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Karin B Nelson - One of the best experts on this subject based on the ideXlab platform.

  • Genetic polymorphisms and spontaneous preterm birth.
    Obstetrics & Gynecology, 2007
    Co-Authors: Catherine S Gibson, Alastair H Maclennan, Gustaaf A Dekker, Paul N Goldwater, James M Dambrosia, David J Munroe, Shirley Tsang, Claudia Stewart, Karin B Nelson
    Abstract:

    OBJECTIVE To examine whether selected genetic polymorphisms in the infant are associated with spontaneous preterm birth (less than 37 weeks) among children with or without later-diagnosed cerebral palsy. METHODS Exploratory case-control study investigating the relationship of gestational age at delivery to 31 single nucleotide polymorphisms measured in newborn screening bloodspots. Among all 443 children with later-diagnosed cerebral palsy born to white women in South Australia in 1986-1999, 234 were born after spontaneous onset of labor, and 108 of these were preterm (gestational age less than 37 weeks). The comparison group was 549 infants born after spontaneous onset of labor, of whom 147 were preterm. Distributions of genotypic frequencies were examined in preterm compared with term infants with and without cerebral palsy. Genotyping was performed using a Taqman assay. RESULTS In children without cerebral palsy, preterm birth after spontaneous onset of labor was more frequent in association with a variant of the beta2 adrenergic receptor gene (ADRB2 Q27E, P=.003), inducible nitric oxide synthase (iNOS or NOS2A, P=.042), or thrombomodulin (G127A, P=.006). Among children with cerebral palsy, preterm birth was associated with polymorphisms in genes for endothelial nitric oxide synthase (eNOS -922, P=.012), plasminogen activator inhibitor-2 (P=.015 and .019), and Alpha Adducin (ADD1, P=.047). CONCLUSION We confirm previous observations that variants of the beta adrenergic receptor and of nitric oxide synthase are associated with prematurity, and suggest that genetic variants of the placental antifibrinolytic plasminogen activator inhibitor-2, and thrombomodulin and Alpha Adducin may be contributors to risk of spontaneous preterm birth. LEVEL OF EVIDENCE II.

  • Genetic polymorphisms and spontaneous preterm birth.
    Obstetrics and gynecology, 2007
    Co-Authors: Catherine S Gibson, Alastair H Maclennan, Gustaaf A Dekker, Paul N Goldwater, James M Dambrosia, David J Munroe, Shirley Tsang, Claudia Stewart, Karin B Nelson
    Abstract:

    To examine whether selected genetic polymorphisms in the infant are associated with spontaneous preterm birth (less than 37 weeks) among children with or without later-diagnosed cerebral palsy. Exploratory case-control study investigating the relationship of gestational age at delivery to 31 single nucleotide polymorphisms measured in newborn screening bloodspots. Among all 443 children with later-diagnosed cerebral palsy born to white women in South Australia in 1986-1999, 234 were born after spontaneous onset of labor, and 108 of these were preterm (gestational age less than 37 weeks). The comparison group was 549 infants born after spontaneous onset of labor, of whom 147 were preterm. Distributions of genotypic frequencies were examined in preterm compared with term infants with and without cerebral palsy. Genotyping was performed using a Taqman assay. In children without cerebral palsy, preterm birth after spontaneous onset of labor was more frequent in association with a variant of the beta2 adrenergic receptor gene (ADRB2 Q27E, P=.003), inducible nitric oxide synthase (iNOS or NOS2A, P=.042), or thrombomodulin (G127A, P=.006). Among children with cerebral palsy, preterm birth was associated with polymorphisms in genes for endothelial nitric oxide synthase (eNOS -922, P=.012), plasminogen activator inhibitor-2 (P=.015 and .019), and Alpha Adducin (ADD1, P=.047). We confirm previous observations that variants of the beta adrenergic receptor and of nitric oxide synthase are associated with prematurity, and suggest that genetic variants of the placental antifibrinolytic plasminogen activator inhibitor-2, and thrombomodulin and Alpha Adducin may be contributors to risk of spontaneous preterm birth. II.

Gordon H. Williams - One of the best experts on this subject based on the ideXlab platform.

  • Genetic factors associated with volume-sensitive hypertension.
    Molecular and cellular endocrinology, 2004
    Co-Authors: Gordon H. Williams
    Abstract:

    Defining the genetic basis of essential hypertension is most informative when the blood pressure regulation is correlated with physiologic mechanisms, e.g., responses of the renin-angiotensin aldosterone system (RAAS) in hypertensive subjects. The aldosterone response to angiotensin II (Ang II) on a low salt diet is influenced by gender, plasma renin activity, and most significantly, familial resemblance, but only in males and in post-menopausal females. There is familial aggregation of low-renin hypertension, no association with candidate genes of the RAAS, but, a highly significant association with polymorphisms in the Alpha-Adducin gene. Finally, angiotensinogen (AGT) genotype effects renal and adrenal responses to Ang II in patients with hypertension. These results strongly suggest that in contrast to population-based studies that use hypertension as the phenotype, classifying patients by the variability in physiologic, mechanistic traits enhances the probability of identifying the genetic factors influencing a rise in blood pressure.

  • low renin hypertension altered sodium homeostasis and an α Adducin polymorphism
    Hypertension, 2002
    Co-Authors: Frederick D. Grant, Jose R. Romero, Xavier Jeunemaitre, Steven C. Hunt, Paul N. Hopkins, Norman Hollenberg, Gordon H. Williams
    Abstract:

    Defining the genetic basis of common forms of human essential hypertension is most informative when correlated with physiological mechanisms that underlie blood pressure regulation. A polymorphism of the Alpha-Adducin gene as been associated with elevated blood pressure in the rat, but previous studies of the 460Trp polymorphism of the human Alpha-Adducin gene have not clearly identified an association with hypertension. In this study, the frequency of the 460Trp allele was 19% and 9 of 279 subjects (3.2%) were homozygous for the 460Trp allele. The systolic blood pressure response to changes in dietary sodium was significantly greater in subjects homozygous for the 460Trp allele (25±4 mm Hg) compared with subjects heterozygous for 460Trp (12±2 mm Hg) or homozygous for the 460Gly allele (14±1 mm Hg). Intracellular erythrocyte sodium content, sodium-lithium countertransport, and renal fractional excretion of sodium were significantly decreased in subjects homozygous for the 460Trp polymorphism ( P

  • Homozygosity for an Alpha-Adducin Polymorphism (460TRP) Is Associated with Salt-Sensitivity and Low-Renin Hypertension in Humans
    Hypertension, 2000
    Co-Authors: Frederick D. Grant, Jose R. Romero, Xavier Jeunemaitre, Steven C. Hunt, Paul N. Hopkins, Norman K. Hollenberg, Gordon H. Williams
    Abstract:

    P133 Single nucleotide polymorphisms of the Adducin genes have been associated with the development of elevated blood pressure in the rat. However, previous studies of the 460Trp polymorphism of human Alpha-Adducin have not clearly identified an association with the development of human hypertension. In this study, 281 hypertensive subjects were subgrouped by the intermediate phenotypes of plasma renin status and sensitivity of systolic blood pressure to dietary sodium. The frequency of the 460Trp allele was 19% and 9 of 281 subjects (3.2%) were homozygous (TT) for the 460Trp allele. The systolic blood pressure response to changes in dietary sodium (>150 meq/d vs. ≤30 meq/d) was significantly (p

Daniele Cusi - One of the best experts on this subject based on the ideXlab platform.

  • Functional alterations of mesenteric small resistance arteries in Milan hypertensive and normotensive rats.
    Hypertension research : official journal of the Japanese Society of Hypertension, 2009
    Co-Authors: Damiano Rizzoni, Daniele Cusi, Patrizia Ferrari, Maurizio Castellano, Enzo Porteri, M. Giacchè, Carolina De Ciuceis, Gianluca E.m. Boari, Enrico Agabiti Rosei
    Abstract:

    The Milan hypertensive rat strain (MHS) is a genetic strain in which cardiovascular phenotypes seem to be dependent, at least in part, on Adducin gene polymorphisms. The aim of our study was to evaluate the structure, contractile responses and endothelium-dependent vasodilation in mesenteric small resistance arteries in 12-week-old MHS, (n=7), age-matched Milan normotensive rats (MNS, n=7) and congenic strains in which the DNA segments carrying the Alpha-Adducin locus from the MHS have been introgressed into the MNS (MNA, n=7). Systolic blood pressure (tail cuff) and left ventricular weight to body weight were measured. Mesenteric small arteries were dissected and mounted on a micromyograph; the media:lumen ratio was then calculated. Concentration-response curves to acetylcholine and to norepinephrine (NE) were created. Systolic blood pressure was significantly increased in the MHS and MNA strains compared with the MNS. No significant difference in mesenteric small resistance artery structure was observed among the groups; however, a slightly more elevated media:lumen ratio was observed in MNA compared with the MNS. In contrast, left ventricular weight to body weight was significantly increased and ACH-induced dilatation was significantly impaired in the MHS and in MNA compared with MNS. The concentration-response curve to NE in the MHS showed significantly reduced sensitivity to NE; however, maximum contraction was increased in the MHS vs. the other groups. The MHS presents cardiac (but not vascular) remodeling, endothelial dysfunction and a peculiar contractile response to NE, compared with the other groups. The systolic blood pressure increase and trend to vascular remodeling in MNA support the pathogenic role of Alpha-Adducin.

  • The 460Trp allele of Alpha-Adducin increases carotid intima-media thickness in young adult males
    'Ovid Technologies (Wolters Kluwer Health)', 2006
    Co-Authors: R. Sarzani, Daniele Cusi, C Barlassina, F. Salvi, F. Macciardi, F. Pietrucci, G. Cola, R. Catalini, Dal C. Fiume, P. Dessi-fulgheri
    Abstract:

    BACKGROUND: The 460Trp allele of the Alpha-Adducin gene (ADD1), which is involved in a form of salt-sensitive hypertension, has been associated with patterns of target organ damage. OBJECTIVES: As carotid artery intima-media thickness (IMT) largely depends upon unknown genetic factors, besides being associated to conventional risk factors, we tested the association of the 460Trp allele of ADD1 with IMT in a well-characterized sample of young healthy normotensive subjects, to assess the role of ADD1 polymorphism without overlapping effects of age or already elevated blood pressure. METHODS: Anthropometric measurements, blood pressure (BP), and carotid artery wall IMT (high-resolution sonography and digitalized morphometry) were obtained in 420 healthy normotensive Caucasian university students. Genotypes for ADD1 were detected by automated genomic polymerase chain reaction (PCR). RESULTS: ADD1 genotypes were evenly distributed between genders. IMT was significantly larger in carriers of the 460Trp allele of ADD1, while a significant gender x ADD1 interaction (P = 0.02) demonstrated that IMT was increased only in males carrying the 460Trp allele (P < 0.001). No significant association was found in females. CONCLUSIONS: The 460Trp allele of ADD1 contributes substantially to increase carotid IMT, in a male hormonal milieu only, at least in the young age range

  • RFX-1, a putative Alpha Adducin interacting protein in a human kidney library.
    FEBS letters, 2005
    Co-Authors: Rosalia Boito, Daniele Cusi, Grazia Tripodi, Miranda Menniti, Rosario Amato, Camillo Palmieri, Cinzia Marinaro, Rodolfo Iuliano, Giorgio Fuiano, Nicola Perrotti
    Abstract:

    Adducin regulates tubular absorption of sodium by modulating the expression levels of the sodium–potassium-ATPase in renal tubular cells. Adducin is a candidate gene in the pathogenesis of hypertension. Yeast two hybrid screen showed a specific interaction between human Alpha Adducin and the regulatory factor for X box (RFX-1), a nuclear protein that down regulates the expression of several proteins in non neuronal cells. The interaction was confirmed in cells through coimmunoprecipitation and colocalization experiments. The binding of Alpha Adducin to RFX-I and their nuclear co-localization suggests that Adducin can have a role in modulating the transcriptional regulating activity of RFX-I.

  • in a human kidney library
    2005
    Co-Authors: Rosalia Boito, Daniele Cusi, Grazia Tripodi, Miranda Menniti, Rosario Amato, Camillo Palmieri, Cinzia Marinaro, Rodolfo Iuliano, Giorgio Fuiano, Nicola Perrotti
    Abstract:

    Abstract Adducin regulates tubular absorption of sodium by 17 modulating the expression levels of the sodium–potassium-ATP- 18 ase in renal tubular cells. Adducin is a candidate gene in the 19 pathogenesis of hypertension. Yeast two hybrid screen showed 20 a specific interaction between human Alpha Adducin and the reg- 21 ulatory factor for X box (RFX-1), a nuclear protein that down 22 regulates the expression of several proteins in non neuronal cells. 23 The interaction was confirmed in cells through coimmunoprecip- 24 itation and colocalization experiments. The binding of Alpha 25 Adducin to RFX-I and their nuclear co-localization suggests that 26 Adducin can have a role in modulating the transcriptional regu- 27 lating activity of RFX-I. 28 2005 Published by Elsevier B.V. on behalf of the Federation of 29 European Biochemical Societies. 30 Keywords: Adducin; Hypertension; RFX-1; Sodium 31 absorption; Yeast two hybrid; Kidney library 3233 1. Introduction 34 Essential hypertension is a multifactorial disease due to ge-

  • α Adducin 460trp allele is associated with erythrocyte na transport rate in north sardinian primary hypertensives
    Hypertension, 2002
    Co-Authors: Nicola Glorioso, Daniele Cusi, Fabiana Filigheddu, Chiara Troffa, Milena Conti, Marcella Natalizio, Giuseppe Argiolas, Cristina Barlassina, Giuseppe Bianchi
    Abstract:

    Erythrocyte membrane alterations mirror those of vascular smooth muscle and renal tubular cell membrane. The interaction between Adducin and Na-K pump is the most likely biochemical mechanism responsible for the increased tubular Na reabsorption and hypertension in Milan hypertensive strain (MHS) rats. To substantiate this hypothesis in humans, we tested to see if Alpha-Adducin Gly460Trp genotype is associated with erythrocyte sodium transport rate in a new cohort of n=268 never-treated North Sardinian primary hypertensives. Plasma renin activity and blood pressure response to hydrochlorothiazide were also measured to evaluate the relationship between sodium transport rate and two intermediate phenotypes with a higher degree of genetic complexity. Na-K pump, Na-K-Cl cotransport, and Li-Na countertransport at V(max) were faster (P<0.0001), whereas intracellular Na concentration was lower (P<0.0001) in patients carrying one or two 460Trp alleles. Such behavior was mirrored by opposite changes of intracellular Na concentration. Plasma renin activity and blood pressure response to diuretic treatment, on the other hand, showed a weaker association with the sodium transport rate. In conclusion, our findings are consistent with the hypothesis that the Gly460Trp Alpha-Adducin polymorphism may affect renal Na handling through an alteration in ion transport across the cell membrane mirrored by erythrocytes. These results may also have clinical relevance because the Gly460Trp Alpha-Adducin polymorphism may explain, at least in part, the variability of blood pressure response to diuretics in primary hypertensive patients.

Catherine S Gibson - One of the best experts on this subject based on the ideXlab platform.

  • Genetic polymorphisms and spontaneous preterm birth.
    Obstetrics & Gynecology, 2007
    Co-Authors: Catherine S Gibson, Alastair H Maclennan, Gustaaf A Dekker, Paul N Goldwater, James M Dambrosia, David J Munroe, Shirley Tsang, Claudia Stewart, Karin B Nelson
    Abstract:

    OBJECTIVE To examine whether selected genetic polymorphisms in the infant are associated with spontaneous preterm birth (less than 37 weeks) among children with or without later-diagnosed cerebral palsy. METHODS Exploratory case-control study investigating the relationship of gestational age at delivery to 31 single nucleotide polymorphisms measured in newborn screening bloodspots. Among all 443 children with later-diagnosed cerebral palsy born to white women in South Australia in 1986-1999, 234 were born after spontaneous onset of labor, and 108 of these were preterm (gestational age less than 37 weeks). The comparison group was 549 infants born after spontaneous onset of labor, of whom 147 were preterm. Distributions of genotypic frequencies were examined in preterm compared with term infants with and without cerebral palsy. Genotyping was performed using a Taqman assay. RESULTS In children without cerebral palsy, preterm birth after spontaneous onset of labor was more frequent in association with a variant of the beta2 adrenergic receptor gene (ADRB2 Q27E, P=.003), inducible nitric oxide synthase (iNOS or NOS2A, P=.042), or thrombomodulin (G127A, P=.006). Among children with cerebral palsy, preterm birth was associated with polymorphisms in genes for endothelial nitric oxide synthase (eNOS -922, P=.012), plasminogen activator inhibitor-2 (P=.015 and .019), and Alpha Adducin (ADD1, P=.047). CONCLUSION We confirm previous observations that variants of the beta adrenergic receptor and of nitric oxide synthase are associated with prematurity, and suggest that genetic variants of the placental antifibrinolytic plasminogen activator inhibitor-2, and thrombomodulin and Alpha Adducin may be contributors to risk of spontaneous preterm birth. LEVEL OF EVIDENCE II.

  • Genetic polymorphisms and spontaneous preterm birth.
    Obstetrics and gynecology, 2007
    Co-Authors: Catherine S Gibson, Alastair H Maclennan, Gustaaf A Dekker, Paul N Goldwater, James M Dambrosia, David J Munroe, Shirley Tsang, Claudia Stewart, Karin B Nelson
    Abstract:

    To examine whether selected genetic polymorphisms in the infant are associated with spontaneous preterm birth (less than 37 weeks) among children with or without later-diagnosed cerebral palsy. Exploratory case-control study investigating the relationship of gestational age at delivery to 31 single nucleotide polymorphisms measured in newborn screening bloodspots. Among all 443 children with later-diagnosed cerebral palsy born to white women in South Australia in 1986-1999, 234 were born after spontaneous onset of labor, and 108 of these were preterm (gestational age less than 37 weeks). The comparison group was 549 infants born after spontaneous onset of labor, of whom 147 were preterm. Distributions of genotypic frequencies were examined in preterm compared with term infants with and without cerebral palsy. Genotyping was performed using a Taqman assay. In children without cerebral palsy, preterm birth after spontaneous onset of labor was more frequent in association with a variant of the beta2 adrenergic receptor gene (ADRB2 Q27E, P=.003), inducible nitric oxide synthase (iNOS or NOS2A, P=.042), or thrombomodulin (G127A, P=.006). Among children with cerebral palsy, preterm birth was associated with polymorphisms in genes for endothelial nitric oxide synthase (eNOS -922, P=.012), plasminogen activator inhibitor-2 (P=.015 and .019), and Alpha Adducin (ADD1, P=.047). We confirm previous observations that variants of the beta adrenergic receptor and of nitric oxide synthase are associated with prematurity, and suggest that genetic variants of the placental antifibrinolytic plasminogen activator inhibitor-2, and thrombomodulin and Alpha Adducin may be contributors to risk of spontaneous preterm birth. II.

Giuseppe Bianchi - One of the best experts on this subject based on the ideXlab platform.

  • Blood pressure in relation to three candidate genes in a Chinese population.
    Journal of hypertension, 2004
    Co-Authors: Ji-guang Wang, Giuseppe Bianchi, Laura Zagato, Lifang Liu, Jinxiang Xie, Robert Fagard, Kugen Jin, Jinxiang Wang, Jan A. Staessen
    Abstract:

    OBJECTIVE In a prospective analysis of a Caucasian population, we recently found that the genes encoding angiotensin-converting enzyme (ACE, I/D polymorphism), Alpha-Adducin (Gly460Trp) and aldosterone synthase (-344C/T) jointly influence the incidence of hypertension. We therefore investigated the association between blood pressure and these three genes in a Chinese population. METHODS We genotyped 479 Han Chinese from 125 nuclear families recruited in northern China via random sampling (approximately 75%) and at specialized hypertension clinics (approximately 25%). We performed population-based and family-based association analyses using generalized estimating equations (GEE) and the quantitative transmission disequilibrium test (QTDT), respectively, while controlling for covariables. RESULTS The participants included 239 (49.9%) women and 132 (27.6%) hypertensive patients, of whom 77 took antihypertensive drugs. The blood pressure, measured at the subjects' homes, averaged 126/80 mmHg. Mean values of urinary sodium, potassium and Na/K ratio were 226 mmol/day, 37 mmol/day and 6.31, respectively. In adjusted GEE analyses, systolic blood pressure was 9.3 mmHg (95% confidence interval 3.6-15.0 mmHg; P = 0.001) and 14.6 mmHg (95% confidence interval 3.4-25.8 mmHg; P = 0.01) higher in the ACE DD than II subjects among the Alpha-Adducin TrpTrp (n = 141) and aldosterone synthase CC (n = 33) homozygotes, respectively (P < or =0.05 for interactions of the ACE genotype with the Alpha-Adducin and aldosterone synthase polymorphisms). Among 40 informative offspring homozygous for the Alpha-Adducin Trp allele, systolic blood pressure was significantly associated with transmission of the ACE D allele (beta = 5.5 mmHg; P = 0.046). CONCLUSIONS The ACE I/D, Alpha-Adducin Gly460Trp and aldosterone synthase -344C/T polymorphisms interact to influence systolic blood pressure in Chinese, suggesting that these genes might indeed predispose to hypertension, especially in an ecogenetic context characterized by a high salt intake.

  • α Adducin 460trp allele is associated with erythrocyte na transport rate in north sardinian primary hypertensives
    Hypertension, 2002
    Co-Authors: Nicola Glorioso, Daniele Cusi, Fabiana Filigheddu, Chiara Troffa, Milena Conti, Marcella Natalizio, Giuseppe Argiolas, Cristina Barlassina, Giuseppe Bianchi
    Abstract:

    Erythrocyte membrane alterations mirror those of vascular smooth muscle and renal tubular cell membrane. The interaction between Adducin and Na-K pump is the most likely biochemical mechanism responsible for the increased tubular Na reabsorption and hypertension in Milan hypertensive strain (MHS) rats. To substantiate this hypothesis in humans, we tested to see if Alpha-Adducin Gly460Trp genotype is associated with erythrocyte sodium transport rate in a new cohort of n=268 never-treated North Sardinian primary hypertensives. Plasma renin activity and blood pressure response to hydrochlorothiazide were also measured to evaluate the relationship between sodium transport rate and two intermediate phenotypes with a higher degree of genetic complexity. Na-K pump, Na-K-Cl cotransport, and Li-Na countertransport at V(max) were faster (P<0.0001), whereas intracellular Na concentration was lower (P<0.0001) in patients carrying one or two 460Trp alleles. Such behavior was mirrored by opposite changes of intracellular Na concentration. Plasma renin activity and blood pressure response to diuretic treatment, on the other hand, showed a weaker association with the sodium transport rate. In conclusion, our findings are consistent with the hypothesis that the Gly460Trp Alpha-Adducin polymorphism may affect renal Na handling through an alteration in ion transport across the cell membrane mirrored by erythrocytes. These results may also have clinical relevance because the Gly460Trp Alpha-Adducin polymorphism may explain, at least in part, the variability of blood pressure response to diuretics in primary hypertensive patients.

  • Alpha-Adducin 460Trp allele is associated with erythrocyte Na transport rate in North Sardinian primary hypertensives.
    Hypertension (Dallas Tex. : 1979), 2002
    Co-Authors: Nicola Glorioso, Daniele Cusi, Fabiana Filigheddu, Chiara Troffa, Milena Conti, Marcella Natalizio, Giuseppe Argiolas, Cristina Barlassina, Giuseppe Bianchi
    Abstract:

    Erythrocyte membrane alterations mirror those of vascular smooth muscle and renal tubular cell membrane. The interaction between Adducin and Na-K pump is the most likely biochemical mechanism responsible for the increased tubular Na reabsorption and hypertension in Milan hypertensive strain (MHS) rats. To substantiate this hypothesis in humans, we tested to see if Alpha-Adducin Gly460Trp genotype is associated with erythrocyte sodium transport rate in a new cohort of n=268 never-treated North Sardinian primary hypertensives. Plasma renin activity and blood pressure response to hydrochlorothiazide were also measured to evaluate the relationship between sodium transport rate and two intermediate phenotypes with a higher degree of genetic complexity. Na-K pump, Na-K-Cl cotransport, and Li-Na countertransport at V(max) were faster (P

  • PST 2238: a new antihypertensive compound that modulates renal Na-K pump function without diuretic activity in Milan hypertensive rats.
    Journal of cardiovascular pharmacology, 2002
    Co-Authors: Mara Ferrandi, Giuseppe Bianchi, Paolo Barassi, E. Minotti, Liliana Duzzi, Isabella Molinari, Patrizia Ferrari
    Abstract:

    PST 2238 is a new antihypertensive compound that is able to correct the molecular and functional alterations of the renal Na-K pump and the pressor effect associated with either Alpha-Adducin mutations or high circulating levels of endogenous ouabain (EO) in genetic and experimental rat models. Due to the close relationship between renal Na-K pump function and tubular Na reabsorption, PST 2238 was investigated to determine whether it is endowed with diuretic activity and consequently might trigger alterations of the renin-aldosterone system and the carbohydrate and lipid metabolism often associated with chronic diuretic therapy. In Milan hypertensive (MHS) rats, in which hypertension is genetically associated with Alpha-Adducin mutation, increased tubular Na reabsorption, and hyperactivation of the renal Na-K pump. PST 2238 reduced blood pressure and normalized the renal Na-K pump activity at oral doses of micro g/kg, but did not induce, either acutely or chronically, any diuretic activity or hormonal or metabolic alterations. In contrast, HCTZ, given to MHS rats orally at 40 mg/kg, although it displayed diuretic activity and reduced the renal Na-K pump activity, did not lower blood pressure and caused hyperactivation of the renin-aldosterone system, hypokaliemia, and hyperglycemia. The findings lead to the conclusion that PST 2238 is a new antihypertensive compound that normalizes the altered function of the renal Na-K pump associated with hypertension in rat models, but that it is devoid of diuretic activity and does not induce the diuretic-associated side effects.

  • α-Adducin 460Trp Allele Is Associated With Erythrocyte Na Transport Rate in North Sardinian Primary Hypertensives
    Hypertension, 2002
    Co-Authors: Nicola Glorioso, Daniele Cusi, Fabiana Filigheddu, Chiara Troffa, Milena Conti, Marcella Natalizio, Giuseppe Argiolas, Cristina Barlassina, Giuseppe Bianchi
    Abstract:

    Erythrocyte membrane alterations mirror those of vascular smooth muscle and renal tubular cell membrane. The interaction between Adducin and Na-K pump is the most likely biochemical mechanism responsible for the increased tubular Na reabsorption and hypertension in Milan hypertensive strain (MHS) rats. To substantiate this hypothesis in humans, we tested to see if Alpha-Adducin Gly460Trp genotype is associated with erythrocyte sodium transport rate in a new cohort of n=268 never-treated North Sardinian primary hypertensives. Plasma renin activity and blood pressure response to hydrochlorothiazide were also measured to evaluate the relationship between sodium transport rate and two intermediate phenotypes with a higher degree of genetic complexity. Na-K pump, Na-K-Cl cotransport, and Li-Na countertransport at V(max) were faster (P