ovarian renin production.

Although renin-secreting tumors are rare, they must be considered in the differential diagnosis of hypertension associated with hypokalemia, which occurs commonly in the hypertensive population. The finding of an ovarian renin-secreting tumor emphasizes the potential importance of the ovary as an extrarenal source of renin; the local ovarian renin-angiotensin system may play a key role in reproductive function by regulating vascular reactivity, local blood flow, steroidogenesis and other physiologic effects. In the illustrative case presented, a renin-secreting ovarian leiomyosarcoma was obtained from a women who presented with hypertension and hypokalemia. Plasma prorenin levels were markedly elevated. Tumor excision was quickly followed by a fall in prorenin levels and tumor recurrence was accompanied by an increase in prorenin levels. Active renin concentration in the tumor homogenates was similar to that found in kidney homogenates while the tissue prorenin concentration was approximately 20 times that found in kidney tissue. When cultured for up to 4 weeks, ovarian tumor cells secreted greater than 95% prorenin. Immunoblot analysis demonstrated that tumor renin had a molecular weight of 47,000, similar to that of human recombinant prorenin. Immunohistochemical staining of tumor tissue with antibodies against human renal renin at the electron microscopic level demonstrated the presence of renin primarily in membrane-bound vesicles and rarely in dense-core secretory granules. These findings suggest that prorenin in this ovarian tumor was secreted by the constitutive pathway, which is mediated by these amorphous vesicles.