Determination of bisphenol A and bisphenol S concentrations and assessment of estrogen- and anti-androgen-like activities in thermal paper receipts from Brazil, France, and Spain.

Bisphenol A (BPA) is a high-production-volume chemical with endocrine disrupting properties commonly used as color developer in thermal paper. Concerns about the potential hazards of human BPA exposure have led to the increasing utilization of alternatives such as bisphenol S (BPS) and bisphenol F (BPF). This study was designed to assess: (i) BPA, BPS, and BPF concentrations in 112 thermal paper receipts from Brazil, France, and Spain by liquid chromatography coupled to mass spectrometry (LC-MS); and (ii) hormone-like activities of these receipts using two receptor-specific bioassays, the E-Screen for (anti-)estrogenicity and PALM luciferase assay for (anti-)androgenicity. BPA was present in 95.3% of receipts from Spain, 90.9% of those from Brazil, and 51.1% of those from France at concentrations up to 20.27 mg/g of paper. Only two samples from Brazil, two from Spain, and ten from France had a BPS concentration ranging from 6.46 to 13.29 mg/g; no BPA or BPS was detected in 27.7% of French samples. No BPF was detected in any receipt. Estrogenic activity was observed in all samples from Brazil and Spain and in 74.5% of those from France. Anti-androgenic activity was observed in > 90% of samples from Brazil and Spain and in 53.2% of those from France. Only 25.5% of French samples were negative for both estrogenic and anti-androgenic activity. Estrogenic and anti-androgenic activities per gram of paper were up to 1.411 µM estradiol (E2) equivalent units (E2eq) and up to 359.5 mM procymidone equivalent units (Proceq), respectively. BPA but not BPS concentrations were positively correlated with both estrogenic and anti-androgenic activities. BPA still dominates the thermal paper market in Brazil and Spain, and BPS appears to be one of the main alternatives in France. There is an urgent need to evaluate the safety of alternatives proposed to replace BPA as developer in thermal printing. The large proportion of samples with hormonal activity calls for the adoption of preventive measures.

HCV infection induces mitochondrial bioenergetic unbalance: causes and effects.

Cells infected by the hepatitis C virus (HCV) are characterized by endoplasmic reticulum stress, deregulation of the calcium homeostasis and unbalance of the oxido-reduction state. In this context, mitochondrial dysfunction proved to be involved and is thought to contribute to the outcome of the HCV-related disease. Here, we propose a temporal sequence of events in the HCV-infected cell whereby the primary alteration consists of a release of Ca(2+) from the endoplasmic reticulum, followed by uptake into mitochondria. This causes successive mitochondrial alterations comprising generation of reactive oxygen and nitrogen species and impairment of the oxidative phosphorylation. A progressive adaptive response results in an enhancement of the glycolytic metabolism sustained by up-regulation of the hypoxia inducible factor. Pathogenetic implications of the model are discussed.

Regulation of connexin 43-mediated gap junctional intercellular communication by Ca2+ in mouse epidermal cells is controlled by E-cadherin.

Gap junctional intercellular communication (GJIC) of cultured mouse epidermal cells is mediated by a gap junction protein, connexin 43, and is dependent on the calcium concentration in the medium, with higher GJIC in a high-calcium (1.2 mM) medium. In several mouse epidermal cell lines, we found a good correlation between the level of GJIC and that of immunohistochemical staining of E-cadherin, a calcium-dependent cell adhesion molecule, at cell-cell contact areas. The variant cell line P3/22 showed both low GJIC and E-cadherin protein expression in low- and high-Ca2+ media. P3/22 cells showed very low E-cadherin mRNA expression. To test directly whether E-cadherin is involved in the Ca(2+)-dependent regulation of GJIC, we transfected the E-cadherin expression vector into P3/22 cells and obtained several stable clones which expressed high levels of E-cadherin mRNA. All transfectants expressed E-cadherin molecules at cell-cell contact areas in a calcium-dependent manner. GJIC was also observed in these transfectants and was calcium dependent. These results suggest that Ca(2+)-dependent regulation of GJIC in mouse epidermal cells is directly controlled by a calcium-dependent cell adhesion molecule, E-cadherin. Furthermore, several lines of evidence suggest that GJIC control by E-cadherin involves posttranslational regulation (assembly and/or function) of the gap junction protein connexin 43.

Toxoplasma gondii antibody profile in HIV-infected pregnant women and the risk of congenital toxoplasmosis.

The purpose of this study was to investigate the antibodies to Toxoplasma gondii in human immunodeficiency virus (HIV)-infected pregnant women and to determine the association between serological profile and the risk of congenital toxoplasmosis. The study, conducted in a public maternity ward from May 2002 to April 2005, included all HIV-infected women who delivered live infants during the 36 months, and, as a control group, all HIV-negative women that delivered live infants in the first 12 months of the study. Antibodies to T. gondii were detected in 1,624 of 2,421 HIV-negative women (67%; 95% confidence interval [CI] 65-69%) and in 121 of 168 HIV-infected patients (72%; 95% CI 65-79%). A total of 547 HIV-negative and 103 HIV-infected patients were tested at delivery and had positive T. gondii-specific IgG. In HIV-negative women, the median of the specific IgG concentration was 79 (interquartile range 38-160), and in HIV-infected patients, it was 283 (interquartile range 94-704) (P < 0.001). In the group of co-infected women, the only infant with congenital toxoplasmosis was born to a mother with acute toxoplasmosis infection acquired during pregnancy who did not have a high specific IgG concentration or a positive result for specific IgM. We concluded that high T. gondii-specific IgG values were much more frequent among HIV-infected pregnant women, but it did not translate into an increased risk of maternal-fetal transmission of toxoplasmosis.

Coexistence of mutations in PINK1 and mitochondrial DNA in early onset parkinsonism.

AIMS AND BACKGROUND: Various genes have been identified for monogenic disorders resembling Parkinson's disease. The products of some of these genes are associated with mitochondria and have been implicated in cellular protection against oxidative damage. In the present study we analysed fibroblasts from a patient carrying the homozygous mutation p.W437X in the PTEN-induced kinase 1 (PINK1), which manifested a very early onset parkinsonism. RESULTS: Patient's fibroblasts did not show variation in the mtDNA copy number or in the expression of the oxidative phosphorylation complexes. Sequence analysis of the patient's mtDNA presented two new missense mutations in the ND5 (m.12397A>G, p.T21A) and ND6 (m. 14319T>C, p.N119D) genes coding for two subunits of complex I. The two mutations were homoplasmic in both the patient and the patient's mother. Patient's fibroblasts resulted in enhanced constitutive production of the superoxide anion radical that was abrogated by inhibitor of the complex I. Moreover enzyme kinetic analysis of the NADH:ubiquinone oxidoreductase showed changes in the substrates affinity. CONCLUSION: To our knowledge, this is the first report showing co-segregation of a Parkinson's disease related nuclear gene mutation with mtDNA mutation(s). Our observation might shed light on the clinical heterogeneity of the hereditary cases of Parkinson's disease, highlighting the hitherto unappreciated impact of coexisting mtDNA mutations in determining the development and the clinical course of the disease.

Topological organization of NADPH-oxidase in haematopoietic stem cell membrane: preliminary study by fluorescence near-field optical microscopy.

The aim of this study was to characterize the local distribution and organization of the plasma membrane NADPH-oxidase (NOX) in human haematopoietic stem cell (HSC) by means of the fluorescence scanning near-field optical microscopy approach. The presence of NOX in haematopoietic stem cells is thought to have a functional role as O(2) sensor and/or as low-level reactive oxygen species (ROS) producer to be used as redox messenger for controlling cell growth and differentiation. Given the harmful potential of ROS, a fine-tuning of NOX activity is needed. The high resolution imaging of haematopoietic stem cell membrane obtained in this study combined with the immunodetection of NOX indicates for this the occurrence of a cluster-organized structure. These membrane 'rafts'-like micro-compartments may constitute localized protein aggregates whereby the assembly/activation of the NOX components are functionally integrated with upstream factors constituting signal-transduction platforms.

Exposure to 1.8 GHz electromagnetic fields affects morphology, DNA-related Raman spectra and mitochondrial functions in human lympho-monocytes.

Blood is a fluid connective tissue of human body, where it plays vital functions for the nutrition, defense and well-being of the organism. When circulating in peripheral districts, it is exposed to some physical stresses coming from outside the human body, as electromagnetic fields (EMFs) which can cross the skin. Such fields may interact with biomolecules possibly inducing non thermal-mediated biological effects at the cellular level. In this study, the occurrence of biochemical/biological modifications in human peripheral blood lympho-monocytes exposed in a reverberation chamber for times ranging from 1 to 20 h to EMFs at 1.8 GHz frequency and 200 V/m electric field strength was investigated. Morphological analysis of adherent cells unveiled, in some of these, appearance of an enlarged and deformed shape after EMFs exposure. Raman spectra of the nuclear compartment of cells exposed to EMFs revealed the onset of biochemical modifications, mainly consisting in the reduction of the DNA backbone-linked vibrational modes. Respirometric measurements of mitochondrial activity in intact lympho-monocytes resulted in increase of the resting oxygen consumption rate after 20 h of exposure, which was coupled to a significant increase of the FoF1-ATP synthase-related oxygen consumption. Notably, at lower time-intervals of EMFs exposure (i.e. 5 and 12 h) a large increase of the proton leak-related respiration was observed which, however, recovered at control levels after 20 h exposure. Confocal microscopy analysis of the mitochondrial membrane potential supported the respiratory activities whereas no significant variations in the mitochondrial mass/morphology was observed in EMFs-exposed lympho-monocytes. Finally, altered redox homeostasis was shown in EMFs-exposed lympho-monocytes, which progressed differently in nucleated cellular subsets. This results suggest the occurrence of adaptive mechanisms put in action, likely via redox signaling, to compensate for early impairments of the oxidative phosphorylation system caused by exposure to EMFs. Overall the data presented warn for health safety of people involved in long-term exposure to electromagnetic fields, although further studies are required to pinpoint the leukocyte cellular subset(s) selectively targeted by the EMFs action and the mechanisms by which it is achieved.

Correction: Exposure to 1.8 GHz electromagnetic fields affects morphology, DNA-related Raman spectra and mitochondrial functions in human lympho-monocytes.

[This corrects the article DOI: 10.1371/journal.pone.0192894.].

Mitochondrial dysfunction in hepatitis C virus infection.

The mechanisms of liver injury in chronic hepatitis C virus (HCV) infection are poorly understood though HCV induces a state of hepatic oxidative stress that is more pronounced than that present in many other inflammatory diseases. This mini-review will focus on recent findings revealing an unexpected role of mitochondria in providing a central role in the innate immunity and in addition will illustrate the application of stably transfected human-derived cell lines, inducibly expressing the entire HCV open reading frame for in vitro studies on mitochondria. Results obtained by a comparative analysis of the respiratory chain complexes activities along with mitochondrial morpho-functional confocal microscopy imaging show a detrimental effect of HCV proteins on the cell oxidative metabolism with specific inhibition of complex I activity, decrease of mtDeltaPsi, increased production of reactive oxygen species. A possible de-regulation of calcium recycling between the endoplasmic reticulum and the mitochondrial network is discussed to provide new insights in the pathogenesis of hepatitis C.

[Promoter effect induced by HgCl2 by studying the intercellular communication]. / Effetto promoter indoitto da HgCl2 attraverso lo studio della comunicazione intercellulare.

This work aims at assessing at molecular level the effect caused by the HgCl9 intercellular communication inhibition at non-cytotoxic doses. On the basis of our previous experiences, we exposed the human keratinocytes (HUKE) at 10 nM of HgCl2 for 24 hours Next, we estimated: a) the protein expression of connexines Cx43, Cx32 and Cx26 by western blotting; b) the amount of mRNA corresponding to the three connexines by semi-quantitative RT-PCR; and c) the production of reactive oxygen species in HgCl2 treated cells using a specific probe, i.e. DCF in confocal microscopy. Our study demonstrated a higher expression of the transcripts for Cx26, Cx32, Cx43, and a higher amount of proteins Cx43, Cx32 and Cx26, compared to the negative controls. Furthermore, we studied the effect of HgCl2 on the ROS production in keratinocytes, by the analysis in confocal microscopy carried out with the DCF, fit for marking the oxygen free radicals. In HgCl2 treated keratinocytes we obtained an increase of the ROS production compared to controls; and further the mitochondrions resulted the place of ROS production. The results of this study suggest that non-cytotoxic HgCl2 concentrations, might cause an unbalancing of the redox cellular state (ROS increased level), and we can assume that the activation of a redox signalling involves the inactivation of gap junctions.

Regulation by the cAMP cascade of oxygen free radical balance in mammalian cells.

A study is presented of the effect of the cAMP cascade on oxygen metabolism in mammalian cell cultures. Serum-starvation of the cell cultures resulted in depression of the forward NADH-ubiquinone oxidoreductase activity of complex I, decreased content of glutathione, and enhancement of the cellular level of H2O2. Depressed transcription of cytosolic Cu/Zn-SOD 1, mitochondrial glutathione peroxidase and catalase was also observed. Activation of the cAMP cascade reversed the depression of the activity of complex I and the accumulation of H2O2. The effect of cAMP involved the cAMP-dependent protein kinase.

A tumor suppressor gene, Cx26, also mediates the bystander effect in HeLa cells.

The connexin 26 (Cx26) gene suppresses the growth of HeLa cells in vitro and in vivo. We explored the possibility that the Cx26 gene not only suppresses growth but can also mediate the bystander effect that is observed in some gene therapy. In gene therapy mediated by the herpes simplex virus thymidine kinase, the toxicity of ganciclovir affects not only the cells transduced with the gene but also affects neighboring tumor cells; it has been suggested that gap junctional intercellular communication (GJIC) may play a role in such a bystander effect. HeLa cells expressing the Cx26 gene (Cx26+) or not expressing the Cx26 gene were transfected with the herpes simplex virus thymidine kinase (tk+) gene, producing Cx26(-)-tk-, Cx26(-)-tk+, Cx26+-tk-, and Cx26+-tk+ cells. By making different kinds of cocultures of these cells, we observed a clear bystander killing effect, assessed by the neutral red toxicity test, in the coculture of Cx26+-tk-/Cx26+-tk+ cells. The bystander effect was markedly prevented by a long-term inhibitor of GJIC, 18-alpha-glycyrrhetinic acid, demonstrating that a major part of the bystander effect seen occurred through Cx-mediated GJIC. These data suggest the possibility of using of Cxs as both tumor suppressor genes and as diffusers of ganciclovir toxicity in therapeutic approaches.

Negative growth control of HeLa cells by connexin genes: connexin species specificity.

In order to examine whether different connexin gene species exert different degrees of tumor-suppressing activity, we characterized growth characteristics of a gap junction-deficient human cancer cell line, HeLa cells, before and after transfection with cDNA for three different connexins, connexin (cx) 26, cx 40, and cx 43. All transfected cell lines (3 clones transfected with the cx 26 gene, 2 clones with cx 40, and 1 with cx 43) showed establishment of gap junctional intercellular communication (GJIC). Two of the cx 26-transfected clones showed significantly slower growth compared with the parental HeLa cells. When transfectants were grown in soft agar, the three cx 26-transfected clones grew much less than the other transfectants and parent HeLa cells. When injected into nude mice, the two cx 26 clones which exhibited the highest amount of cx 26 transcript induced almost no tumors, whereas other transfectants, including the cx 26 clone which exhibited the lowest amount of cx 26 transcript, were tumorigenic. Among transfectants of various connexin genes, there was no good inverse correlation between their GJIC and tumorigenicity. GJIC levels were significantly higher in tumors induced in nude mice by clone cx 26 A and E transfectants. These results suggest that all of the connexin genes examined could induce recovery of GJIC of HeLa cells, but only the cx 26 gene exerts strong negative growth control on HeLa cells; thus, this connexin gene may have different functions from other connexin genes.

Gap-junctional intercellular communication in epidermal cell lines from selected stages of SENCAR mouse skin carcinogenesis.

Homologous and heterologous gap-junctional intercellular communication (IC) was characterized in a panel of cell lines derived from selected stages of SENCAR mouse skin carcinogenesis. This panel included a "carcinogen-altered" cell line, 3PC, obtained from Ca2+-resistant primary adult keratinocytes after exposure to dimethylbenz(a)anthracene as well as cell lines obtained from early and late-stage papillomas and a squamous cell carcinoma (CA3/7) generated during standard in vivo initiation/promotion protocols (dimethylbenz(a)anthracene/12-O-tetradecanoyl-phorbol-13-acetate). Also studied was a cell line (B66BA) obtained from a metastatic lesion following benzo(a)pyrene-induced skin tumorigenesis. Intercellular communication was measured in low-calcium (0.05 mM) medium by quantitation of cell-cell transfer of microinjected fluorescent dye Lucifer Yellow CH. Homologous IC ability diminished progressively from 68 dye-coupled cells per injection for 3PC cultures, to between 21 and 54 dye-coupled cells per injection for three papilloma-derived cell lines, to six and three dye-coupled cells per injection for CA3/7 and B66BA cells, respectively. To test communication of these cells with their normal counterparts, heterologous IC was examined in cocultures with primary adult keratinocytes. Under the conditions used, normal cells established functional communication channels with each cell line tested, showing no selectivity. These results suggest that progressive loss of homologous but not heterologous IC capacity accompanies neoplastic development in mouse skin carcinogenesis.

Isolation and characterization of e3B1, an eps8 binding protein that regulates cell growth.

Eps8, a substrate of receptor tyrosine kinases, is an SH3 domain containing protein that plays an important role in mitogenic signaling. To determine the cellular function of eps8, we used the SH3 domain of eps8 to screen a human fibroblast M426 expression library and identified, a full-length cDNA clone of 3.2 kb. We designated this clone e3B1 for eps8 SH3 domain binding protein 1. Northern analysis revealed that expression of e3B1 mRNA was ubiquitous in human tissues. The e3B1 gene encodes a SH3 domain containing protein. We show that anti-e3B1 antibodies detect three cytosolic protein species of 65, 68 and 72 kDa in cell lysate isolated from asynchronously growing NIH3T3 cells. E3B1 binds to the SH3 domain of eps8 and Abl in vitro. We also demonstrated that e3B1 associates with eps8 in vivo. Phosphatase digestion and phosphoamino acid analysis revealed that p65e3B1 is a phosphoserine containing protein and p72e3B1 and p68e3B1 are hyperserine-phosphorylated form of p65e3B1. We further determined that the p65e3B1 was the most abundant in serum-starved NIH/EGFR cells. Time course studies initiated by the addition of epidermal growth factor (EGF) revealed that the p72e3B1 started to accumulate at 4 h, peaked at 8 h and remained high until 24 h. Finally, we demonstrate that NIH/EGFR fibroblasts overexpressing e3B1 grow more slowly relative to matched controls.

Differential effect of subcellular localization of communication impairing gap junction protein connexin43 on tumor cell growth in vivo.

There is a large body of evidence suggesting the connexin gap junction proteins appear to act as tumor suppressors, and their tumor inhibitory effect is usually attributed to their main function of cell coupling through gap junctions. However, some cancer cells (e.g. the rat bladder carcinoma BC31 cell line) are cell-cell communication proficient. Using specific site-directed mutagenesis in the third membrane-spanning (3M) domain of connexin43 (Cx43), we abolished the intrinsic gap junction intercellular communication (GJIC) in BC31 cells either by closing the gap junctional channels or by disruption of the transport of connexin complexes to the lateral membrane. Clones of BC31 cells transfected with a dominant negative Cx43 mutant giving rise to gap junctional channels, permeable only for a small tracer (neurobiotin), displayed accelerated growth rate in vivo, showing the critical role of selective gap junctional permeability in the regulation of cell growth in vivo. The use of other dominant-negative mutants of Cx43 also suggested that the effect of impaired communication on the tumorigenicity of cancer cells depends on the subcellular location of connexin. Inhibition of intrinsic GJIC in BC31 cells by sequestering of Cx protein inside the cytoplasm, due to expression of dominant-negative transport-deficient Cx43 mutants, did not significantly enhance the growth of transfectants in nude mice, but occasionally slightly retarded it. In contrast, augmentation of GJIC in BC31 cells by forced expression of wild-type Cx43, or a communication-silent mutant, fully suppressed tumorigenicity of these cells. Overall, these results show that cell coupling is a strong, but not the sole, mechanism by which Cx suppresses growth of tumorigenic cells in vivo; a GJIC-independent activity of Cx proteins should be considered as another strong tumor-suppressive factor.

Responsiveness of plasma 18-hydroxycorticosterone and aldosterone to angiotensin II or corticotropin in nonazotemic diabetes mellitus.

To assess the function of the final step of the pathway for aldosterone biosynthesis, the responsiveness of plasma 18-hydroxycorticosterone and aldosterone concentrations to angiotensin II infusion was studied in 14 patients with nonazotemic diabetes mellitus as compared with 14 normal controls approximately matched for sex and age. In addition, the responses of both steroids to corticotropin injection were investigated in the diabetic patients. Under basal conditions, plasma aldosterone levels were slightly lower in the patients than in normal controls, while plasma 18-hydroxycorticosterone concentrations were similar in the two study groups. Angiotensin II induced marked and comparable increases in plasma 18-hydroxycorticosterone and aldosterone levels in normal and diabetic subjects. Plasma 18-hydroxycorticosterone and aldosterone levels before and after angiotensin II infusion were significantly interrelated; this correlation was similar in normal subjects (r = 0.61; P less than 0.001) and diabetic patients (r = 0.51; P less than 0.005). Plasma 18-hydroxycorticosterone and aldosterone were significantly increased by corticotropin in the patients. These findings indicate that the terminal step of aldosterone biosynthesis, which involves the production of 18-hydroxycorticosterone and aldosterone, is largely unaltered in patients with nonazotemic diabetes mellitus.

Application of the compound probability density function for characterization of breast masses in ultrasound B scans.

The compound probability density function (pdf) is investigated for the ability of its parameters to classify masses in ultrasonic B scan breast images. Results of 198 images (29 malignant and 70 benign cases and two images per case) are reported and compared to the classification performance reported by us earlier in this journal. A new parameter, the speckle factor, calculated from the parameters of the compound pdf was explored to separate benign and malignant masses. The receiver operating characteristic curve for the parameter resulted in an A(z) value of 0.852. This parameter was combined with one of the parameters from our previous work, namely the ratio of the K distribution parameter at the site and away from the site. This combined parameter resulted in an A(z) value of 0.955. In conclusion, the parameters of the K distribution and the compound pdf may be useful in the classification of breast masses. These parameters can be calculated in an automated fashion. It should be possible to combine the results of the ultrasonic image analysis with those of traditional mammography, thereby increasing the accuracy of breast cancer diagnosis.

Antihypertensive therapy with Ca2+. Antagonist verapamil and/or ACE inhibitor enalapril in NIDDM patients.

OBJECTIVE: To assess the efficacy and tolerance of a diuretic-free antihypertensive therapy with a Ca2+ antagonist and an angiotensin-converting enzyme (ACE) inhibitor in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: After a 2-wk washout and a 4-wk placebo phase, 47 hypertensive patients with NIDDM randomly received verapamil or enalapril alone and, if blood pressure remained elevated, both agents combined over 30 wk. RESULTS: Verapamil or enalapril alone normalized blood pressure to less than 90 mmHg diastolic in 30 patients; verapamil decreased mean +/- SE blood pressure from 159/98 +/- 3/1 to 146/87 +/- 3/2 mmHg (n = 18, P less than 0.001) and enalapril from 166/99 +/- 5/2 to 146/86 +/- 3/1 mmHg (n = 12, P less than 0.001). In 17 patients who were still hypertensive after 10 wk of monotherapy, combination of both drugs decreased blood pressure from 170/104 +/- 4/2 to 152/90 +/- 4/2 mmHg (P less than 0.001). Fasting plasma glucose, glycosylated hemoglobin, serum fructosamine, total lipids, high-density and low-density lipoprotein cholesterol, apolipoproteins A-I and B, creatinine, and urinary albumin-creatinine ratio were not significantly modified. CONCLUSIONS: In hypertensive patients with NIDDM, a diuretic-free therapy based on the Ca2+ antagonist verapamil and/or the ACE inhibitor enalapril can effectively decrease blood pressure without adversely affecting carbohydrate and lipid metabolism.

Alpha 1-adrenergic blockade and cardiovascular pressor responses in essential hypertension.

The effects of selective alpha 1-adrenergic blockade with terazosin on blood pressure and cardiovascular pressor responsiveness were assessed in 17 subjects with mild to moderate essential hypertension (mean age, 48 +/- 2 [SEM] years). As compared with a 2-week placebo period, 8 weeks of terazosin treatment (mean dose, 10.5 +/- 1.7 mg/day) caused a fall of supine (from 153/103 +/- 3/2 to 143/96 +/- 4/2 mm Hg; p less than 0.025) and upright (from 145/106 +/- 4/2 to 131/94 +/- 5/3 mm Hg; p less than 0.01) arterial pressure; a marked blunting of cardiovascular pressor responsiveness to norepinephrine, as judged from the pressor dose (from 73 +/- 9 to 2156 +/- 496 ng/kg/min; p less than 0.02) and from the rightward shift (p less than 0.01) of the plasma concentration-blood pressure response curve; and a slight increase in plasma norepinephrine concentration (from 37.7 +/- 3.3 to 52.2 +/- 7.8 ng/dl; p less than 0.01). Heart rate, body weight, exchangeable sodium, blood volume, and norepinephrine plasma clearance; plasma epinephrine, renin, angiotensin II, and aldosterone levels; the relationships between angiotensin II-induced increases in arterial pressure or plasma aldosterone and the concomitant increments of plasma angiotensin II; and heart rate responsiveness to isoproterenol did not change significantly after terazosin treatment. These findings suggest that the fall of arterial pressure induced by selective alpha 1-adrenergic blockade in subjects with essential hypertension is associated with, and probably explained by, inhibition of alpha 1-mediated, noradrenergic-dependent vasoconstriction. alpha 1-Adrenergic receptor antagonism did not modify body sodium concentration, the adrenomedullary component of the sympathetic nervous system, angiotensin II levels, or beta-adrenergic dependent mechanisms.