Alterations of cardiac and lymphocyte β-adrenoceptors in rat with chronic heart failure

The alterations of cardiac and lymphocyte β-adrenoceptors were observed in the rats with chronic heart failure produced by constriction of both abdominal aorta and renal artery. The results showed that β₁-adrenoceptor density and mRNA levels were increased, whereas these levels remained unchanged for β₂. The concentrationcontractile response curve for isoproterenol was shifted m the right in cardiac atrium, whereas the concentration-CAMP accumulation response curve for isoproterenol in myocardium was not changed. The number of β-adrenoceptom in blood lymphocyte was markedly reduced. Thus in the heart-failure rats the density of cardiac β-adrenoceptor was increased accompanying reduced β-adrenoceptormediated positive inotropic response, suggesting a post adenylate cyclase dysfunction or impaired contractile components. In contrast, the alteration of β-adrenoceptor in lymphocyte is consistent with the reduced β-adrenoceptor-mediated inotropic response in heart.     

β-adrenergic receptor desensitization in cardiac hypertrophy and heart failure

Conclusion Based on our recent data (37,54,56) and the association that profound alterations in βAR signaling are found in chronic end-stage human heart failure (64), it is possible that defects in this pathway are primary elements that underlie the transition from compensated to decompensated cardiac failure. Decreasing the level of myocardial βARK1 in established heart failure, is a novel approach to improving impaired βAR receptor function and potentially alter the pathogenesis in this disease.     

Cytochrome P4501A induced differentially in endothelial cells cultured from different organs of Anguilia rostrata

Summary Endothelial cells are a structural barrier and an active regulator of many bodily processes. Cytochrome P4501A (CYPIA) activity is induced in the endothelium of teleosts and mammals exposed to lipophilic xenobiotics, such as polycyclic aromatic hydrocarbons, and can have significant consequences for endothelial functions. We exposed cultures of characterized endothelial cells from the heart, kidney, and rete mirabile of the eel, Anguilla rostrata, to aryl hydrocarbon receptor (AhR) agonists. In heart endothelial cells, the maximum response (based on O-deethylation of 7-ethoxyresorufin to resorufin [EROD] activity) to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 113 pmol/mg/min, was at 1 nM TCDD and the peak response to β-napthoflavone (βNF), 135 pmol/mg/min, was at 3 μM βNF. The maximum response to TCDD in the kidney endothelial cells is 12 pmol/mg/min at 0.3 nM TCDD. The rete mirabile capillary endothelial cells responded minimally or not at all to exposure to TCDD and βNF. Both the heart and kidney endothelial cells (but not the rete mirabile capillary cells) have a low level of EROD activity (12.7 and 5.2 pmol/mg/min, respectively) in untreated or dimethylsulfoxide-treated cells. The robust response of the heart endothelial cells to induction and the lack of response in the rete mirabile capillary endothelial cells indicate that these cells are a good resource to use to investigate the physiological consequences of AhR agonist exposure and CYP1A induction in different areas of the vasculature.     

The calcium channel β2 (CACNB2) subunit repertoire in teleosts

Background  

Cardiomyocyte contraction is initiated by influx of extracellular calcium through voltage-gated calcium channels. These oligomeric channels utilize auxiliary β subunits to chaperone the pore-forming α subunit to the plasma membrane, and to modulate channel electrophysiology [1]. Several β subunit family members are detected by RT-PCR in the embryonic heart. Null mutations in mouse β2, but not in the other three β family members, are embryonic lethal at E10.5 due to defects in cardiac contractility [2]. However, a drawback of the mouse model is that embryonic heart rhythm is difficult to study in live embryos due to their intra-uterine development. Moreover, phenotypes may be obscured by secondary effects of hypoxia. As a first step towards developing a model for contributions of β subunits to the onset of embryonic heart rhythm, we characterized the structure and expression of β2 subunits in zebrafish and other teleosts.     

Debate: Do all patients with heart failure require automatic implantable defibrillators for the prevention of sudden death?

Recent clinical trials indicate that approximately two-thirds of patients in New York Heart Association (NYHA) class II and III, who comprise almost 90% of patients with heart failure, die suddenly. Patients in NYHA class IV usually die of progressive heart failure. Implantation of implantable cardioverters defibrillators (ICDs) in this population would represent a huge logistic problem and economic expense. Clinical trials have recently demonstrated that β-blocker therapy with carvedilol, bisoprolol, and toprol XL decrease the sudden death rate by almost 50%, in addition to impacting significantly on death due to worsening heart failure. This medical approach is beneficial to all patients, and should be our major therapy. However, it is reasonable to attempt to identify that subpopulations of heart failure patients who could benefit from an ICD.     

Malignant familial hypertrophic cardiomyopathy in a family with a 453Arg→Cys mutation in the β-myosin heavy chain gene: Coexistence of sudden death and end-stage heart failure

Recent genotype-phenotype correlation studies in familial hypertrophic cardiomyopathy (FHC) have revealed that some mutations in the β-myosin heavy chain (BMHC) gene may be associated with a high incidence of sudden death and a poor prognosis. Coexistence of sudden death and end-stage heart failure in several families with FHC has recently being reported; however, the genetic basis of such families has not been clearly demonstrated. A three-generation Chinese familial hypertrophic cardiomyopathy (FHC) family (family HL1) with two cases of end-stage heart failure and three cases of sudden death was analyzed. The average age of death in the affected members in this family was 34 years old. Genetic linkage analysis using polymorphisms in the α- and β-myosin heavy chain genes revealed that FHC in this family is significantly linked to the BMHC gene without recombinations. Single-strand conformation polymorphism analysis of exons 8, 9 and 13 to 23 in the BMHC gene showed a polymorphic band on exon 14 that is in complete linkage with the disease status in this family. DNA sequencing analysis in the affected members revealed an 453Arg→Cys mutation in the BMHC gene. To our knowledge this is the first reported mutation of FHC in Chinese. Our data suggest that the 453Arg→Cys mutation is associated with a malignant clinical course in FHC due not only to sudden death but also to end-stage heart failure. Received: 6 July 1995 / Revised: 20 September 1995     

Cardiovascular responses of the taurine-depleted rat to vasoactive agents

Summary. The objective of this study was to assess the effect of taurine-depletion on cardiovascular responses of rat to vasoactive agents. Male Wistar-Kyoto (WKY) rats were given either tap water (control) or 3% β-alanine (taurine-depleted) for three weeks. Thereafter, mean arterial pressure (MAP) and heart rate of the freely moving animal were measured in response to vasoactive agents. Administration of phenylephine (5–40 μg/kg/min; i.v.) resulted in a similar and significant increase in MAP but a reduction in heart rate in both control and taurine-depleted groups. On the other hand, administration of sodium nitroprusside (15–300 μg/kg/min; i.v.) elicited a similar and significant reduction in MAP but increased heart rate in both groups. Lack of a differential response to phenylephrine and sodium nitroprusside between the two groups suggests that baroreflex regulation of cardiovascular function is not adversely affected by taurine-depletion. Administration of angiotensin II (0.1–3.0 μg/kg/min; i.v.) resulted in a dose-related increase in the pressor response and a decrease in heart rate in both groups. However, angiotensin II-induced pressor response was reduced in the taurine-depleted compared to the control rats (p < 0.05); heart rate was similarly reduced in both groups. Acute exposure to β-alanine (3 g/kg; i.v., 30-minutes) did not alter angiotensin II-induced hemodynamic responses. Similarly, incubation of aortic rings with β-alanine (40 mM, 30 minutes) did not affect the contractile responses to angiotensin II. The results suggest that β-alanine, per se, does not affect angiotensin II-induced responses in rat. However, β-alanine-induced taurine depletion is associated with a reduction in the pressor response to angiotensin II without impairing baroreflex function. Received December 17, 1999/Accepted January 12, 2000     

Immunization of mice with fucosyl-GM1 conjugated with keyhole limpet hemocyanin results in antibodies against human small-cell lung cancer cells

Fucosyl-GM1 (Fuc-GM1) [Fucα1 → 2Galβ1 → 3GalNAcβ1 → 4(NeuAcα2-3)Galβ1 → 4Glcβ1 → O-Cer] is a small-cell-lung-cancer (SCLC)-associated ganglioside initially defined by the murine monoclonal antibody F12. On the basis of its known distribution, Fuc-GM1 is a potential target for active immunotherapy in SCLC patients. Fuc-GM1 has been extracted and purified from bovine thyroid. The immunogenicity of Fuc-GM1 was tested in mice either alone, mixed with carrier protein keyhole limpet hemocyanin (KLH) or covalently linked with KLH, plus immunological adjuvant QS-21. The Fuc-GM1-KLH conjugate plus QS-21 adjuvant was found to be optimal. It induced consistent IgM and IgG enzyme-linked immunosorbent assay (ELISA) titers against Fuc-GM1. These antibodies were strongly reactive with the strongly Fuc-GM1-positive rat hepatoma cell line H4-II-E, and they were moderately reactive with the moderately positive human SCLC cell line H146 by flow cytometry and complement-mediated lysis. Both ELISA and fluorescence-activated cell sorting (FACS) reactions were inhibited with Fuc-GM1or H4-II-E but not with the structurally related ganglioside GM1 or Fuc-GM1-negative colon cancer cell line LS-C. On the basis of these results, a vaccine comprising Fuc-GM1-KLH plus QS-21 is being prepared for testing in patients with SCLC. Received: 25 March 1999 / Accepted: 5 August 1999     

Assessment of glycosaminoglycan-protein linkage tetrasaccharides as acceptors for GalNAc- and GlcNAc-transferases from mouse mastocytoma

Two glycosaminoglycan-protein linkage tetrasaccharide-serine compounds, GlcAβ1-3Galβ1-3Galβ1-4Xylβ1-O-Ser and GlcAβ1-3Gal(4-O-sulfate)β1-3Galβ1-4Xylβ1-O-Ser, were tested as hexosamine acceptors, using UDP-[3H]GlcNAc and UDP-[3H]GalNAc as sugar donors, and solubilized mouse mastocytoma microsomes as enzyme source. The nonsulfated Ser-tetrasaccharide was found to function as an acceptor for a GalNAc residue, whereas the Ser-tetrasaccharide containing a sulfated galactose unit was inactive. Characterization of the radio-labelled product by digestion with α-N-acetylgalactosaminidase and β-N-acetylhexosaminidase revealed that the [3H]GalNAc unit was α-linked, as in the product previously synthesized using serum enzymes, and not β-linked as found in the chondroitin sulfate polymer. Heparan sulfate/heparin biosynthesis could not be primed by either of the two linkage Ser-tetrasaccharides, since no transfer of [3H]GlcNAc from UDP-[3H]GlcNAc could be detected. By contrast, transfer of a [3H]GlcNAc unit to a [GlcAβ1-4GlcNAcα1-4]2-GlcAβ1-4-aMan hexasaccharide acceptor used to assay the GlcNAc transferase involved in chain elongation, was readily detected. These results are in agreement with the recent proposal that two different N-acetylglucosaminyl transferases catalyse the biosynthesis of heparan sulfate. Although the mastocytoma system contains both the heparan sulfate/heparin and chondroitin sulfate biosynthetic enzymes the Ser-tetrasaccharides do not seem to fulfil the requirements to serve as acceptors for the first HexNAc transfer reactions involved in the formation of these polysaccharides. This revised version was published online in November 2006 with corrections to the Cover Date.     

Zinc and Copper Levels in Severe Heart Failure and the Effects of Atrial Fibrillation on the Zinc and Copper Status

Oxidative stress is involved in the pathogenesis of congestive heart failure (CHF). Some trace elements serve as antioxidant defenses. The purpose of this study was to analyze the effect of atrial fibrillation (AF) on zinc (Zn) and copper (Cu) levels in patients with advanced CHF. In this prospective study, serum Zn and Cu levels in 78 patients with clinically advanced CHF, i.e., New York Heart Association (NYHA) functional class III or IV (40 patients with AF and 38 in sinus rhythm) were measured using atomic absorption spectrophotometry. All patients also had a left ventricular ejection fraction (EF) of <35%. We recruited 40 volunteers with nearly the same age and weight as control. They had normal EF. There was no significant difference between patients with AF and those with sinus rhythm regarding serum Zn and Cu levels. However, both groups showed significant hypozincemia (p < 0.000) and a decreased Zn/Cu ratio (p < 0.03) compared with control group. Serum Cu levels were similar in the two groups and did not differ significantly from the control group. In patients with advanced CHF, irrespective of the rhythm, profound hypozincemia, and a decreased Zn/Cu ratio were present, which could be secondary to the activation of the renin–angiotensin–aldosterone system and CHF medications. The results suggest the need for more studies focusing on possible benefits with Zn nutriceutical replacement in patients with advanced CHF.     

Metabolic modulation and cellular therapy of cardiac dysfunction and failure

At present the prevalence of heart failure rises along with aging of the population. Current heart failure therapeutic options are directed towards disease prevention via neurohormonal antagonism (β-blockers, angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers and aldosterone antagonists), symptomatic treatment with diuretics and digitalis and use of biventricular pacing and defibrillators in a special subset of patients. Despite these therapies and device interventions heart failure remains a progressive disease with high mortality and morbidity rates. The number of patients who survive to develop advanced heart failure is increasing. These patients require new therapeutic strategies. In this review two of emerging therapies in the treatment of heart failure are discussed: metabolic modulation and cellular therapy. Metabolic modulation aims to optimize the myocardial energy utilization via shifting the substrate utilization from free fatty acids to glucose. Cellular therapy on the other hand has the goal to achieve true cardiac regeneration. We review the experimental data that support these strategies as well as the available pharmacological agents for metabolic modulation and clinical application of cellular therapy.     

Prognostic value of circulating levels of stem cell growth factor beta (SCGF beta) in patients with Chagas’ disease and idiopathic dilated cardiomyopathy

Chagas’ disease (CD) often leads to dilated cardiomyopathy (DCM), and during its chronic stage hematopoietic stem or progenitor cells are involved in its pathological process. However, it is not clear whether stem cell growth factor (SCGF) beta can be regulated in patients with CD and idiopathic DCM. In present study, we aim to investigate the plasma SCGF beta concentration and its correlation with echocardiographic parameters and clinical outcome.In this prospective cohort study, SCGF beta levels were quantified in patients with CD (n = 94), DCM (n = 48), and control healthy subjects (n = 25). In comparison with healthy subjects, no statistical difference can be detected in NYHA classes I–II patients. However, SCGF beta was significantly increased in advanced heart failure patients (NYHA III–IV), compared to CD patients without heart failure. There was no group difference between CD and DCM. However, despite this significant increase in advanced heart failure patients, SCGF beta had no significant correlation with echocardiographic parameters, and it cannot be used as a prognostic marker for mortality and heart transplantation.To our best knowledge, this is the first report of SCGF beta in heart failure patients. Although it is significantly increased in advanced heart failure patients caused by CD or DCM, its prognostic value for end points is minor.     

Cytogenetic study of the effect of <Emphasis Type="Italic">Schistosoma mansoni</Emphasis> infection on human peripheral blood lymphocytes and the role of β-carotene and vitamin E in modulating this effect

This study has been made to determine the potential genotoxicity of Schistosoma mansoni on lymphocytes of infected patients using different mutagenic end points. The protective role of antioxidants pro vitamin β-carotene and vitamin E in minimizing these genotoxic effect was also studied. The study focused on the effect of schistosomiasis on the induction of sister chromatid exchange (SCEs) and other chromosomal aberrations. This work was conducted on 24 Schistosoma mansoni infected patients and 10 healthy adults as a control group. Lymphocytes from peripheral blood of patients and control group were used for culture and subsequent cytogenetic studies. The results indicated that schistosomiasis was genotoxic in all examined tests. It induced a significant increase in the percentage of structural chromosomal aberrations and the frequency of SCEs. It also inhibited cell division and caused cell cycle delay. Lymphocyte cultures of S. mansoni patients treated with 10 μg/ml β-carotene or 20 mg/ml vitamin E showed a significant decrease in the percentage of structural chromosomal aberrations and the frequency of SCEs. Schistosomiasis has a genotoxic effect on peripheral blood lymphocytes. The use of the antioxidants β-carotene and vitamin E can be considered a promising approach not only toward inhibiting the genetic damage of schistosomiasis but also as prophylactic agents against infection with S mansoni. Furthermore, higher doses of antioxidant drugs, β-carotene and vitamin E, should be tried as an adjuvants to conventional therapy in a trial to improve treatment of schistosomiasis.     

Characterization of β-lapachone and methylated β-cyclodextrin solid-state systems

The purpose of this research was to explore the utility of β cyclodextrin (βCD) and β cyclodextrin derivatives (hydroxypropyl-β-cyclodextrin [HPβCD], sulfobutylether-β-CD [SB\CD], and a randomly methylated-β-CD [RMβCD]) to form inclusion complexes with the antitumoral drug, β-lapachone (βLAP), in order to overcome the problem of its poor water solubility. RMβCD presented the highest efficiency for βLAP solubilization and was selected to develop solid-state binary systems. Differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier transform infrared (FTIR) and optical and scanning electron microscopy results suggest the formation of inclusion complexes by both freeze-drying and kneading techniques with a dramatic improvement in drug dissolution efficiency at 20-minute dissolution efficiency (DE_20-minute 67.15% and 88.22%, respectively) against the drug (DE_20-minute 27.11%) or the βCD/drug physical mixture (DE_20-minute 27.22%). However, the kneading method gives a highly crystalline material that together with the adequate drug dissolution profile make it the best procedure in obtaining inclusion complexes of RMβCD/βLAP convenient for different applications of βLAP. Published: July 27, 2007     

Gene therapy with cytokine-transfected xenogenic cells (Vero-IL-2) in patients with metastatic solid tumors: mechanism(s) of elimination of the transgene-carrying cells

Eleven patients with advanced cancer were treated in a clinical gene therapy trial by repeated intra- tumoral injections with different doses of xenogenic fibroblasts secreting high amounts of human interleukin-2 (Vero-IL2). Treatments in a total of 14 courses were well tolerated and resulted in clinical responses and measurable biological effects. Together with increases in serum interleukin-2 (IL-2), modifications of the V-β T cell receptor repertoire and induction of intratumoral T-cell infiltration were observed. When the intratumoral expression of endogenous cytokine genes and the persistence of the IL-2 transgene at the application site and in peripheral blood were investigated, rapid disappearance of the transgene at the application site appeared to be the most prominent biological effect. Tests detecting a single Vero-IL2 cell against a background of 10⁵ non-transfected cells were not able to demonstrate significant expression of exogenous IL-2 (i.e. the transgene or transgene-carrying cells) in tumor biopsies or blood at different times. Therefore, further studies were performed to evaluate the mechanism(s) involved in the rapid disappearance of xenogenic carrier cells in more detail. We show here that significant in vitro cytotoxicity against transgene-carrying Vero cells can be observed in peripheral blood of all the patients before treatment as well as in healthy controls. “Cold” target inhibition shows that significant killing of Vero-IL2 cells is mediated by natural killer (NK) cells. This was confirmed by showing that established CD3⁻/CD16 ⁺ /CD56 ⁺ peripheral blood NK cell clones kill both K562 and Vero-IL2 target cells. The failure of other mechanisms (complement, antibody-dependent cell cytotoxicity or cytotoxic T lymphocytes) to destroy xenogenic, histoincompatible Vero cells in vitro suggests that NK cells also might be responsible for the killing of Vero-IL2 in vivo and for the failure to detect the transgene at the application site. These results might also be of importance for some aspects of the current discussion of xenotransplantation. Received: 9 April 1999 / Accepted: 14 June 1999     

−509C>T polymorphism in the TGF-β1 gene promoter,impact on the hepatocellular carcinoma risk in Chinese patients with chronic hepatitis B virus infection

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The risk for developing HCC increases with severity of inflammation and fibrosis. Transforming growth factor-β1 (TGF-β1) is most frequently upregulated in tumor cells. The most studied −509C>T polymorphism of TGF-β1 gene has been associated with colorectal, gynecologic, and lung cancers. To assess whether this polymorphism in TGF-β1 gene is associated with susceptibility to and/or clinicopathologic characteristics of HBV-related HCC, a total of 575 patients with chronic HBV infection and 299 healthy volunteers with no evidence of recent or remote HBV infection were prospectively enrolled. The patients were divided into two groups: those without (n = 196) and those with HCC (n = 379). These 379 HCC patients with chronic HBV infection were designated as cases, the remaining 196 patients without HCC and 299 healthy volunteers served as disease and healthy controls, respectively. −509C>T polymorphism in the TGF-β1 gene promoter was studied using restriction fragment-length polymorphism. In addition, tumor tissues of liver (n = 60) were obtained from the studied HCC patients for measurement of TGF-β1 mRNA expression levels. We also assessed the plasma TGF-β1 levels of HBV patients without (n = 94) or with HCC (n = 136) and healthy subjects (n = 120). In our study group, the risk of HCC in Chinese patients with HBV infection was significantly lower with the TT genotypes than in those with the CC genotypes at position −509 of TGF-β1 gene (P = 0.01). In addition, in the case group, patients with the CC genotype had a statistically significant higher median plasma TGF-β1 or liver tumor tissue TGF-β1 mRNA level compared with the individuals with the TT genotype. However, in a subsequent analysis of the association between this polymorphism and clinicopathological characteristics including tumor number, size, grade, stage, and invasiveness, there was no significant difference in both the distribution of genotype or allelic frequency within HCC patients, indicating that −509C>T exchange in TGF-β1 gene may play an important role in the occurrence, not the progression of HBV-related HCC through influencing plasma concentrations of TGF-β1 or TGF-β1 mRNA expression of liver tumor tissue.     

Is immunotherapy an effective treatment for Alzheimer's disease?

Immunotherapy in patients with Alzheimer's disease (AD) is rapidly becoming a hot topic of modern geriatric and clinical gerontology. Current views see immunization with Aβ peptide, the amyloidogenic protein found in senile plaque of AD patient's brains, or the infusion of preformed antibody specific for human Aβ, as possible therapeutic approaches to improve the cognitive status in the disease. Animal models of the disease have provided positive results from both approaches. Thus, an initial clinical trial using immunization with human Aβ in AD patients was started, but then shortly halted because of an unusually high incidence (6%) of meningoencephalitis. A long and currently ongoing debate in the scientific community about the pro or contra of vaccination or passive immunization with Aβ in AD is thereafter started. Here, the authors would like to stress few points of concern regarding these approaches in clinical practice.     

The effects of 10 weeks of resistance training combined with β-alanine supplementation on whole body strength, force production, muscular endurance and body composition

Carnosine (Carn) occurs in high concentrations in skeletal muscle is a potent physico-chemical buffer of H⁺ over the physiological range. Recent research has demonstrated that 6.4 g.day⁻¹ of β-alanine (β-ala) can significantly increase skeletal muscle Carn concentrations (M-[Carn]) whilst the resultant change in buffering capacity has been shown to be paralleled by significant improvements in anaerobic and aerobic measures of exercise performance. Muscle carnosine increase has also been linked to increased work done during resistance training. Prior research has suggested that strength training may also increase M-[Carn] although this is disputed by other studies. The aim of this investigation is to assess the effect of 10 weeks resistance training on M-[Carn], and, secondly, to investigate if increased M-[Carn] brought about through β-ala supplementation had a positive effect on training responses. Twenty-six Vietnamese sports science students completed the study. The subjects completed a 10-week resistance-training program whilst consuming 6.4 g.day⁻¹ of β-ala (β-ALG) or a matched dose of a placebo (PLG). Subjects were assessed prior to and after training for whole body strength, isokinetic force production, muscular endurance, body composition. β-Alanine supplemented subjects increased M-[Carn] by 12.81 ± 7.97 mmol.kg⁻¹ dry muscle whilst there was no change in PLG subjects. There was no significant effect of β-ala supplementation on any of the exercise parameters measured, mass or % body fat. In conclusion, 10 weeks of resistance training alone did not change M-[Carn].     

β-Adrenergic blockade does not prevent polycythemia or decrease in plasma volume in men at 4300 m altitude

When humans ascend to high altitude (ALT) their plasma volume (PV) and total blood volume (BV) decrease during the first few days. With continued residence over several weeks, the hypoxia-induced stimulation of erythropoietin increases red cell production which tends to restore BV. Because hypoxia also activates the β-adrenergic system, which stimulates red blood cell production, we investigated the effect of adrenergic β-receptor inhibition with propranolol on fluid volumes and the polycythemic response in 11 healthy unacclimatized men (21–33 years old exposed to an ALT of 4300 m (barometric pressure 460 Torr) for 3 weeks on Pikes Peak, Colorado. PV was determined by the Evans blue dye method (PV_EB), BV by the carbon monoxide method (BV_CO), red cell volume (RCV) was calculated from hematocrit (Hct) and BV_CO, and serum erythropoietin concentration ([EPO]) and reticulocyte count, were also determined. All determinations were made at sea level and after 9–11 (ALT-10) and 19–20 (ALT-20) days at ALT. At sea level and ALT, six men received propranolol (pro, 240 mg · day⁻¹), and five received a placebo (pla). Effective β-blockade did not modify the mean (SE) maximal values of [EPO] [pla: 24.9 (3.5) vs pro: 24.5 (1.5) mU · ml⁻¹] or reticulocyte count [pla: 2.7 (0.7) vs pro: 2.2 (0.5)%]; nor changes in PV_EB [pla: −15.8 (3.8) vs pro: −19.9 (2.8)%], RCV_CO [pla: +7.0 (6.7) vs pro: +10.1 (6.1)%], or BV_CO [pla: −7.3 (2.3) vs pro: −7.1 (3.9)%]. In the absence of weight loss, a redistribution of body water with no net loss is implied. Hence, activation of the β-adrenergic system did not appear to affect the hypovolemic or polycythemic responses that occurred during 3 weeks at 4300 m ALT in these subjects. Accepted: 25 August 1997