BACKGROUND: Four cardiac hormones synthesized by the same gene, i.e. atrial natriuretic peptide, vessel dilator, long acting natriuretic peptide and kaliuretic peptide, and the kidney hormone urodilatin have anticancer effects in vitro. MATERIALS AND METHODS: These cardiac hormones and urodilatin were infused subcutaneously for 28 days with weekly fresh hormones since they lose biological effects at body temperature for more than a week at 0.3 nm kg(-1) body weight in athymic mice bearing human small-cell lung carcinomas. RESULTS: Long acting natriuretic peptide, vessel dilator, kaliuretic peptide, atrial natriuretic peptide and urodilatin eliminated 86%, 71%, 57%, 43%(P < 0.001 for the cardiac hormones) and 25%(P < 0.05; urodilatin) of the human small-cell lung carcinomas. The treated small-cell lung carcinomas that were not cured grew rapidly, similar to the untreated controls, whose volume was 7 fold larger in 1 week, 18-fold increased in 2 weeks, 39-fold increased in 3 weeks, 63-fold increased in 1 month and 97-fold increased in volume in 6 weeks. One vessel dilator treated small-cell lung carcinoma animal developed a large tumour (8428 mm3 volume) on treatment and this tumour was eliminated with utilizing atrial natriuretic peptide and then long acting natriuretic peptide sequentially. CONCLUSIONS: Four cardiac hormones eliminate up to 86% of human small-cell lung carcinomas in athymic mice. Urodilatin can also eliminate small-cell lung carcinomas but at a lower cure rate of 25%. Unresponsive lesions can be eliminated by utilizing different hormones synthesized by the atrial natriuretic peptide gene in a sequential manner.

M1 myeloid leukemic cells were used to dissect the molecular mechanisms of myeloid cell survival and apoptosis. A salient feature of M1 cells is that they respond to the physiological survival factor interleukin-6 (IL-6), yet lack the tumor suppressor gene p53. Functional wild-type activation of temperature-sensitive p53 protein (p53 val) at permissive temperature in M1-t-p53 cells results in rapid apoptosis, which is blocked by IL-6. How p53 induces M1 apoptosis and how IL-6 protects against p53-induced apoptosis are not fully understood. Here it is shown that p53-mediated apoptosis of M1 cells involves rapid activation of the proapoptotic Fas/CD95 death pathway, which activates caspases 8 and 10. Functional p53 also targets the mitochondria, causing upregulation of proapoptotic Bax, downregulation of prosurvival Bcl-2 and activation of caspase 9. IL-6 was found to protect against p53-induced apoptosis via activation of the PI3K/Akt survival pathway, which in turn counters both the Fas/CD95 and mitochondrial apoptotic pathways and activates the prosurvival transcription factor nuclear factor-kappaB (NF-kappaB). Taken together, this work supports a novel model for leukemic progression where cells that acquire the ability to produce an autocrine survival factor, such as IL-6, can bypass normal p53 surveillance function by targeting Akt, which in turn can exert effects on the regulators of apoptosis, such as the Fas/CD95 pathway, the mitochondria and NF-kappaB.Oncogene advance online publication, 13 November 2006; doi:10.1038/sj.onc.1210109.

Background Mortality from renal-cell cancer remains a significant problem with an estimated 12 600 deaths in the United States in 2005 even with current treatment(s) of surgery, chemotherapy, radiation and immunotherapy. Four cardiac natriuretic peptides, that is, atrial natriuretic peptide, vessel dilator, long-acting natriuretic peptide and kaliuretic peptide have significant anti-cancer effects in breast, pancreatic, prostate and colon adenocarcinomas. Materials and methods These four peptide hormones plus brain natriuretic peptide (BNP), C-natriuretic peptide (CNP) and urodilatin, a peptide hormone formed in the kidney by a different post-translational processing of the atrial natriuretic peptide prohormone, were evaluated for their anti-cancer effects in renal carcinomas. Results Dose-response curves revealed a significant (P < 0.0001) decrease in human renal carcinoma cells with each 10-fold increase in concentration from 1 microm to 100 microm of five of these peptide hormones. There was an 81%, 74%, 66%, 70% and 70% elimination within 24 h in renal carcinoma cells secondary to vessel dilator, kaliuretic peptide, urodilatin, atrial natriuretic peptide and long-acting natriuretic peptide, respectively (P < 0.0001 for each), whereas BNP had no effect and CNP decreased renal cancer cell number by 10%(P = 0.04) at their 100 microm concentrations. Three days after treatment with these peptide hormones, the cancer cells began to proliferate again. The four cardiac hormones and urodilatin decreased DNA synthesis from 65-84%(P < 0.00001), whereas BNP and CNP decreased DNA synthesis 3% and 12%(both non-significant). Western blots revealed for the first time natriuretic peptide receptors (NPR)-A,-B and -C were present in the renal cancer cells. Conclusions These results indicate that urodilatin and the four cardiac hormones have potent anti-cancer effects by eliminating up to 81% of renal carcinoma cells within 24 h of treatment.

Hematology variables were measured in blood samples obtained every 3h (8/24h) from 10 multiple sclerosis (MS) patients and 34 healthy subjects and analyzed for circadian characteristics using the population multiple-components method. Red blood cell (RBC) and hemoglobin levels as well as hematocrits exhibited circadian rhythms with minimal amplitudes in healthy individuals and insignificant variability in the smaller group of MS patients. In contrast the total white blood cell (WBC) and platelet counts for MS patients and healthy individuals both showed significant circadian characteristics while the mean 24h WBC and platelet levels did not significantly differ between the two groups. When the different WBC subsets were examined independently, statistically significant circadian rhythms were seen for lymphocytes and eosinophils for both MS patients and healthy individuals and for neutrophils only in the latter. Moreover, the 24h mean levels of lymphocytes, basophils, and eosinophils were significantly higher for the healthy controls while those of monocytes were higher for the MS patients. However, of all the variables tested with significant circadian rhythms in both groups of individuals, only those of lymphocyte numbers exhibited different patterns with somewhat higher amplitude in healthy individuals and a peak level occurring over an hour after that of MS patients. These changes may be the reflection of a disturbance in the regulation of patterns of lymphocyte activity and migration in MS patients. In addition, the elevation in circulating monocytes in MS patients is consistent with the inflammatory nature of the disease.

Four cardiac peptide hormones, i.e., vessel dilator, long acting natriuretic peptide (LANP), kaliuretic peptide, and atrial natriuretic peptide (ANP) synthesized by the same gene decrease within 24 hours up to 97% the number of human breast, colon, pancreatic, and prostate adenocarcinoma cells as well as human small-cell and squamous carcinomas of the lung cells. These peptide hormones completely inhibit the growth of human pancreatic adenocarcinomas growing in athymic mice. Immunocytochemical investigations have revealed that LANP, vessel dilator, kaliuretic peptide and ANP localize to the nucleus and cytoplasm of human pancreatic adenocarcinomas, which is consistent with their ability to decrease DNA synthesis in the nucleus of this cancer mediated by the intracellular messenger cyclic GMP. These peptide hormones also localize to the endothelium of capillaries and fibroblasts within these cancers. These are the first growth-inhibiting peptide hormones ever demonstrated to localize to the nucleus. Their ability to decrease the activation of growth promoting substances such as Extracellular Receptor Kinase (ERK)-1/2 and Nuclear Factor Kappa Beta (NFkappaB) suggests that in addition to inhibiting DNA synthesis their ability to decrease the activation of growth promoting substances helps to mediate their ability to inhibit the growth of human cancers.

Background Mortality from prostate cancer remains a significant problem with current treatment(s), with an expected 30 350 deaths from prostate cancer in 2005. Long-acting natriuretic peptide, vessel dilator, kaliuretic peptide and atrial natriuretic peptide have significant anticancer effects in breast and pancreatic adenocarcinomas. Whether these effects are specific and whether they have anticancer effects in prostate adenocarcinoma cells has not been determined. Materials and methods These peptide hormones were evaluated to determine if they have specific anticancer effects in human prostate adenocarcinomas. Results Dose-response curves revealed a significant (P < 0.05) decrease in human prostate cancer number with each tenfold increase in the concentration from 1 microM to 1000 microM (i.e. 1 mM) of these four peptide hormones. There was a 97.4%, 87%, 88% and 89%(P < 0.001 for each) decrease in prostate cancer cells secondary to vessel dilator, long-acting natriuretic peptide, kaliuretic peptide and atrial natriuretic peptide, respectively, at their 1-mM concentrations within 24 h, without any proliferation in the 3 days following this decrease. These same hormones decreased DNA synthesis from 68% to 89%(P < 0.001). When utilized with their respective antibodies their ability to decrease prostate adenocarcinoma cells or inhibit their DNA synthesis was completely blocked. Western blots revealed that for the first time natriuretic peptide receptors (NPR) A- and C- were present in prostate cancer cells. Conclusions These results indicate that these peptide hormones' anticancer effects are specific. Furthermore, they have very potent effects of eliminating up to 97% of prostate cancer cells within 24 h of treatment. Eur J Clin Invest 2005; 35 (11): 700 -710.

BACKGROUND: Four peptide hormones of a family of six hormones, i.e. atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-natriuretic peptide (CNP), long acting natriuretic peptide (LANP), vessel dilator and kaliuretic peptide, significantly decrease the number of adenocarcinoma cells in culture. The present investigation was designed to determine whether these peptide hormones' effects are specific to adenocarcinomas or whether they might decrease the number of cancer cells of a different type of cancer, i.e. small-cell lung cancer. METHODS AND MATERIALS: These six hormones were evaluated for their ability to decrease the number and/or proliferation of human small-cell lung cancer cells in culture for 24, 48, 72, and 96 h. RESULTS: Within 24 h, vessel dilator, LANP, kaliuretic peptide, ANP and their intracellular mediator cyclic GMP, each at 1 microM, decreased the number of small-cell lung cancer cells by 63%(P < 0.001), 21%(P < 0.05), 30%(P < 0.05), 39%(P < 0.05), and 31%(P < 0.05), respectively. There was no proliferation in the 3 days following this decrease in cell number. These same hormones decreased DNA synthesis 68% to 82%(P < 0.001). Brain natriuretic peptide and CNP did not decrease the number of small-cell lung cancer cells or inhibit their DNA synthesis at 1 microM or 10 microM concentrations. Dose-response curves revealed that at 100 microM, the vessel dilator decreased 92% of the cancer cells in 24 h while BNP had no effect, but CNP caused a 39% decrease. Western blots revealed that the natriuretic peptide receptors A- and C- were present in these cancer cells. CONCLUSIONS: Five peptide hormones significantly decrease the number of human small-cell lung cancer cells within 24 h and inhibit their proliferation for at least 96 h. Their mechanism of doing so involves inhibition of DNA synthesis mediated in part by cyclic GMP.

BACKGROUND: A family of six hormones, i.e. atrial natriuretic peptide, brain natriuretic peptide, C-natriuretic peptide, long-acting natriuretic peptide, vessel dilator, and kaliuretic peptide's main known biologic properties are sodium and water excreting and blood pressure lowering. METHODS AND MATERIALS: These six hormones, each at their 1-microm concentrations, were evaluated for their ability to decrease the number and/or proliferation of breast adenocarcinoma cells in culture for 24, 48, 72, and 96 h. RESULTS: Within 24 h, vessel dilator, long-acting natriuretic peptide, kaliuretic peptide, atrial natriuretic peptide and 8-bromo-cyclic GMP, a cell-permeable analogue of their intracellular mediator cyclic GMP (each at 1 microm), decreased the number of breast adenocarcinoma cells 60%, 31%, 27%, 40%, and 31%, respectively. There was no proliferation in the 3 days following this decrease in breast adenocarcinoma cell number. These same hormones decreased DNA synthesis 69% to 85%(P < 0.001). Brain natriuretic peptide and CNP did not decrease the number of breast adenocarcinoma cells or inhibit their DNA synthesis. Vessel dilator, long-acting natriuretic peptide, kaliuretic peptide and 8-bromo-cyclic GMP (each at 1 microM) decreased the number of cells in the S phase of the cell cycle by 62%, 33%, 50%, and 39%, respectively (all P < 0.05). Natriuretic peptide receptors-A and -C were present in the breast adenocarcinoma cells. CONCLUSIONS: Four peptide hormones significantly decrease the number of human breast adenocarcinoma cells within 24 h and inhibit the proliferation of these cells for at least 96 h. Their mechanism of doing so involves inhibition of DNA synthesis and a decrease in cells in the S phase of the cell cycle mediated in part by cyclic GMP.

BACKGROUND: The atrial natriuretic peptide (ANP) gene synthesizes four cardiovascular hormones, i.e. vessel dilator, long-acting natriuretic peptide, kaliuretic peptide and ANP, which decrease the number of human pancreatic adenocarcinoma cells in culture by 65%, 47%, 37%, and 34%, respectively. METHODS AND MATERIALS: None of the cardiovascular hormones has been investigated to determine whether they inhibit the growth of cancers in vivo. These four hormones were evaluated for their ability to inhibit the growth of human pancreatic adenocarcinomas in athymic mice. RESULTS: Vessel dilator (139 ng min(-1) kg(-1) of body weight) infused for 14 days completely stopped the growth of human pancreatic adenocarcinomas in athymic mice (n = 14) with a decrease in their tumour volume, while the tumour volume increased 69-fold (P < 0.001) in the placebo (n = 30)-treated mice. When these peptide hormones (each at 1.4 microg min(-1) kg(-1) body weight) were infused for 4 weeks, vessel dilator, long-acting natriuretic peptide and kaliuretic peptide decreased tumour volume after 1 week by 49%, 28%, and 11%, respectively, with a one- and 20-fold increase in the tumour volume in ANP- and placebo-treated mice. Cyclic GMP (2.4 microg min(-1) kg(-1) body weight) inhibited after 1 week the growth of this cancer 95%. CONCLUSIONS: These results suggest that these peptide hormones have useful anticancer properties, as they each inhibited the growth of the human pancreatic adenocarcinomas in vivo and three of the four peptide hormones decreased the volume of the tumours (up to 49%, i.e. vessel dilator). Part of their mechanism of action appears to be mediated by cyclic GMP.

OBJECTIVE: To review the causes of nonpancreatic tumor-associated hypoglycemia and report the first case of hypoglycemia attributable to a leiomyosarcoma, which did not cause hypoglycemia in its primary site but only after metastasizing. METHODS: A case report is presented of a 62-year-old man with a gastric leiomyosarcoma diagnosed and surgically treated 8 years previously, who was found to have 14 large, rounded masses in his liver and a blood glucose level of 19 mg/dL. Biopsy of the largest mass revealed a leiomyosarcoma. RESULTS: Evaluation of the cause of the hypoglycemia revealed that circulating insulin, connecting peptide, proinsulin, insulin-like growth factor-I (somatomedin C), and insulin-like growth factor-II levels were below normal, whereas the insulin-like growth factor-II prohormone concentration was increased twofold. Basal and corticotropin-stimulated serum cortisol values were normal. CONCLUSION: This is the first case report of hypoglycemia occurring only after metastasis of a leiomyosarcoma. A possible causal relationship between the hypoglycemia and the increased circulating insulin-like growth factor-II prohormone is suggested, and alternative explanations and treatment are discussed.

The objective of this study was to test the hypothesis that a release of alpha-artrial natriuretic peptide (ANP) is depressed resulting in the reduction of urinary output in patients receiving controlled mechanical ventilation (CMV) with positive end-expiratory pressure (PEEP). Five normovolemic patients with no apparent cardiac, renal, endocrine, or pulmonary dysfunctions were included in this study. After the patients were mechanically ventilated using a volume-cycled ventilator with zero cmH(2)O PEEP for one hour, hemodynamic variables were measured. Urine and blood samples were collected after the measurements. Plasma alpha-ANP levels were determined on blood samples taken from radial artery using specific radioimmunoassay. Then PEEP levels were changed to 5, 10, 15 and, finally, 0 cmH(2)O in four consecutive one-hour periods. At the end of each period, the measurements and collection of the samples were repeated. With increasing levels of PEEP, central venous pressure (CVP), pulmonary artery wedge pressure (PAWP), and heart rate were pressure-dependently increased. On the other hand, cardiac output and urinary output were decreased. Plasma levels of alpha-ANP were also increased by the institution of PEEP. These changes occurred in a pressure-dependent fashion. Urinary sodium excretion, potassium excretion, fractional excretion of sodium and free water clearance remained unchanged. It is concluded that a release of alpha-ANP was augmented rather than depressed with PEEP. This suggests that a decrease in urinary excretion in patients with PEEP may not be due to a reduced release of alpha-ANP.

Elevated plasma natriuretic peptide levels after AMI (acute myocardial infarction) are associated with adverse outcome. The aim of the present study was to examine the relationship of plasma N-ANP (N-terminal pro-atrial natriuretic peptide) and N-BNP (N-terminal pro-B-type natriuretic peptide) with mortality and heart failure following AMI. We studied 403 patients with AMI. Blood was sampled for measurement of N-ANP and N-BNP on a single occasion between 72 and 96 h after symptom onset. Natriuretic peptide levels were related to all-cause mortality and heart failure episodes. During follow up (median, 462 days; range 5-764), 43 (10.7%), 25 (6.2%) and 49 (12.2%) patients suffered death, heart failure hospitalization and outpatient heart failure respectively. Only N-BNP (P < 0.0005), N-ANP (P = 0.005) and previous AMI (P = 0.016) were independently predictive of death. N-BNP, but not N-ANP, predicted 30-day mortality. N-ANP, but not N-BNP, predicted mortality after 30 days. N-BNP was the better predictor of heart failure. N-ANP and N-BNP were above the median in 35 and 38 respectively, of 43 patients who later died. N-ANP, N-BNP, or both were above the median in 41 out of 43 patients. Of 25 patients hospitalized with heart failure, N-ANP and N-BNP was above the median in 20 and 24 respectively, and one or other was elevated in all cases. Above-median N-ANP predicted 36 and N-BNP predicted 41 out of 49 episodes of outpatient heart failure. One or other peptide was above the median in 45 out of 49 patients. Our results indicate that N-BNP predicts 30-day and N-ANP >30-day mortality. We conclude that consideration of both N-ANP and N-BNP identifies a greater number of patients at risk of death or heart failure than either peptide alone.

SUMMARY: OBJECTIVE To examine the mechanisms of ventilator-induced lung injury at low and high lung volumes.DESIGN Prospective, randomized, laboratory study.SETTING University research laboratory.SUBJECTS Eighty-eight adult male Sprague-Dawley rats.INTERVENTIONS Mechanical ventilation using low and high lung volumes.MEASUREMENTS AND MAIN RESULTS An ex vivo rat lung model was used. In study I (ventilation at low lung volumes), rat lungs (n = 40) were randomly assigned to various modes of ventilation: a) opening and closing with positive end-expiratory pressure (PEEP; control): tidal volume 7 mL/kg and PEEP 5 cm H2O; b) opening and closing from zero end-expiratory pressure (ZEEP): tidal volume 7 mL/kg and PEEP 0; or c) atelectasis. Peak inspiratory pressure was monitored at the beginning and end of 3 hrs of ventilation. At the end of 3 hrs of ventilation, the lungs were lavaged, and the concentrations of tumor necrosis factor-alpha, macrophage inflammatory protein-2, and interleukin-6 cytokines were measured in the lavage. In study II (ventilation at high volumes), rat lungs (n = 45) were randomly assigned to a) cyclic lung stretch: pressure-controlled ventilation, peak inspiratory pressure 50 cm H2O, and PEEP 8 cm H2O; b) continuous positive airway pressure at 50 cm H2O (CPAP50); or c) CPAP at the mean airway pressure of the cyclic stretch group (CPAP 31 cm H2O). Bronchoalveolar lavage cytokine concentrations (tumor necrosis factor-alpha, macrophage inflammatory protein-2, and interleukin-6) were measured at the end of 3 hrs of ventilation. In the low volume study, there was no difference in bronchoalveolar lavage cytokine concentrations between the PEEP group and the atelectatic group. All cytokines were significantly higher in the ZEEP group compared with the atelectasis group. Macrophage inflammatory protein-2 was significantly higher in the ZEEP group compared with the PEEP group. Lung compliance, as reflected by change in peak inspiratory pressure, was also significantly worse in the ZEEP compared with the PEEP group. In the high-volume study, tumor necrosis factor-alpha and interleukin-6 were significantly higher in the cyclic stretch group compared with the CPAP 31 group. There was no significant difference between the cytokine concentrations in the cyclic stretch group compared with the CPAP 50 group.CONCLUSION We conclude that at low lung volumes, cyclic opening and closing from ZEEP leads to greater increases in bronchoalveolar lavage cytokines than atelectasis. With high-volume ventilation, over time, the degree of overdistension is more associated with increases in bronchoalveolar lavage cytokines than cyclic opening and closing alone.

In 30 individuals with class III congestive heart failure (CHF), negative feedback of 4 cardiac peptide hormones, ie, long-acting natriuretic peptide (LANP), vessel dilator, kaliuretic peptide, and atrial natriuretic factor (ANF) from the same 126-amino acid (aa) prohormone were studied with the infusion of 100 ng/kg body weight (BW) for 60 minutes of each of the 4 cardiac hormones and a saline control (n = 6 for each). LANP decreased the circulating concentrations of vessel dilator, kaliuretic peptide, and ANF by 24%, 55%, and 30%, respectively. Vessel dilator decreased the circulating concentrations of ANF, kaliuretic peptide, and LANP 27%, 12%, and 62%, respectively. Kaliuretic peptide decreased the circulating concentrations of LANP, ANF, and vessel dilator 89%, 67%, and 70%, respectively. ANF decreased the circulating concentrations of LANP, vessel dilator, and kaliuretic peptide 88%, 59%, and 98%, respectively. Infusion of each of these 4 cardiac hormones decreased the excretion of the other 3 hormones into the urine by 11% to 92%. These results suggest that the respective cardiac hormones inhibit the release of each other rather than their breakdown, which would have increased their urinary concentrations. The feedback regulation of these hormones found previously in healthy humans is, thus, preserved in persons with CHF despite their increased endogenous circulating concentrations.

OBJECTIVE: To examine the isolated and combined effects of positive end-expiratory pressure (PEEP) and partial liquid ventilation (PLV) on the development of ventilator-induced lung injury in an ovine model. DESIGN: Prospective controlled animal study. SETTING: University-based cardiovascular animal physiology laboratory. SUBJECTS: Thirty-eight anesthetized supine sheep weighing 22.3 +/- 2.2 kg. INTERVENTIONS: Animals were ventilated for 6 hrs (respiratory rate, 15; FIO2, 1.0, inspiratory/expiratory ratio, 1:1) with one of five pressure-controlled strategies, expressed as peak inspiratory pressure (PIP)/PEEP: low-PIP, 25/5 cm H2O (n = 8); high-PIP, 50/5 cm H2O (n = 8); high-PIP-PLV, 50/5 cm H2O-PLV (n = 8); high-PEEP, 50/20 cm H2O (n = 7); and high-PEEP-PLV, 50/20 cm H2O-PLV (n = 7). MEASUREMENTS AND MAIN RESULTS: Compared with the low-PIP control, high-PIP ventilation increased airleak, shunt, histologic evidence of lung injury, neutrophil infiltrates, and wet lung weight. Maintaining PEEP at 20 cm H2O or adding PLV reduced the development of physiologic shunt and dependent histologic injury indexes. Neither higher PEEP nor PLV reduced the high incidence of barotrauma observed in high-PIP animals. CONCLUSIONS: We conclude that application of PLV or PEEP at 20 cm H2O may improve gas exchange and afford lung protection from ventilator-induced lung injury during high-pressure mechanical ventilation in this model.

The present investigation was designed to determine whether atrial natriuretic peptides (ANPs) consisting of amino acids 1-30 [i.e. long-acting natriuretic hormone (LANH)], 31-67 (vessel dilator), 79-98 (kaliuretic hormone), and 99-126 (atrial natriuretic hormone [ANH]) of the 126-amino acid ANH prohormone decrease the circulating concentrations of total and free T4 and/or free T3 in healthy humans (n = 30). Vessel dilator, kaliuretic hormone, LANH, and ANH decreased the circulating concentrations of total T4 by 61%, 58%, 47%, and 55% and of free T4 by 60%, 67%, 79%, and 79%, whereas free T3 decreased 72%, 67%, 71%, and 67%(P < 0.05 for each), respectively, when infused at 100 ng/kg BW x min for 60 min. Vessel dilator, kaliuretic hormone, LANH, and ANH simultaneously increased circulating TSH concentrations 4- to 12.5-fold (P < 0.004). The decreases in T4 and T3 with reciprocal increases in TSH lasted 2-3 h after cessation of the respective ANP infusions. The reciprocal increase in TSH with the decreases in T4 and T3 suggests that their modulation of T4 and T3 concentrations occurs in the thyroid rather than in the pituitary or hypothalamus, because TSH would be decreased in the circulation if their inhibitory effects were in either the hypothalamus or pituitary.

The present investigation was designed to determine whether atrial natriuretic peptides consisting of amino acids 1-30 (i.e. long-acting natriuretic hormone), 31-67 (vessel dilator), 79-98 (kaliuretic hormone), and 99-126 (atrial natriuretic hormone) of the 126 amino acid atrial natriuretic hormone prohormone decrease CRH, ACTH, and/or cortisol in healthy humans (n = 30). Vessel dilator, kaliuretic hormone, long-acting natriuretic hormone, and atrial natriuretic hormone decreased the circulating concentration of CRH 84%, 74%, 67%, and 62%(P < 0.001 for each), respectively, when infused at 100 ng/kg body weight.min for 60 min. Vessel dilator, kaliuretic hormone, long-acting natriuretic hormone, and atrial natriuretic hormone decreased circulating ACTH concentrations 58%, 80%, 81%, and 70%(P < 0.001) and the circulating concentration of cortisol 73%, 72%, 73%, and 67%(P < 0.001), respectively. The decreases in CRH, ACTH, and cortisol lasted 11/2 to 3 h after cessation of the respective atrial natriuretic peptide infusions. These data, along with the knowledge that cortisol upregulates atrial natriuretic peptides' gene expression and CRH and ACTH stimulate atrial natriuretic peptides' release, suggest that these four atrial natriuretic peptides may be part of an intricate feedback system to help regulate cortisol concentrations via their ability to decrease the circulating concentration of CRH which, in turn, results in a decrease in ACTH and cortisol.

BACKGROUND: Biologically active N-terminal fragments such as proANP(1-30), proANP(31-67), and proANP(1-98) derive from the prohormone of alpha-human atrial natriuretic peptide [proANP(99-126) or alpha-ANP]. No systematic data are available for patients with different kidney diseases. METHODS: Specific immunoassays were developed to determine plasma and urine concentrations of these fragments in 121 patients with different degrees of kidney function and urinary protein excretion, respectively. RESULTS: In patients with kidney disease and normal renal function without proteinuria, circulating proANP(1-30) and proANP(31-67) increased 2.8-fold and 6.5-fold, respectively. Urinary excretion of proANP(31-67) increased by a factor of 7.7 in these patients, whereas proANP(1-30) was not affected. Patients with impaired renal function had a dramatic increase of urinary proANP(31-67) excretion even before serum creatinine levels started to rise. The progression of renal failure caused a significant rise of circulating proANP(1-30)(4.3-fold) and proANP(31-67)(3.0-fold) compared with patients with normal renal function. Urinary excretion of proANP peptides significantly increased, particularly when the serum creatinine level was> 5.0 mg/dL [proANP(1-30) 26-fold, proANP(31-67) 8.4-fold]. Urinary excretion of proANP(1-30) increased up to 4.4-fold and urinary excretion of proANP(31-67) increased up to 2.4-fold in patients with proteinuria in excess of 3 g/24 h. CONCLUSIONS: Plasma concentrations and urinary excretion of proANP(1-30) and proANP(31-67) are affected by kidney disease and function, but not by proteinuria per se. It is proposed that the diseased kidney increases early urinary excretion of proANP fragments to participate in the regulation of renal function as well as sodium and water excretion.

The atrial natriuretic peptide (ANP) gene synthesizes a 126-amino acid (aa) prohormone from which four peptide hormones are derived. These 4 peptide hormones consisting of aa 1 to 30 (ie, long-acting natriuretic peptide [LANP]), aa 31 to 67 (vessel dilator), aa 79 to 98 (kaliuretic peptide), and aa 99 to 126 (ie, ANP) have diuretic, natriuretic, and/or kaliuretic properties. ANP has been reported to have its natriuretic and protein-excreting effects via both the proximal and distal tubules, but where in the kidney the other three peptide hormones have their natriuretic and/or diuretic effects is unknown. Further, it has never been investigated as to whether these three other peptide hormones enhance protein excretion. The present investigation was designed to determine (1) if these atrial peptides enhance protein excretion and (2) if their effects involve the proximal tubules of healthy humans by examining the excretion rate of beta2-microglobulin, a marker of proximal tubule function. Twenty-four healthy human subjects were studied following the infusion of 100 ng/kg body weight/min for 60 minutes of each of the respective peptides. LANP enhanced the excretion rate of beta2-microglobulin 2-fold within 20 minutes of beginning its infusion (P <.05) and was 2.5-fold higher than the preinfusion excretion rate at the end of the infusion. The excretion rate of beta2-microglobulin continued to be significantly (P <.01) increased for 3 hours after cessation of the LANP infusion, with the maximal excretion rate (ie, 3.8-fold increase) at 2.5 hours after stopping the infusion. Vessel dilator showed a more marked enhancement of beta2-microglobulin during its infusion, with the excretion rate increasing 2.5-fold at 20 minutes, and was increased 4-fold (P <.01) at the end of the infusion. With cessation of the vessel dilator infusion, the excretion rate of beta2-microglobulin decreased but was still elevated 2-fold (P <.05) 3 hours after stopping the infusion. Kaliuretic peptide enhanced the beta2-microglobulin excretion rate a maximal 3-fold, which occurred at the end of its infusion. The beta2-microglobulin excretion secondary to kaliuretic peptide remained 2-fold (P <.05) above baseline during the 3-hour postinfusion period. These peptide hormones similarly enhanced the albumin and total protein excretion rates 2- to 4-fold. These results indicate that LANP, vessel dilator, and kaliuretic peptide each (1) enhance protein excretion in healthy humans and (2) inhibit proximal tubular protein reabsorption.

The use of a ventilation strategy with high positive end-expiratory pressure (PEEP) that is intended to recruit collapsed alveoli and to prevent recurrent collapse can reduce alveolar protein influx in experimental acute lung injury (ALI). This could affect the pulmonary response to treatment with surfactant, since plasma proteins inhibit surfactant function. We studied the effect of exogenous surfactant on lung mechanics after 4 h of mechanical ventilation with high or low PEEP. Twenty-two adult male Sprague-Dawley rats were anaesthetized, tracheotomized and submitted to pressure-controlled mechanical ventilation with 100% oxygen. One group served as healthy controls (n = 6). In the remaining animals acute lung injury was induced by repeated lung lavages to obtain a PaO2 < 13 kPa during ventilation with a peak inspiratory pressure (PIP) of 26 cm H2O and a PEEP of 6 cm H2O. These animals were allocated randomly to ventilation with high PEEP (n = 8; 100 breaths min-1, I:E = 1:1 PIP 35 cm H2O, PEEP 18 cm H2O) or to conventional mechanical ventilation (PIP 28 cm H2O, PEEP 8 cm H2O; n = 8; ventilated control group). After 4 h of ventilation, all animals were given surfactant (120 mg kg-1) via the trachea and ventilation was continued for 15 min. At the end of the study, pressure-volume curves were constructed to measure total lung capacity at 35 cm H2O (TLC35) and maximal compliance (Cmax), and bronchoalveolar lavage was then used to measure alveolar protein influx. After lavage, PaO2, remained around 13 kPa in the ventilated control group and was > 66 kPa in the high-PEEP group. After surfactant treatment, PaO2 increased to > 53 kPa in both groups. In the ventilated control group alveolar protein influx was greater and TLC35 and Cmax were lower than in the high-PEEP group. We conclude that the pulmonary response to exogenous surfactant after mechanical ventilation in experimental ALI is improved when a ventilation strategy with high PEEP is used.