Unusual human lymphoma phenotype defined by monoclonal antibody.

The phenotype of three large cell (histiocytic) lymphomas of man has been defined with convential lymphocyte surface marker techniques, a panel of monoclonal antisera of hybridoma derivation (Ortho Pharmaceutical Corp.), and the fluorescence microscope. Two tumors exhibited surface IgG of lambda light-chain type, whereas the third was negative for surface Ig but contained the same Ig in the cytoplasm. With the monoclonal antisera, all three were found to bear two surface antigens (OKT9 and OKT10) previously described on early thymocytes, and were devoid of the Ia antigen. The available knowledge suggests that these neoplasms represent the expansion of a clone of B lymphocytes along the pathway that leads to plasma cell differentiation rather than a clone with both B and T surface membrane markers.

Malignant lymphoma with dual B and T cell markers. Analysis of the neoplastic cells with monoclonal antibodies directed against T cell subsets.

In the course of analyzing human lymphoma tissue with conventional surface marker techniques and with monoclonal antibodies directed against T cell subsets, five tumors were encountered with dual B and T cell determinants. All bore on their surface membrane IgM of kappa light chain type, complement receptors, and the Ia-like antigen. In each of the five cases, the neoplastic lymphocytes reacted with a monoclonal antibody that detects the sheep erythrocyte receptor (OKT11); all but one reacted with a monoclonal antibody for peripheral T cells (OKT3); and all but one reacted with a monoclonal antibody specific for either the inducer-helper (OKT4) or the cytotoxic-suppressor (OKT8) T cell subsets. In addition, lymphocytes from two of the five cases formed spontaneous rosettes with sheep erythrocytes (E-rosettes). These tumors with dual B and T surface characteristics were confined to human malignant lymphomas that originate from B lymphocytes of the follicle center.

Mechanism of sodium modulation of glomerular angiotensin receptors in the rat.

Specific binding of 125I-angiotensin to high affinity glomerular receptors varies directly with the level of dietary sodium. To investigate the mechanism of sodium regulation of glomerular angiotensin receptors, groups of Sprague-Dawley rats were maintained on one of three levels of sodium intake for at least 5 d: high sodium (7.39 meq/24 h), moderate sodium (0.88 meq/24 h), and low sodium diets (0.01 meq/24 h). An additional group was given low sodium diet with daily injections of furosemide (1 mg/kg i.p.). To dissociate the effects of dietary sodium from those of circulating angiotensin II levels on glomerular receptor regulation, a fifth group was placed on high sodium diet and given a continuous infusion of angiotensin via an implanted minipump (100 ng/min) for 21 d. There was a strong negative correlation (r = -0.98, P less than 0.01) between plasma angiotensin II and glomerular angiotensin receptor density. Dietary sodium, potassium, or water consumption did not correlate with angiotensin II receptor concentration. The affinity constant did not vary in any of the groups (2.33 +/- 0.30 X 10(8) M-1). The time course of sodium regulation of glomerular angiotensin II receptors was studied in rats switched from a moderate sodium to either a high sodium diet or a low sodium diet plus furosemide. Receptor density was unchanged at 24 h, varied directly with sodium intake for 1-5 d when induction was maximal, and remained constant for at least 21 d. The time course of receptor regulation closely paralleled changes in plasma angiotensin II. Additional studies were undertaken to demonstrate that glomerular angiotensin II receptors are down-regulated by circulating hormone. Rats maintained on moderate sodium intake were killed 2 min after the induction of anesthesia with pentobarbital (50 mg/kg i.p.) or by rapid decapitation. Despite a 50-fold elevation of plasma angiotensin II in anesthetized rats (424 +/- 154 vs. 8.6 +/- 1.0 pg/ml, P less than 0.001) angiotensin receptor density was unchanged (anesthetized, 1,016 +/- 126 vs. unanesthetized, 1,290 +/- 84 fmol/mg). The infusion of angiotensin II (100 mg/min) for 15 min or 2 h into anesthetized rats maintained on moderate sodium intake resulted in a 50% reduction in specific angiotensin binding that could not be reversed by the dissociation of endogenous angiotensin. These data are compatible with modulation of receptor density by circulating hormone and can not be accounted for by prior receptor occupancy.

Rearrangement of the genes for the beta and gamma chains of the T cell receptor is rarely observed in adult B cell lymphoma and chronic lymphocytic leukemia.

We determined the configuration of the genes for the beta (T beta) and gamma (T gamma) chains of the T cell receptor in DNA from 100 consecutive cases of B cell lymphoma and B cell chronic lymphocytic leukemia (B-CLL), and compared the findings with those in 18 T cell neoplasms. In 7 of the 100 B cell specimens, a single nongermline band was detected after digestion with the restriction enzyme BamHI, but the rearrangement could be confirmed with a second restriction enzyme in only two. The B cell fragments were small in size and of limited size diversity when compared with the T cell cases, and germline bands of equal intensity were present. A rearrangement of the T gamma gene was never seen in a B cell sample. In contrast, T cell specimens usually rearranged both alleles of T beta (15 of 18), the rearrangement could be confirmed with a second restriction enzyme (17 of 18), both alleles of the first constant region gene segment of T beta always underwent either rearrangement or deletion, and the T gamma gene was also rearranged or deleted (17 of 18). We conclude that ordered rearrangement of the T cell receptor is a rare event in B cell lymphoma and B-CLL. T cell receptor gene studies allow B and T cell lymphomas to be distinguished from each other and from common acute lymphoblastic leukemia antigen-positive non-T, non-B acute lymphoblastic leukemia.

Osmolar regulation of endothelin signaling in rat renal medullary interstitial cells.

We tested the hypothesis that endothelin (ET) responsiveness in the renal medulla is modulated by ambient osmolarity. Cultured renal medullary interstitial cells (RMICs) were incubated from 3 to 24 h in isosmolar culture medium (300 mOsm/kg H2O) or media rendered hyperosmolar (600 mOsm/kg H2O) by the addition of urea. Under hyperosmolar conditions, the peak of ET-evoked Ca2+ transient was blunted by 45-58% (P < 0.02) and PGE2 accumulation decreased from 16- to 2-fold above basal values (P < 0.001). To explore whether hyperosmolar conditions blunt intracellular signaling via modulation of receptor number or expression, kinetics of ET binding and Northern blot analysis of ETA receptor mRNA was performed. Under hyperosmolar conditions, ETA receptor density was reduced by 84% versus isosmolar conditions (238 +/- 12 vs. 1450 +/- 184 fmol/mg) (P < 0.01). In contrast to the ligand binding studies, ETA receptor mRNA was increased by 58% (P < 0.05) in cells grown under hyperosmolar versus isosmolar media. These observations indicate that in the hyperosmolar setting, ET-evoked intracellular signaling is blunted in RMICs due to ET receptor downregulation. Since ETA receptor mRNA is increased under hyperosmolar conditions, we conclude that ET receptor downregulation is the consequence of either decreased translation of message, increased degradation of receptor peptide, or increased internalization of specific receptor sites.

Relevance of surface markers in chronic lymphocytic leukemia to acute lymphocytic leukemia.

The surface membrane of the B-lymphocyte of chronic lymphocytic leukemia (CLL) has been subject to detailed investigation over the past decade. Surface immunoglobulin of low density, punctate in distribution, without the tendency to polar cap formation, and clonal with respect to light and heavy chains, is characteristic. Other B-cell properties include the presence of the Ia antigen and the receptor for the C3d portion of complement. The CLL surface membrane lacks such T-cell attributes as the ability to form rosettes with sheep erythrocytes and reactivity with anti-T-cell antisera, although T-cells may be increased early in the disorder. CLL is believed to be a proliferation of a B-lymphocyte of the medullary cord of the lymph node, although the exact place of this cell in lymphocyte development remains to be clarified. Surface markers are useful in distinguishing classical B-cell CLL from other proliferations of small lymphocytes (lymphosarcoma cell leukemia of follicle-center B-cells, T-cell CLL, Sézary syndrome, and reactive lymphocytosis).

Different T-cell receptor gene configurations in T-cell neoplasms and acute lymphoblastic leukemia.

Southern blotting and multiple restriction enzymes were used to analyze T-cell receptor (TCR) and immunoglobulin heavy chain genes in 20 postthymic T-cell neoplasms, ten prethymic and thymic T-cell tumors, and 45 cases of precursor-B acute lymphoblastic leukemia (ALL). Immunoglobulin heavy chain, never rearranged in a postthymic specimen and only once in a prethymic/thymic sample, was rearranged in all but two cases of precursor-B ALL. In contrast, biallelic rearrangement of TCR beta with deletion of the first constant region germline fragment was regularly seen in T-cell neoplasms, but only twice in the 45 precursor-B ALL cases. TCR gamma was rearranged in all but one postthymic sample, in all prethymic/thymic samples, and in approximately half of precursor-B ALL specimens as well. Preferential use of V gamma regions was evident among the various disorders: V8 and V10 in postthymic neoplasms; and V3, V5, V7, and, particularly, V9 in precursor-B ALL. In all the studied conditions, TCR delta was rarely in germline configuration. Extensive biallelic deletion of J delta 1, J delta 2, and C delta, almost always (19 of 20 specimens) present in postthymic neoplasms, was observed in only a minority (14 of 45) of precursor-B ALL samples. In precursor-B ALL, rearranged antigen receptor genes were more frequently found in common acute lymphoblastic leukemia antigen-positive and terminal deoxynucleotidyl transferase-positive specimens. Furthermore, TCR gene rearrangement in that disorder was characterized by a hierarchical pattern: TCR beta was not rearranged without TCR gamma nor TCR gamma without TCR delta. Despite uncertainty of the mechanism, the various disorders can be distinguished on the basis of characteristic antigen receptor gene patterns.

Lymphocyte surface markers in orbital lymphoid neoplasms.

Since the malignant nature of many orbital lymphoid infiltrates is difficult to assess from pathologic examination alone, over the past four years lymphocyte surface marker studies have been added to the evaluation of 23 such cases. Only 10 of the 23 could be confidently classified as malignant lymphoma by histology alone. However, monoclonal surface immunoglobulin was found in 15, supporting the pathologic diagnosis of malignancy in eight and adding seven that could not have been diagnosed otherwise. Clinical evaluation, including a median follow-up of 18 months, revealed manifestations of systemic lymphoma in six of those 15; two had been diagnosed only by surface markers. In contrast, only one of eight cases lacking monoclonal surface immunoglobulin exhibited clinical evidence of malignancy (that case was also indeterminate by histologic criteria). The addition of surface marker analysis permits more accurate diagnosis of orbital lymphoma than is possible from pathologic study alone. This technique can suggest the subtype of lymphoma.

PUlmonary embolism Low incidence in chronic renal failure.

The records of 2,255 autopsies performed on adults between Jan 1, 1969, and Dec 31, 1981, were reviewed for the presence of pulmonary embolism. The overall incidence was 32.3% (18.4%, microscopic; 4%, microscopic; and 9.9%, both). During this period, 95 patients with chronic renal failure (serum creatinine level, greater than 5.0 mg/dL) were identified. The incidence in this group was 9.47% (all microscopic). We conclude that pulmonary embolism is an infrequent cause of mortality in patients with chronic renal failure.

Reduced glomerular angiotensin II receptor density in diabetes mellitus in the rat: time course and mechanism.

Glomerular angiotensin II receptors are reduced in number in early diabetes mellitus, which may contribute to hyperfiltration and glomerular injury. The time course and role of the renin-angiotensin-aldosterone system in the pathogenesis of the receptor abnormality were studied in male Sprague-Dawley rats made diabetic with streptozotocin (65 mg, iv). Glomerular angiotensin II receptors were measured by Scatchard analysis; insulin, renin activity, angiotensin II, and aldosterone were measured by RIA. Diabetes mellitus was documented at 24 h by a rise in plasma glucose (vehicle-injected control, 133 +/- 4; diabetic, 482 +/- 22 mg/dl; P less than 0.001) and a fall in plasma insulin (control, 53.1 +/- 5.7; diabetic, 35.6 +/- 4.0 microIU/ml; P less than 0.05). At 24 h glomerular angiotensin II receptor density was decreased by 26.5% in diabetic rats (control, 75.5 +/- 9.6 X 10(6); diabetic, 55.5 +/- 8.3 X 10(6) receptors/glomerulus; P less than 0.01). Receptor occupancy could not explain the defect, because there was reduced binding in diabetic glomeruli after pretreatment with 3 M MgCl2, a maneuver that caused dissociation of previously bound hormone. There was a progressive return of the receptor density toward normal over the 60 days following induction of diabetes, with diabetic glomeruli measuring 22.7%, 14.8%, and 3.7% fewer receptors than age-matched controls at 11 days, 1 month, and 2 months, respectively (r = 0.99; n = 4; P less than 0.01). Three lines of evidence suggested that reduced angiotensin II receptor density at 24 h was not due to down-regulation by angiotensin II: PRA and angiotensin II were identical in control and diabetic rats; angiotensin II infusion (50 ng/min) caused down-regulation in both control and diabetic rats, but the change in receptor density persisted (control, 33.6 +/- 6.9 X 10(6); diabetic, 18.5 +/- 1.3 X 10(6) receptors/glomerulus; P less than 0.05); and angiotensin-converting enzyme inhibition with enalapril caused receptor up-regulation, but the differences persisted (control, 105.5 +/- 21.2 X 10(6); diabetic, 67.1 +/- 3.0 X 10(6) receptors/glomerulus; P less than 0.05). Rats with chronic diabetes (7-60 days) had normal PRA and angiotensin II, but plasma aldosterone was elevated (control, 29.8 +/- 3.3; diabetic, 68.6 +/- 12.4 ng/dl; P less than 0.005). The return of angiotensin II receptor density to normal levels in chronic diabetes may be the result of receptor up-regulation by increased plasma aldosterone rather than recovery of the underlying defect.

Plasma angiotensins and blood pressure during converting enzyme inhibition.

The relationship between plasma angiotensin and the reduction of blood pressure with the angiotensin converting enzyme inhibitor enalapril was studied in rats. Blood pressure was measured in conscious rats with indwelling arterial catheters. To measure angiotensin II, plasma was analyzed by physical separation of angiotensins using high performance liquid chromatography followed by radioimmunoassay. The effects of both single (acute) and long-term (chronic) dosages of enalapril were measured. After a single oral dose of enalapril (10 mg/kg), mean arterial pressure fell from 111 +/- 3 to 86 +/- 3 mm Hg (p less than 0.005). Despite the blood pressure reduction, plasma angiotensin II was unaffected (control, 9.9 +/- 1.8 vs 9.7 +/- 1.1 pg/ml). After a higher single oral dose of enalapril (30 mg/kg), there was a reduction in both mean arterial pressure (81 +/- 5 mm Hg, p less than 0.005) and plasma angiotensin II concentration (2.3 +/- 0.6 pg/ml, p less than 0.01). The chronic effects of converting enzyme inhibition were evaluated in rats given enalapril in their drinking water (30 mg/kg 24 hr) for 1 week or 2 months. Mean arterial pressure remained equally low after chronic administration (for 1 week or 2 months), but plasma angiotensin II increased above normal (after 1 week, 28.9 +/- 8.7, p less than 0.01 vs control; after 2 months, 43.1 +/- 16.2 pg/ml, p less than 0.05 vs control). Although plasma angiotensin converting enzyme activity was undetectable at any time after enalapril administration, there was a partial return of the angiotensin I pressor response with chronic administration. The data are most compatible with actions of converting enzyme inhibitors independent of the blockade of plasma angiotensin II formation.

Combined renin and converting enzyme inhibition in rats.

The effects of combined renin inhibition and converting enzyme inhibition on mean arterial pressure and the plasma renin-angiotensin system were studied in conscious rats. In sodium-replete rats the infusion of the renin inhibitor CP71362 (100 micrograms/kg/min) decreased blood pressure by 13 +/- 1 mm Hg (p less than 0.0001), reduced plasma renin activity to undetectable levels, but did not lower plasma angiotensin II. In rats treated chronically with enalapril (30 mg/kg/day), CP71362 decreased blood pressure by an additional 5 +/- 2 mm Hg (p less than 0.025) and reduced plasma renin activity and angiotensin II concentrations to undetectable levels. The effects of renin inhibition were also tested under conditions where the renin-angiotensin system was stimulated. In rats on a low sodium diet, CP71362 decreased blood pressure by 15 +/- 2 mm Hg (p less than 0.0001), a decrease similar to that in rats on a normal diet. Plasma renin activity was decreased below detectable limits, but plasma angiotensin II concentrations were not reduced. In rats on a low sodium diet treated chronically with enalapril, CP71362 did not further decrease blood pressure although angiotensin II levels were significantly reduced. An additive effect of combined converting enzyme and renin inhibition on blood pressure lowering and inhibition of plasma angiotensin II was found in rats anesthetized with Inactin.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of angiotensin receptor subtype inhibitors on plasma angiotensin clearance.

The aim of this study was to determine whether angiotensin receptor subtypes play a role in angiotensin clearance from plasma. Angiotensin metabolic clearance rate was measured in rats by the constant infusion method. Increasing doses of angiotensin II were infused for 15 minutes, and blood was sampled for angiotensin II. The type 1 angiotensin II receptor antagonist losartan decreased the apparent metabolic clearance rate by > 50% at low-dose infusion, suggesting that type 1 angiotensin II receptors are involved in angiotensin II clearance from plasma. At higher angiotensin infusion rates, the-metabolic clearance rate of angiotensin was unaffected. To dissect the contribution of renin-generated angiotensin, additional experiments were performed in nephrectomized rats. In anephric rats, angiotensin clearance was unaffected by type 1 angiotensin II receptor inhibition. In contrast, the type 2 angiotensin II receptor ligand PD123319 in intact rats caused a > 50% increase in metabolic clearance rate of angiotensin at higher infusion rates (P < .05). In anephric rats, the type 2 angiotensin II receptor ligand alone or combined with type 1 receptor inhibition was without effect on the metabolic clearance rate or the T1/2 for angiotensin disappearance. These data argue against a role for type 1 or 2 angiotensin II receptors as clearance receptors. Increased clearance of angiotensin by type 2 receptor blockade in the presence but not the absence of kidneys suggests an alternative renal mechanism by which selective type 2 ligands may alter angiotensin effects.

Effects of chronic infusion of renin inhibitor A-64662 in sodium-depleted monkeys.

The potent and primate-selective renin inhibitor A-64662 (n = 8) or vehicle (n = 6) was administered intravenously for 7 days to sodium-depleted cynomolgus monkeys to investigate the chronic effects on arterial pressure, sodium excretion, and the renin-angiotensin-aldosterone system. A 0.1-mg/kg i.v. bolus followed by a continuous 0.01-mg/kg/min infusion of A-64662 lowered mean arterial pressure from 89 +/- 3 (average of 4 control days) to 75 +/- 4 mm Hg (p less than 0.05) after 1 day of administration. This decrement was associated with marked inhibition of plasma renin activity (PRA) from 57.7 +/- 11.1 to 1.3 +/- 0.6 ng angiotensin I (Ang I)/ml/hr (p less than 0.05). Similar hypotensive levels (range 73 +/- 4 to 77 +/- 4 mm Hg) were observed on days 2-7 of A-64662 infusion and PRA remained suppressed, ranging from 0.6 +/- 0.4 to 1.9 +/- 1.0 ng Ang I/ml/hr. Plasma angiotensin II (Ang II) levels were reduced (p less than 0.05) from the control value of 66.7 +/- 20.2 to 12.4 +/- 3.3 and 26.4 +/- 6.5 pg/ml on the second and seventh days, respectively, of A-64662 infusion. In contrast, infusion of vehicle alone had no discernible effect on mean arterial pressure, PRA, or plasma Ang II concentrations. Plasma aldosterone decreased (p less than 0.05) from control on the second and third days of A-64662 infusion, although differences between the treatment groups were not detected throughout the study. Urinary sodium excretion remained at control levels throughout the infusion of A-64662. Cessation of A-64662 administration resulted in a recovery of mean arterial pressure to preinfusion levels within 1 day. This study indicates that continuous infusion of A-64662 results in a sustained hypotension in sodium-depleted monkeys. This effect appears to be related, at least partially, to inhibition of PRA and lower plasma Ang II levels.

Immunoglobulin gene rearrangements in adult non-Hodgkin's lymphoma.

Southern blotting was employed to analyze the immunoglobulin heavy and light chain genes and the gene for the T cell receptor beta chain in genomic DNA derived from the tumor specimens of 120 adults with pathologically classified and immunotyped non-Hodgkin's lymphoma and B cell chronic lymphocytic leukemia. In a consecutive series of 100 patients, one or two rearranged heavy chain genes could be detected in each of the 80 samples expressing clonal surface immunoglobulin. The kappa gene was rearranged in 70 percent of kappa-bearing tumors and in 23 percent of lambda-bearing specimens. Furthermore, a rearranged immunoglobulin gene was also observed in 21 of 29 lymphomas (nine from the consecutive series and 20 selected for surface immunoglobulin-negative status) in which B cell lineage was in doubt because of absent clonal surface immunoglobulin. These findings indicate that most cases of lymphoma and lymphocytic leukemia in adults are of B cell lineage, even when phenotypic evidence is inconclusive. The exceptional cases (only 3 percent in the consecutive series) were of either follicular lymphoma or diffuse large cell (histiocytic) lymphoma subtype; the lineage in cases of diffuse lymphocytic lymphoma or chronic lymphocytic leukemia was never in doubt. Although the convenience of surface marker analysis assures its continuing clinical application, gene study resolves indeterminate cases and extends the understanding of the pathogenesis of lymphoproliferative disease.

T-cell chronic lymphocytic leukemia. Report of a case studied with monoclonal antibody.

A previously healthy 74 year old woman presented with T-cell chronic lymphocytic leukemia, lymphadenopathy, hepatosplenomegaly and a mediastinal mass. The circulating lymphocytes were small to medium in size (some with convoluted nuclei) and W rosette-positive; they could be assigned to the inducer-helper subset of T cells with the acid of monoclonal antisera. These cells reacted with OKT3, which detects peripheral T cells; OKT4, which detects the inducer-helper subset of T cells; and OKT11, which detects the sheep cell receptor. It is noteworthy that they were also positive for the la-like antigen found on T cells only after activation. Microscopic examination of a lymph node biopsy specimen revealed a diffuse pattern of pleomorphic large cells characteristic of the T-cell lymphomas and lymphocytic leukemias reported from Japan. However, the lymph node cells lacked the T-cell differentiation antigens present on the circulating lymphocytes. The findings in this case provide insight into the pathogenesis of this unusual disorder and are relevant to our understanding of the spectrum of surface antigens in the more common malignant lymphomas.

Predictors of survival in patients undergoing dialysis.

Survival and risk analyses were performed on all 532 patients in whom long-term dialysis was started from 1970 through 1985. During this 16-year period, starting age increased from 47 to 60 years (p less than 0.001), and the incidence of diabetes mellitus and renal vascular disease increased. Survival analysis showed age, renal diagnosis, type of dialysis, and year starting dialysis to be important predictors of survival. There was a fourfold rise in the risk ratio as starting age increased from 25 to 65 years. The risk was 1.5 times higher for those patients who did not start dialysis in 1978 through 1981 than for those who did. Risk decreased fivefold for patients choosing home hemodialysis. Home hemodialysis patients survived longer compared with patients utilizing other dialysis modalities, possibly because of a younger average age and a lower incidence of diabetes mellitus and renal vascular disease. There was greater than a threefold rise in risk ratio with the diagnosis of diabetes mellitus compared with either chronic glomerulonephritis or polycystic kidney disease. Older patients and those with diabetes mellitus formed the high-risk group; these two characteristics have been increasing during the last eight years of the study. It is concluded that although patients with high risk have an increased and a high mortality, overall survival has improved.

Localization of endothelin-1-like immunoreactivity in human placenta.

We examined the distribution of endothelin-1-like immunoreactivity in human placenta, using the immunoperoxidase technique. A specific polyclonal antibody to endothelin-1 was raised in rabbits, which recognized endothelin-1 and its precursor molecule, big endothelin. Immunoperoxidase staining revealed that endothelin-1-like immunoreactivity was widely distributed in the placenta. Endothelin-1-like immunoreactivity was present in endothelial cells of capillaries of the microvilli and in small- and medium-sized arteries and veins. The distribution of endothelin-1-like immunoreactivity was similar to the distribution of Factor VIII-related antigen, which stains endothelial cells. The nature of endothelin in the human placenta was further examined with cultured umbilical vein endothelial cells. Endothelial cells released endothelin-like material into the culture medium. The amount of endothelin-like material varied directly with time of incubation and the amount of fetal calf serum in the culture medium. Fractionation of the endothelin-1-like material by reversed-phase high-performance liquid chromatography (HPLC) and quantitation by radioimmunoassay (RIA) revealed that endothelin-like immunoreactivity co-eluted with endothelin-1 but not with big endothelin-1. We conclude that endothelin-1-like immunoreactivity is widely distributed in vascular endothelium of the human placenta. These data are compatible with a role for endothelin as an autocrine or paracrine modulator of vascular tone in the human placenta.

Reduced thromboxane receptor affinity and vasoconstrictor responses in placentae from diabetic pregnancies.

Thromboxane has been implicated in the pathogenesis of maternal hypertension in high-risk pregnancies, but potential abnormalities in thromboxane-mediated constriction of fetoplacental vessels has not been examined. Using the isolated perfused fetoplacental cotyledon, we compared the vasoconstrictor responses to a thromboxane mimetic, U46619, in placentae from normal women and women with diabetes mellitus (classes C, D and R). Increases in perfusion pressure in response to bolus injections of U46619 were used to construct dose-response curves. The threshold dose of U46619 to cause a pressor response was similar in placentae from normal and diabetic pregnancies, but the slope of the dose-response curve was decreased by 39 per cent in placentae from diabetic pregnancies compared with normal controls (P < 0.01). To examine the potential contribution of altered thromboxane receptors, equilibrium binding studies were performed using the thromboxane antagonist [3H]-SQ29548 to a 44,000 g fraction of placental homogenate. The affinity of thromboxane receptors was significantly decreased in placentae from diabetic pregnancies compared with normal controls [Kd = 41.9 +/- 7.9, (n = 6) versus control, 21.4 +/- 1.3 nM (n = 26), P < 0.001]. In contrast, the density of thromboxane receptor sites was not significantly changed (diabetes, 176.0 +/- 6.2 versus control, 150.3 +/- 6.5 fmol/mg, P = not significant). Placental production of thromboxane and prostacyclin were measured by the incorporation of [14C]-arachidonic acid into [14C]-thromboxane B2 and [14C]-6-keto-prostaglandin F1 alpha, respectively. Incorporation of [14C]-arachidonic acid into both thromboxane B2 and 6-keto-prostaglandin F1 alpha was similar in placentae from diabetic and normal pregnancies. We conclude that vascular responsiveness to thromboxane is reduced in placentae from mothers with diabetes by a receptor-mediated mechanism. These changes may contribute to abnormalities in the regulation of fetoplacental haemodynamics, growth and development in pregnancies complicated by diabetes mellitus.

Simultaneous lowering of serum phosphate and LDL-cholesterol by sevelamer hydrochloride (RenaGel) in dialysis patients.

The aim of the current investigation was to study the effects of sevelamer hydrochloride (RenaGel) on serum phosphate, intact parathyroid hormone levels (iPTH), and lipid profiles in stable hemodialysis patients. Hemodialysis patients maintained on calcium containing phosphate binders were enrolled in this study. Following two weeks of washout of the phosphate binders, serum phosphate rose from 6.4 +/- 0.6 to 10.5 +/- 0.7 mg/dl (p <0.001). After 8 weeks of titration with sevelamer hydrochloride, serum phosphate fell by 4.5 +/- 0.3 to 6.3 +/- 0.7 mg/dl (p <0.0001). Serum calcium levels fell during washout (9.8 +/- 0.4 to 8.9 +/- 0.3 mg/dl, p <0.004) and were unaffected by sevelamer hydrochloride. Sevelamer hydrochloride administration was associated with a 23.0 +/- 3.1% fall in total cholesterol, a 35.9 +/- 3.0% fall in LDL cholesterol, and a 35.2 +/- 5.3% fall in the LDL:HDL cholesterol ratio (p <0.001). There was no change in HDL cholesterol, triglycerides or the concentration of fat soluble vitamins. Sevelamer hydrochloride is a well tolerated alternative to calcium or aluminum containing phosphate binders and may offer an advantage to patients who become hypercalcemic on calcium-containing antacids and vitamin D supplementation. Furthermore, sevelamer hydrochloride lowers LDL cholesterol without affecting HDL cholesterol. The potential usefulness of the lipid lowering effects of sevelamer hydrochloride needs to be determined in additional prospective studies.