Lymphadenectomy for renal cell carcinoma and urothelial carcinoma of the upper urinary tract: analysis of evidence in the minimally invasive era.

Although lymphnode dissection (LND) provides staging and therapeutic benefit in bladder cancer, the role of lymphadenectomy in renal cell carcinoma (RCC) and urothelial cancer of the upper urinary tract (UCUUT) remains undefined. The aim of this paper was to examine the staging and therapeutic role of LND in RCC and UCUUT with emphasis on applicability to modern minimally invasive approaches. A Pubmed search was conducted to identify literature published between January 1, 2008 and March 11, 2013 addressing the role of lymphadenectomy in renal and upper urinary tract cancer. Key words included "lymphadenectomy", lymphnode dissection", "lymphnode excision", "lymphatic metastasis", "renal cancer", "renal neoplasm", "renal cell carcinoma", "kidney cancer", "kidney neoplasm", "upper urinary tract", "urothelial carcinoma", "kidney pelvis", "ureteral neoplasm", "transitional cell", "ureter, and upper tract urothelial neoplasm". The staging benefit of LND in RCC and UCUUT remains controversial although lymphnode metastasis is an important prognostic factor in both disease processes. It is not well established whether LND improves survival in RCC and UCUUT. There is no consensus regarding the optimal lymphnode yield or template. Much of the current literature is derived from studies of open surgery. Patients with higher grade and stage may derive the most benefit from LND. LND may provide both staging and survival benefit in select patients undergoing surgery for treatment of either RCC or UTUUC. Patients with clinical stage T2 or higher, those with aggressive histologic subtypes and features, and those with clinically enlarged nodes should undergo LND. Simple LND templates based on tumor location should be used and are amenable to both open and minimally invasive approaches.

Enzymatic dissection of embryonic cell adhesive mechanisms.

In this paper we describe a kinetic assay for cell adhesion which measures the formation of cell clusters. Cluster formation is dependent on both calcium and protein synthesis, two parameters essential for the formation of histotypic aggregates. We also describe modifications of the stndard method for trypsinization of tissues which result in populations of single cells that appear to bear intact and functional cell surface adhesive systems. These modifications involve the use of chymotrypsin and the inclusion of calcium during enzyme digestion of tissues with trypsin and chymotrypsin. Using the cluster formation assay and the modified tissue dissociation techniques, we demonstrate the presence of two functionally distinct adhesive systems operating among embryonic chick neural retina cells. These two systems differ in proteolytic sensitivity, protection by calcium against proteolysis, dependence on calcium for function and morphogenetic potential. Cells possessing one of these intact adhesive systems are capable of extensive morphogenetic interactions in the absence of protein synthesis.

Inability of antiserum active in antibody-dependent cellular cytotoxicity and arming tests to protect against simian virus 40 tumor cell challenge.

Previous studies have shown that simian virus 40 (SV40) hamster tumor cells that were pretreated with antiserum from syngeneic hosts sensitized to SV40 were killed following exposure to nonsensitized spleen cells. In this study preincubation of nonadherent spleen or lymph node cells with SV40 antiserum rendered the cells specifically cytotoxic for the SV40-transformed fibroblasts. The capacity of a particular antiserum to "arm" (i.e., to be made specifically cytotoxic) was comparable with its ability to mediate antibody-dependent cellular cytotoxicity (ADCC). Experiments were performed to determine if the SV40 antiserum had prophylactic activity. Two hours after passive transfer of serum, cytotoxic effector cells could be demonstrated in the blood, spleen, and mesenteric lymph node, and the recipients' sera were active in ADCC tests. Nevertheless, such hosts were not resistant to challenge with small numbers of SV40 tumor cells that were given intradermally or intracardiacly, nor was tumor growth suppressed by addition of normal lymph node cells to the antiserum-pretreated tumor cell inoculum. Thus SV40 antiserum, active at high titer in ADCC and arming assays, did not prevent or delay growth of SV40 tumor isografts.

Use of cytokines in the treatment of acute myelocytic leukemia: a critical review.

PURPOSE: The colony-stimulating factors (CSFs) have been evaluated in patients with acute myelocytic leukemia (AML), both as potential priming agents and during and/or following induction chemotherapy to shorten the period of myelosuppression. The purpose of this review is to evaluate critically the safety and efficacy of the CSFs, primarily granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF), in the treatment of patients with AML. METHODS: All phase III trials that have either been presented or published that used CSFs during and/or following induction chemotherapy in patients with de novo AML are discussed. Relevant background information and future directions are also addressed. RESULTS AND CONCLUSION: There have been six phase III trials that used either GM-CSF or G-CSF in induction therapy in patients with AML. It is difficult to compare these trials due to differences in patient age, induction therapy administered, disease characteristics, whether leukemia response or documentation of marrow hypoplasia was required before cytokine use, and the different cytokines administered during the study. In particular, the timing of CSF administration in relation to the chemotherapy may be important due to the different biologic effects these agents may have on leukemia cells, such as leukemia cell recruitment. Most of these studies administered either GM-CSF or G-CSF before or during induction therapy, as well as following completion of chemotherapy until neutrophil recovery. Only one of six trials required documentation of marrow hypoplasia before CSF use. Despite these differences, administration of either GM-CSF or G-CSF was found to be safe without an increase in acute toxicity or an increase in relapse rates. In addition, most trials demonstrated a significant improvement in neutrophil recovery, with several trials demonstrating an improvement in complete remission and overall survival rates. Therefore, the use of selected CSFs may be of benefit following induction chemotherapy in those patients with AML who are at increased risk for early morbidity and mortality.

Successful marrow transplantation for acute myelocytic leukemia following therapy for Hodgkin's disease.

Five patients with acute myelocytic leukemia (AML) after combined modality therapy for Hodgkin's disease (HD) were treated with cyclophosphamide and busulfan followed by bone marrow transplantation (BMT). Four patients received allogeneic transplants from histocompatibility locus antigen (HLA)-compatible siblings and the fifth patient received an autologous marrow treated with 4-hydroperoxycyclophosphamide. Two patients died of complications of acute graft-v-host disease (GVHD) despite prophylaxis with either low-dose cyclophosphamide or cyclosporine. The remaining three patients were alive and disease-free 382, 617, and 620 days after transplant. These initial results are encouraging and more patients with treatment-related AML need to be evaluated with both allogeneic and autologous BMT to fully elucidate the potentially curative role of this intensive therapy in an otherwise fatal hematologic malignancy.

Bone marrow transplantation of chronic myelogenous leukemia in chronic phase: evaluation of risks and benefits.

PURPOSE: Allogeneic bone marrow transplantation (BMT) is an option for some patients with chronic myelogenous leukemia (CML). We retrospectively evaluated the effect of various risk factors observed at diagnosis and at transplantation on survival, event-free survival (EFS), and relapse after BMT. PATIENTS AND METHODS: Seventy-nine patients with CML in chronic phase (CP) were treated with cyclophosphamide and total body irradiation followed by BMT. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (CsA) in most instances or CsA plus the use of lymphocyte-depleted bone marrow (BM). RESULTS: Survival at 4.5 years was 52%. Stratified by age and GVHD prophylaxis, the actuarial survival was 65% (95% confidence interval [CI], 47% to 78%) in patients aged less than 30 years receiving unmanipulated BM, 33% (95% CI, 12% to 56%) in patients greater than or equal to 30 years old receiving unmanipulated BM, and 38% (95% CI, 14% to 63%) in patients greater than or equal to 30 years old receiving lymphocyte-depleted BM. In univariate analysis, patient age (greater than or equal to 30 years) and the use of lymphocyte-depleted BM negatively influenced EFS. When stratified by age and GVHD prophylaxis, however, ABO incompatibility, cytomegalovirus (CMV) seropositivity, and chronic GVHD significantly reduced the probability of EFS. Factors that have been associated with early death in nontransplanted patients (ie, sex, spleen size, blast and platelet counts at presentation) were not predictive of long-term survival outcome after BMT. CONCLUSIONS: The data suggest that (1) BMT should be offered early after diagnosis to all patients with CML in CP who have compatible sibling donors regardless of prognostic factors at presentation, (2) GVHD remains the principal cause of mortality after BMT in patients receiving CsA, and (3) T-cell depletion by the physical separation method of counterflow elutriation (CE) is associated with a significant risk of relapse.

Minimal toxicity and mortality in high-risk breast cancer patients receiving high-dose cyclophosphamide, thiotepa, and carboplatin plus autologous marrow/stem-cell transplantation and comprehensive supportive care.

PURPOSE: To assess the clinical toxicity and outcome associated with a comprehensive supportive care approach in poor-risk breast cancer (BrCA) patients with high-dose chemotherapy (HDC). PATIENTS AND METHODS: One hundred twenty-five consecutive patients with stages II, III or metastatic breast cancer received HDC between February 1992 and June 1994. Recipients received 4 days of continuous infusion of cyclophosphamide 1.5 g/m2/d, thiotepa 125 mg/m2/d, and carboplatin 200 mg/m2/d followed by infusion of bone marrow or peripheral-blood stem cells (PBSC) and recombinant human growth factor (rhu-GF) support. Patients received similar supportive care that included administration of prophylactic antibiotics, management of neutropenic fevers, and transfusion support. RESULTS: There were 38 women with stage II or III (27 patients with > or = 10 lymph nodes), four with stage IIIB, and 83 with metastatic breast cancer. The median age was 44 years (range, 27 to 61). Grade II or greater nonhematologic toxicities included diarrhea (66%), stomatitis (33%), hepatic venoocclusive disease (VOD) (5%), and pulmonary toxicity (4%). Myeloid and platelet engraftment was comparable between bone marrow and PBSC recipients (P > .1). Infectious complications were rare and consisted of gram-negative bacteremia (1.6%), gram-positive bacteremia (1.6%), fungemia (1.6%), and documented or suspected aspergillosis infection (3%). There was one treatment-related death secondary to severe VOD. CONCLUSION: A comprehensive supportive care approach was associated with a low treatment-related mortality rate of less than 1%. With the observed reduction in treatment-related mortality, it is reasonable to evaluate the efficacy of HDC in women with less than 10 positive nodes and stage II disease in well-designed clinical trials.

Granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein versus granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for non-Hodgkin's lymphoma: results of a randomized double-blind trial.

PURPOSE: A phase III trial to compare PIXY321 with granulocyte-macrophage colony-stimulating factor (GM-CSF) following high-dose therapy and autologous bone marrow transplant (ABMT) was conducted to evaluate the time to hematopoietic recovery. PATIENTS AND METHODS: One hundred seventy-seven patients with non-Hodgkin's lymphoma (NHL) receiving ABMT were randomized to receive either PIXY321 750 micrograms/m2/d divided into two subcutaneous (SC) doses or GM-CSF 250 micrograms/m2/d as a 2-hour intravenous (IV) infusion starting on day 0 post-ABMT for a maximum of 28 days. RESULTS: The median time to reach an absolute neutrophil count (ANC) > or = 500/microL in the PIXY321 group was 17 days versus 19 days in the GM-CSF group (P = .07) and the median time to reach platelet transfusion independence in the PIXY321 group was 25 days versus 23 days in the GM-CSF group (P = .30). The toxicity profiles of the two agents appeared to be equivalent with the exception of more patients in the PIXY321 group with a rash (64%) compared with the GM-CSF group (48%) (P = .028). A logistic regression model identified the use of a non-total-body irradiation (TBI) regimen and/or receipt of unpurged marrow and a body-surface area greater than 2.0 m2 as predictive of faster neutrophil engraftment, and those three factors, as well as the receipt of < or = two prior chemotherapy regimens as predictive for rapid platelet engraftment. CONCLUSION: There was a trend toward a slight improvement in neutrophil engraftment post-ABMT with the PIXY321 administered by an SC route compared with GM-CSF administered by an IV route. However, no differences could be identified between the two agents with respect to the time to platelet transfusion independence. Patient, regimen, and graft characteristics were most predictive of the engraftment tempo.

Post-remission therapy of acute myelocytic leukemia in adults: curability breeds controversy.

The curability of acute myelocytic leukemia (AML) in adults relies upon two treatment strategies. The first is induction therapy to effectively reduce the patient's leukemia burden and allow for recovery of normal hematopoiesis. Once this is achieved and the patient enters a complete remission, further potentially curative post-remission therapy can be administered. Induction therapy has not changed significantly over the past two decades, relying primarily on conventional-dose cytarabine and an anthracycline combination. Post-remission therapy, on the other hand, has changed with the introduction of more intensive and aggressive cytoreductive treatment as well as utilization of myeloablative regimens followed by either allogeneic or autologous bone marrow transplantation (BMT). The scope of this review is to evaluate the different curative post-remission treatment approaches for adult patients with AML. Discussions will focus on younger patients (less than 65 years) with responsive disease who enter a complete remission and then have post-remission therapy options available to them. Often, decisions concerning post-remission therapies are based solely on age and the availability of compatible donors; however, since understanding of the biology of leukemia has expanded and treatment strategies have improved, our ability to recommend particular treatment approaches has also evolved. We are now in a position to recommend therapeutic options based on disease and host characteristics.

Cures of leukemia with aggressive postremission treatment: an update of timed sequential therapy (Ac-D-Ac).

A cure rate can be obtained with intensive cytoreductive treatment given to a subset of patients with acute myelocytic leukemia in bone marrow remission. This report updates our experience with postremission timed sequential therapy using cytarabine and daunorubicin (Ac-D-Ac) and compares it with other brief, aggressive strategies including bone marrow transplantation. The median disease-free survival (DFS) of all patients treated in remission is 2.5 years with a greater than 40% probability of DFS at 8 years. These results are similar to those achieved with bone marrow-ablative and other intensive but nonablative treatment plans.

Cure of acute myelocytic leukemia in adults: a reality.

Adult acute myelocytic leukemia (AML) is a curable disease in responsive patients with aggressive treatment in remission. Over the past decade at the Johns Hopkins Oncology Center, AML has been treated with either allogeneic bone marrow transplantation or with intensive timed sequential treatment using high dose cytarabine in remission. With either treatment modality comparable cure rates were obtained. The role, if any, of randomized trials to adequately determine the preferred treatment for appropriate patients has yet to be defined.

Orthostatic hypotension in ciguatera fish poisoning.

PURPOSE: The purpose of this study was to investigate the pathophysiology of persistent orthostatic hypotension in a patient with ciguatera fish poisoning. METHODS: A patient who became ill and who developed prolonged and symptomatic orthostatic hypotension with ciguatera fish poisoning after eating barracuda is described. Studies of autonomic function included measurements of plasma catecholamine levels in the supine and standing positions, and pressor responses to infusions of norepinephrine, atropine, and propranolol. RESULTS: Volume depletion was excluded as a cause for hypotension. Our patient showed low plasma catecholamine levels and marked pressor hypersensitivity to norepinephrine infusion. Hypotension and bradycardia were reversed by atropine infusion. The heart rate freed from autonomic influences, ie, after atropine plus propranolol infusion, was normal. CONCLUSIONS: In ciguatera fish poisoning, orthostatic hypotension appears to be a result of both parasympathetic excess and sympathetic failure.

Anemia in primary hyperparathyroidism.

Although anemia has not been widely appreciated as a complication of primary hyperparathyroidism, 5.1% of the individuals with this disorder seen at the Massachusetts General Hospital since 1962 had a normochromic, normocytic anemia that could not be related to blood loss,a deficiency state, or uremia. The anemic group had more advanced bone disease and higher levels of serum calcium, alkaline phosphatase, and parathyroid hormone than the nonanemic group. Results of bone marrow biopsies performed in five patients showed variable degrees of myelofibrosis. However, none of the patients had hepatosplenomegaly, a myelophthisic peripheral blood smear, leukopenia, or thrombocytopenia. Removal of the abnormal parathyroid glands led to improvement or correction of the anemia.

New preparative regimens with diaziquone or cytarabine in combination with busulfan and cyclophosphamide.

Preparative regimens used prior to bone marrow transplantation (BMT) in patients with malignancies must mediate engraftment and eradicate malignant cells without producing significant extramedullary toxicities. The first agents to be tested in BMT preparative regimens, total body irradiation (TBI) and cyclophosphamide (Cy), were ineffective as single agents, but resulted in long-term disease-free survival in some leukemic patients when combined. However, Cy/TBI regimens are associated with significant acute and chronic toxicities as well as technical constraints involving the administration of radiation. Accordingly, a nonradiation-based regimen consisting of Cy and busulfan (Bu) was developed. Regimens using either a 4-day course (BuCy4) or a 2-day course (BuCy2) of Cy have been shown to have significant antileukemic effects. In general, however, BuCy regimens do not appear to result in greater antileukemic activity or lower treatment-related toxicity than Cy/TBI regimens. New preparative regimens are currently being developed to lower the incidence of disease recurrence after BMT. One such regimen consists of BuCy plus etoposide. At our institution, we are currently testing the efficacy and toxicity of regimens in which cytarabine or diaziquone are administered in combination with Bu and Cy. It is hoped that these new preparative regimens will enhance the antileukemic effects of BMT without significantly increasing treatment-related toxicity.

Variation in expression of porcine xenogeneic antigens.

The rejection of organs transplanted between phylogenetically disparate animals such as pigs and primates is thought to be initiated by binding of naturally occurring antibodies of the recipient to blood vessels in the donor organ. The major porcine target antigens are a triad of glycoproteins, gp115/135, which are expressed on endothelial cells and platelets of all animals tested to date. Whether expression of these antigens varies to the extent that selection of particular animals as donors for xenotransplantation would be warranted is an important question that has not been addressed previously. We tested the reactivity of human natural antibodies with platelet-derived antigens isolated from > 60 pigs representing 4 strains. Reactivity with IgM from a single human serum sample varied to such an extent as to suggest a 5-fold difference in the levels of antigen expression. Significantly, approximately 10% of animals express very low levels of the target antigens. The variations in antigen levels were not due to the age or sex of the animal or to environmental effects. There appears to be genetic regulation of the expression, as sibling pairs were more likely to have similar levels of reactivity than nonsiblings. Western blotting of platelet extracts shows the same quantitative differences in expression of the individual glycoproteins gp115, 125, and 135 as is seen by ELISA for all xenogeneic antigens. The levels of expression of gp115/135 appear to be controlled coordinately and are consistent with genetic regulation. While the clinical relevance of these observations is unclear, it is possible that lower levels of expression of these antigens on donor organs might lead to enhanced xenograft survival. In addition, in the experimental situation, the outcome of particular experiments might be affected by the selection of particular donor-recipient pairs.

Evidence that polyreactive antibodies are deposited in rejected discordant xenografts.

The rejection of organs transplanted between phylogenetically disparate species is thought to be initiated by the binding of naturally occurring antibodies of the recipient to the endothelium lining the blood vessels of the donor organ. We recently showed that among the xenoreactive natural antibodies in human serum that react with porcine endothelial cells and endothelial cell--derived glycoproteins are polyreactive antibodies. To test whether polyreactive natural antibodies are present in rejected xenografts we developed a series of hybridoma-derived antibodies specific for the polyreactive human monoclonal antibody 103, which we have shown to bind efficiently to porcine endothelial cells. Using these antiidiotypic reagents we detected antibodies bearing the 103 idiotype in a panel of human sera and on the surface of lymphocytes in the spleen of humans, rhesus monkeys, and baboons. The antiidiotypic reagents reacted in a pattern similar to the distribution of IgM, with immunoglobulin deposits in tissues obtained from pig-to-rhesus monkey and pig-to-baboon xenografts. Analysis of immunoglobulin eluted from these sites showed that they antibodies display the antigen-binding features of natural antibodies. Our findings are consistent with the hypothesis that idiotypes of polyreactive natural antibodies are broadly crossreactive. They also suggest that the polyreactive and xenoreactive IgM, which have been detected based on in vitro assays, may be deposited in a xenogeneic organ graft.

Evaluation of the drug interaction between intravenous high-dose fluconazole and cyclosporine or tacrolimus in bone marrow transplant patients.

The purpose of this open-label, prospective study was to compare steady state concentrations and clearances of intravenously administered cyclosporine or tacrolimus with and without concomitant high-dose (400 mg/day) fluconazole in allogeneic BMT patients. Twenty-one patients were evaluable. The mean steady state cyclosporine and tacrolimus concentrations without fluconazole were 320.3 and 18.2 ng/ml and increased to 389.2 and 21.2 ng/ml, respectively, after the addition of fluconazole, corresponding to a 21% (P=0.031) and 16% (P=0.125) increase. The mean steady state clearance of cyclosporine and tacrolimus without fluconazole was 6.82 and 1.28 ml/min/kg, which decreased to 5.57 and 1.10 ml/min/kg with fluconazole, corresponding to a 21% (P=0.031) and 16% (P=0.125) decrease, respectively. The 21% difference in the cyclosporine concentration and clearance was not thought to be clinically significant. These results suggest that fluconazole's interaction with cyclosporine or tacrolimus may be a result of fluconazole's inhibition of gut metabolism, resulting in a greater extent of absorption.

The role of natural antibodies in the activation of xenogenic endothelial cells.

Hyperacute rejection of organ xenografts is thought to be mediated by the reaction of naturally occurring antibodies and complement of the recipient with blood vessels in the donor organ. We have suggested previously that the pathogenesis of hyperacute rejection might involve the activation of endothelial cells in the graft. To evaluate the potential role of natural antibodies and complement in hyperacute xenograft rejection, sixteen human sera were tested for variation in the ability to activate porcine endothelial cells as manifested by the release of biosynthetically labeled heparan sulfate from the cells. It was then asked to which extent such variation might reflect differences in natural antibody titer and/or complement activity. The sera mediated release of 3.6-57% of endothelial cell-associated heparan sulfate. Heparan sulfate release correlated significantly with the titer, in the sera, of IgM antibodies that bound to cultured endothelial cells (P = 0.0008) or to a triad of glycoproteins believed to represent the major targets of natural antibodies in porcine to primate xenografts (P = 0.001); correlation was also observed with the total concentration of IgM (P = 0.0046). The release of heparan sulfate did not correlate with corresponding properties of serum IgG, with anti-swine hemagglutination or with isohemagglutination titers. Heparan sulfate release correlated with deposition on endothelial cells of iC3b (P = 0.0095), but not with serum complement activity. Our findings indicate that in the reaction between human serum and xenogeneic endothelial cells, it is the concentration of xenoreactive IgM and not differences in complement activity that limits the ensuing pathophysiologic events.

Effects of ranatensin, a polypeptide from frog skin, on isolated smooth muscle.

1. The actions of bretylium tosylate on neuromuscular transmission in the rat phrenic nerve diaphragm preparation have been investigated by electro-2. On the guinea-pig ileum, threshold doses elicit repeated maximal spike contractions which are blocked by atropine. In the presence of atropine, higher concentrations of ranatensin elicit small contraction spikes superimposed on a relatively weak sustained contraction. These latter two actions are not blocked by increasing the concentration of atropine.3. Other smooth muscle preparations respond as follows: rat uterus, rhythmic contractions; rat duodenum, relaxation; rabbit aortic strip, contraction. Atropine has no effect on the above responses. The rat aortic strip does not respond to ranatensin. Ranatensin is four times as active as bradykinin on the rat uterus.4. Ranatensin can be readily distinguished from other known peptides such as angiotensin, bradykinin and the eledoisin-like peptides, by bioassay.

The action of ranatensin, a new polypeptide from amphibian skin, on the blood pressure of experimental animals.

1. The blood pressure response to ranatensin, an undecapeptide from the skin of the frog, Rana pipiens, has been studied in various experimental animals.2. Ranatensin raised blood pressure in the dog and rabbit. The response was not altered by atropine, phentolamine, propranolol or hexamethonium, suggesting a direct peripheral vasoconstrictor action. In both animals ranatensin was about one-tenth as potent as angiotensin. Tachyphylaxis to ranatensin did occur, but there was no cross-tachyphylaxis with angiotensin, bradykinin, or noradrenaline.3. The peptide lowered blood pressure in the monkey, being as potent as eledoisin. The response was not altered by atropine, phentolamine, propranolol, tripelennamine, tetraethylammonium, bretylium, or methysergide. This again suggests a direct peripheral action on vascular smooth muscle. There was no tachyphylaxis to the depressor action, nor was there cross-tachyphylaxis with angiotensin, eledoisin, bradykinin, or noradrenaline.4. Ranatensin did not alter the blood pressure in cats and had a variable action in the guinea-pig with a rapid onset of tachyphylaxis.5. Ranatensin has a variable effect on the blood pressure in the rat that is related to the basal level of blood pressure. When the blood pressure is high, the response to the peptide is hypotension. Ranatensin raises blood pressure in the rat when the basal blood pressure is low. The pressor response to ranatensin appears to be due, in part, to the release of noradrenaline from peripheral sympathetic nerve endings.6. The composite action of ranatensin on blood pressure of various experimental animals is unlike that of any other peptide. Its hypertensive action in the dog or rabbit, together with a potent hypotensive action in the monkey, readily distinguishes it from all other vasoactive peptides.