The heritability of circulating testosterone, oestradiol, oestrone and sex hormone binding globulin concentrations in men: the Framingham Heart Study.

OBJECTIVE: Circulating testosterone, oestradiol and oestrone concentrations vary considerably between men. Although a substantial proportion of this variation may be attributed to morbidity and behavioural factors, these cannot account for its entirety, suggesting genetic inheritance as a potential additional determinant. The analysis described here was intended to estimate the heritability of male circulating total testosterone (TT), calculated free testosterone (cFT), oestrone (E1), oestradiol (E2) and sex hormone binding globulin (SHBG), along with the genetic correlation between these factors. DESIGN: Cross-sectional, observational analysis of data from male members of the Offspring and Generation 3 cohorts of the Framingham Heart Study. Data were collected in the years 1998-2005. PARTICIPANTS: A total of 3367 community-dwelling men contributed to the analysis, including 1066 father/son and 1284 brother pairs among other family relationships. MEASUREMENTS: Levels of serum sex steroids (TT, E1 and E2) were measured by liquid chromatography-tandem mass spectrometry, SHBG by immunofluorometric assay and cFT by mass action equation. Heritability was obtained using variance components analysis with adjustment for covariates including age, diabetes mellitus, body mass index and smoking status. RESULTS: Age-adjusted heritability estimates were 0·19, 0·40, 0·40, 0·30 and 0·41 for cFT, TT, E1, E2 and SHBG, respectively. Adjustment for covariates did not substantially attenuate these estimates; SHBG-adjusted TT results were similar to those obtained for cFT. Genetic correlation coefficients (ρG ) indicated substantial genetic association between TT and cFT (ρG = 0·68), between TT and SHBG (pG = 0·87), between E1 and E2 (ρG = 0·46) and between TT and E2 (ρG = 0·48). CONCLUSION: Circulating testosterone, oestradiol and oestrone concentrations exhibit substantial heritability in adult men. Significant genetic association between testosterone and oestrogen levels suggests shared genetic pathways.

Clinical correlates of sex steroids and gonadotropins in men over the late adulthood: the Framingham Heart Study.

Low serum concentrations of sex steroids and gonadotropins in men have been associated with increased cardiometabolic risk and mortality, but the clinical correlates of these hormones in men over late adulthood are less clearly understood. We analysed up to five serial measurements of total testosterone (TT), dehydroepiandrosterone sulphate (DHEAS), follicle stimulating hormone (FSH), luteinizing hormone (LH) and total estradiol (EST) in older men in the original cohort of the Framingham Heart Study to determine the short- (2-years; 1,165 person-observations in 528 individuals) and long-term (up to 10-years follow-up; 2520 person-observations in 835 individuals with mean baseline age: 71.2 years) clinical correlates of these sex steroids and gonadotropins using multilevel modelling and Generalized Estimating Equations. Age, body mass index and pre-existing type 2 diabetes were inversely related to long-term TT concentrations, whereas higher systolic blood pressure showed a positive association. Furthermore, age and pre-existing cardiovascular disease (CVD) were inversely associated and HDL cholesterol concentrations positively associated with long-term DHEAS concentrations respectively. Analyses of short-term changes revealed age was inversely related to DHEAS, but positively related to FSH and LH concentrations. Our community-based study identified modifiable correlates of decreasing TT and DHEAS concentrations in elderly men, suggesting that maintenance of a low CVD risk factor burden may mitigate the age-related decline of these hormones over the late adulthood.

Circulating testosterone and SHBG concentrations are heritable in women: the Framingham Heart Study.

CONTEXT: Many factors influence the concentration of circulating testosterone and its primary binding protein, SHBG. However, little is known about the genetic contribution to their circulating concentrations in women, and their heritability in women is not well established. OBJECTIVE: Our objective was to estimate the heritability of circulating total testosterone (TT), free testosterone (FT), and SHBG in women in families from the Framingham Heart Study. METHODS: Women in the Framingham Heart Study who were not pregnant, had not undergone bilateral oophorectomy, and were not using exogenous hormones were eligible for this investigation. TT was measured using liquid chromatography tandem mass spectrometry and SHBG using an immunofluorometric assay (Delfia-Wallac), and FT was calculated. Heritability estimates were calculated using variance-components methods in Sequential Oligogenic Linkage Analysis Routines (SOLAR) and were adjusted for age, age(2), body mass index (BMI), BMI(2), diabetes, smoking, and menopausal status. Bivariate analyses were done to assess genetic correlation between TT, FT, and SHBG. RESULTS: A total of 2685 women were studied including 868 sister pairs and 688 mother-daughter pairs. Multivariable adjusted heritability estimates were 0.26 ± 0.05 for FT, 0.26 ± 0.05 for TT, and 0.56 ± 0.05 for SHBG (P < 1.0 × 10(-7) for all). TT was genetically correlated with SHBG [genetic correlation coefficient (ρG) = 0.31 ± 0.10] and FT (ρG = 0.54 ± 0.09), whereas SHBG was inversely correlated with FT (ρG = -0.60 ± 0.08). CONCLUSION: Circulating TT, FT, and SHBG concentrations in women are significantly heritable, underscoring the importance of further work to identify the specific genes that contribute significantly to variation in sex steroid concentrations in women. The strong shared genetic component among pairs of TT, FT, and SHBG concentrations suggests potential pleiotropic effects for some of the underlying genes.

Lipomatosis-associated inflammation and excess collagen may contribute to lower relative resting energy expenditure in women with adiposis dolorosa.

BACKGROUND: Adiposis dolorosa (AD) is a syndrome of obese and non-obese individuals whose hallmark is lipomatosis: unencapsulated painful fatty masses in subcutaneous fat. Lipomatosis may contain excess collagen and multi-nucleated giant (MNG) cells. Case reports suggest metabolic defects in AD. OBJECTIVES: (1) To determine whether women with AD have altered relative resting energy expenditure (REE per total body mass) compared with controls; and (2) to quantitate lipomatosis-associated collagen, MNGs and tissue and blood cytokines that may influence REE. METHODS: A total of 10 women with AD were compared with age, body mass index, fat and weight-matched control women. Adipose tissue was obtained from five women with AD and five controls and evaluated for collagen and macrophages/MNGs. Fat mass and fat-free mass were identified by dual X-ray absorptiometry. REE was by determined indirect calorimetry and related to mass. Adipokines and cytokines were evaluated in blood and tissue. RESULTS: Relative REE (REE per total body mass) was lower in women with AD compared with controls (P=0.007). Only lipomatosis (group) and total body mass were significant predictors of REE in forward stepwise regression (P<0.0001). Adipose interleukin (IL)-6 levels were elevated (P=0.03) and connective tissue was increased fourfold in lipomatosis compared with control tissue (P <0.0001). There was no difference in adipose tissue macrophages between groups; 30% of women with AD had MNG cells. Anti-inflammatory IL-13 levels were elevated (P=0.03), and cytokines important in the recruitment of monocytes, Fraktalkine (P=0.04) and macrophage inflammatory protein-1beta (P=0.009), were significantly lower in the blood of women with AD compared with controls. CONCLUSIONS: The lower relative REE in women with AD compared with controls was associated with increased connective (non-metabolic) tissue in the lipomatosis, and inflammation, although underlying metabolic defects may be important as well. Understanding the pathophysiology and metabolism of lipomatosis in AD may contribute to a better understanding of metabolism in non-lipomatosis obesity.

Insulin improves the endothelium-independent relaxation and the contractile response in aorta from hypertensive diabetic rats.

We investigated the effect of insulin on basal tone and contractile response in isolated aorta from hypertensive streptozotocin-induced diabetic rats (DR) and the role of endothelium in this response. The effect of insulin was tested in rings of control rats (CR) and DR in different protocols: in basal tone, in the plateau of norepinephrine (NE) or KCl contracted rings and in the response to NE or KCl preincubated with insulin. The role of nitric oxide (NO) on insulin response was investigated in rings treated with L-NAME. We found in DR: a) An endothelium independent-vasorelaxant effect of insulin on basal tone; b) A decreased response to NE (without differences in the sensibility) and to KCl (20 mmol/l) and an improvement of this hyporeactivity by insulin pre-treatment, and c) A potentiated vasorelaxant response of insulin dependent of increased vascular tone. Furthermore, an additional action of insulin on endothelial response through NO-release was observed in precontracted vessels from CR, not observed in DR. Our results support that insulin plays a role in regulation of arterial basal tone from DR by a direct effect on smooth muscle vascular cells exposed to high blood pressure. The vasorelaxant effect of insulin dependent of endothelium is blunted in DR by a reduced endothelial NO production. Our work also suggest that insulin could improve the endothelial function in vessels with increased tone in absence of diabetes.

[Effect of angiotensin II and alpha2 adrenergic receptor antagonists on angiotensin II-stimulated nitric oxide release]. / Efecto de antagonistas de los receptores de angiotensina II y alpha 2 adrénergicos sobre la liberación de óxido nitrico inducida por angiotensina II.

The aim of the present work was to characterize the interaction between the adrenergic system and angiotensin II-stimulated nitric oxide (NO) release in rabbit aorta. Rings of thoracic aorta were placed in an isolated organ bath. Equilibration was performed during 30 min, and after washing, angiotensin II was added at different concentrations, during 20 min. In another group two stimulations were performed with an interval of 60 min. Angiotensin II antagonists: losartan, PD 123319 and Sar1-Leu8-angiotensin II, alpha 2 adrenergic antagonist: yohimbine, all at 10(-5) M and L-NAME or D-NAME 10(-2) M, were added before stimulation with angiotensin II 10(-6) M or 5.10(-6) M. In another group, besides losartan or PD 123319, yohimbine was added. Nitrite determination was performed with Griess reagent. Angiotensin II 10(-8) to 10(-6) M increased NO metabolite production measured as nitrites referred to the control. In higher concentrations there was a diminution in relation to 10(-6) M. Angiotensin II nitrite release fell in the second stimulation with the hormone in all cases, whereas it was blocked by L-NAME. It was increased by angiotensin II antagonist only at maximal concentrations of the hormone, an effect abolished by yohimbine. Likewise, yohimbine diminished nitrite production at concentrations of angiotensin II of 5.10(-6) but not at 10(-6) M. These results allow us to postulate that NO release induced by angiotensin II would be in part mediated by alpha 2 receptors. Angiotensin II antagonists unmask these effects at maximal concentrations of the hormone, whereas at supramaximal concentrations inhibitory mechanisms would prevail, which would be balanced by alpha 2 activation.

Structural changes in the kidney induced by coarctation hypertension.

We investigated structural alterations in renal tissue identifying the morphological and histological changes in the non-ischemic kidney (NIK) and their potential significance in aortic coarctation-hypertensive rats (HR). HR's mean arterial pressure (MAP) was higher compared with sham operated rats (SR). An oral 10 mg/kg/day losartan (LOS) dose diminished but not reverted MAP. Hypertrophy was noted in HR NIK's with significant weight increase (p<0.01). The ratio IK/NIK in HR's decreased 22% (p<0.01). LOS proved to cause no ischemic kidney (IK) modification nor did it revert NIK hypertrophy. NIK in HR's presented glomerulosclerosis, mesangial proliferation and arteriolar thickening reverted by LOS. The stereological study of afferent NIK arterioles showed hypertrophy and an increase in the wall/lumen ratio without lumen modification. LOS diminished wall thickness. LOS-induced decrease of NIK alterations might result from arteriosclerosis regression, the media/lumen ratio. glomerulosclerosis and mesangial proliferation dependent on angiotensin 11.

Endothelium-dependent desensitization to angiotensin II in rabbit aorta: the mechanisms involved.

The aim of this study was to characterize the role of the endothelium in angiotensin II-desensitization and its mechanisms of action. Rabbit aortic rings were exposed to increasing doses of angiotensin II (Ang II, 10(-9) to 2.5 x 10(-6)) to generate two cumulative dose-response curves (CDRC I and II). A 50-min interval separated CDRC I and II. Desensitization was observed at all doses in unrubbed aortic tissue and at lower doses in rubbed aortic tissue. Tachyphylaxis was greater in arteries with endothelium. Treatment of intact rings with L-N(G)-nitroarginine methyl ester (L-NAME, 10(-4) M) did not prevent this phenomenon. However, indomethacin (10(-5) M) and miconazol (10(-6) M) attenuated Ang II-desensitization. Treatment of unrubbed rings with nifedipine (10(-6) M) and cromakalim (10(-6) M) inhibited the effect of indomethacin. To confirm the involvement of K+ channels, unrubbed and rubbed aortic rings were treated with the K(Ca2+) blockers apamin (10(-7) M), tetraethylammonium (TEA, 10(-3) M), and iberiotoxin (10(-8) M), and the K(ATP) blocker glibenclamide (10(-5) M). In both arteries apamin, TEA, and glibenclamide abolished the tachyphylaxis without changes in the maximal response. Iberiotoxin diminished Ang II-desensitization in rubbed but not unrubbed arteries. Results from this study suggest that Ang II-desensitization involves endothelium-dependent and -independent mechanisms. Endothelium-dependent desensitization could be mediated by a cyclooxygenase-cytochrome P450 product, which could act by increasing K(Ca2+) channel activity.

[Cyclosporin A inhibits the response of osmotic water permeability to antidiuretic hormone in toad's bladder and to angiotensin II and antidiuretic hormone in toad's skin]. / La ciclosporina A inhibe la respuesta de la permeabilidad osmótica al agua a la hormona antidiurética en la vejiga del sapo y a la angiotensina II y hormona antidiurética en piel de sapo.

The purpose of the present study was to assess the effects of cyclosporine A (CyA) in the osmotic water flow response of isolated toad bladder to arginine-vasotocin (AVT) and to angiotensin II (Ang II) and AVT in isolated toad skin. CyA added to the dermal side of isolated toad skin or to the serosal side of toad bladder in concentrations of 0.42. 10(-6) M to 0.42. 10(-7) M had no effect on basal osmotic water permeability (Posm) but inhibited the hormonal response to AVT in both membranes (AVT 10(-10) M in toad bladder and 10(-8) to 10(-9) M in toad skin). CyA also inhibited the Posm response to Ang II (10(-7) M) in toad skin in concentrations of 0.42. 10(-6) M and 0.42. 10(-7) M. In toad bladder it could be demonstrated that the inhibitory effect was reversible. CyA in concentrations of 0.42. 10(-6) M inhibited the Posm response of toad skin to theophylline (3.2. 10(-3) M) and to dibutyryl cyclic AMP (6.3. 10(-3) M) suggesting an effect distal to the generation of cyclic AMP. These responses would support the possibility of a diuretic effect in the mammalian nephron.

La ciclosporina a inhibe la respuesta de la permeabilidad osmótica al agua a la hormona antidiurética en la vejiga del sapo y a la angiotensina ii y hormona antidiurética en piel de sapo / Ciclosporine A inhibits the osmotic water flow response of isolated toad bladder to arginine-vasotocin and to angiotensin ii and arginine-vasotocin in isolated toad skin

El objeto del presente trabajo fue evaluar los efectos de la ciclosporina A (CyA) en la respuesta del flujo osmótico de agua de la vejiga aislada de sapo a la arginina-vasotocina (AVT) y a la angiotensina II (Ang II) y AVT en piel aislada de sapo. La CyA añadida al lado dérmico de la piel aislada de sapo o al lado seroso de la vejiga en concentraciones de 0,42. 10-6M a 0,42. 10-7M no tuvo efecto en la permeabilidad osmótica basal (Posm) pero inhibió la respuesta hormonal a la AVT en ambas membranas (AVT 10-10M en vejiga de sapo y 10-8 a 10-9M en piel de sapo). La CyA también inhibió la respuesta de la Posm a la Ang II (10-7M) en piel de sapo en concentraciones de 0,42. 10-6M y 0,42. 10-7M. En vejiga de sapo pudo demostrarse que el efecto inhibitorio fue reversible. La CyA en concentraciones de 0,42. 10-6M inhibió la respuesta de la Posm en piel de sapo a la teofilina (3,2. 10-3M) y al dibutiril AMP cíclico (6,2. 10-3M) sugiriendo un efecto distal a la generación de AMP cíclico. Estas respuestas apoyarían la posibilidad de un efecto diurético en el nefrón de los mamíferos. (AU)

Prorenin concentration in the hypertensive disorders in pregnancy.

OBJECTIVE: To evaluate the plasma prorenin levels during the three trimesters of normal pregnancy, their prognostic value, and their correlation with hypertensive disorders of pregnancy. DESIGN: A prospective study in which plasma prorenin and renin levels were measured in 55 healthy pregnant women and 66 who developed gestational hypertension or preeclampsia. The patients were classified as mild preeclampsia (mild PE), severe preeclampsia (severe PE), chronic hypertension and superimposed preeclampsia upon chronic hypertension (superimposed PE). METHOD: Venous blood samples were collected in the first, second and third trimesters and during delivery or cesarean. Plasma renin concentration (PRC) was measured by radioinmmunoassay before and after incubation with trypsin solution. The difference gave plasma prorenin concentration (PProRC). RESULTS: PRC and PProRC were significantly higher in pregnant women compared with healthy non-pregnant. PRC was significantly increased in the first trimester in the chronic hypertension group and a lower value was found in the first trimester in the superimposed PE compared with those in healthy pregnant women. No differences in other groups were found. PProRC showed a significant lower value in the first and third trimesters in the severe PE group. In the superimposed PE a low value of PProRC similar to those of non-pregnant women was found. CONCLUSIONS: The results show that the different types of hypertension in pregnancy have different profiles of PProRC and PRC in relation to development of preeclampsia. The absence of increase of PProRC in the first trimester of superimposed PE may have a prognostic value.

Vascular maternal reactivity and neonatal size in normal pregnancy.

OBJECTIVE: The purpose of the present study was to determine the associations of cold pressor test (CPT) cardiovascular reactivity with gestational age at birth and neonatal size in normotensive pregnant women. METHODS: Seventy (70) healthy pregnant women were enrolled. The CPT consisted of introducing the patients' hands in cold water (4 degrees C) for 3 min. An automatic oscillometric device was used to record blood pressure (BP) every minute for the following 5 min. Perinatal results were correlated with CPT findings. RESULTS: Vascular reactivity assessed by CPT was higher in pregnant hypertensive women and in women with a hypertensive family history. Mean BP increases caused by CPT showed a significant negative correlation for gestational age (r = -0.58, p < 0.001) and cephalic perimeter (r = -0.57, p = 0.03). Diastolic BP increases caused by CPT were negatively correlated with newborn weight (r = -0.78, p < 0.001). Predictable newborn weight, gestational age, and cephalic perimeter were 4046 (47 x diastolic BP increase), 40.2 (0.07 x mean BP increase), and 35.8 (0.09 x mean BP increase), respectively. CONCLUSIONS: Results show that every mm Hg diastolic BP increase in response to CPT was correlated with a 47-g decrease in the newborn normal weight. Furthermore, every mean mm Hg BP increase in response to CPT was associated with a 0.07-week decrease in the newborn normal gestational age and a 0.09-cm decrease in the normal cephalic perimeter at birth.

Efecto de antagonistas de los receptores de angiotensina II y alpha 2 adrénergicos sobre la liberación de óxido nitrico inducida por angiotensina II. / [Effect of angiotensin II and alpha2 adrenergic receptor antagonists on angiotensin II-stimulated nitric oxide release]

The aim of the present work was to characterize the interaction between the adrenergic system and angiotensin II-stimulated nitric oxide (NO) release in rabbit aorta. Rings of thoracic aorta were placed in an isolated organ bath. Equilibration was performed during 30 min, and after washing, angiotensin II was added at different concentrations, during 20 min. In another group two stimulations were performed with an interval of 60 min. Angiotensin II antagonists: losartan, PD 123319 and Sar1-Leu8-angiotensin II, alpha 2 adrenergic antagonist: yohimbine, all at 10(-5) M and L-NAME or D-NAME 10(-2) M, were added before stimulation with angiotensin II 10(-6) M or 5.10(-6) M. In another group, besides losartan or PD 123319, yohimbine was added. Nitrite determination was performed with Griess reagent. Angiotensin II 10(-8) to 10(-6) M increased NO metabolite production measured as nitrites referred to the control. In higher concentrations there was a diminution in relation to 10(-6) M. Angiotensin II nitrite release fell in the second stimulation with the hormone in all cases, whereas it was blocked by L-NAME. It was increased by angiotensin II antagonist only at maximal concentrations of the hormone, an effect abolished by yohimbine. Likewise, yohimbine diminished nitrite production at concentrations of angiotensin II of 5.10(-6) but not at 10(-6) M. These results allow us to postulate that NO release induced by angiotensin II would be in part mediated by alpha 2 receptors. Angiotensin II antagonists unmask these effects at maximal concentrations of the hormone, whereas at supramaximal concentrations inhibitory mechanisms would prevail, which would be balanced by alpha 2 activation.

Angiotensin-(1-7) increases osmotic water permeability in isolated toad skin.

Angiotensin-(1-7) (Ang-(1-7)) increased osmotic water permeability in the isolated toad skin, a tissue with functional properties similar to those of the distal mammalian nephron. Concentrations of 0.1 to 10 microM were effective, with a peak at 20 min. This effect was similar in magnitude to that of frog skin angiotensin II (Ang II) and oxytocin but lower than that of human Ang II and arginine-vasotocin. The AT2 angiotensin receptor antagonist PD 123319 (1.0 microM) fully inhibited the response to 0.1 microM Ang-(1-7) but had no effect on the response to Ang II at the same concentration. The specific receptor antagonist of Ang-(1-7), A-779, was ineffective in blocking the response to Ang-(1-7) and to frog skin Ang II. The AT1 receptor subtype antagonist losartan, which blocked the response to frog skin Ang II, was ineffective in blocking the response to Ang-(1-7). The present results support the view of an antidiuretic action of Ang-(1-7) in the mammalian nephron.

Angiotensin-(1-7) increases osmotic water permeability in isolated toad skin

Angiotensin-(1-7) (Ang-(1-7)) increased osmotic water permeability in the isolated toad skin, a tissue with functional properties similar to those of the distal mammalian nephron. Concentrations of 0.1 to 10 ÁM were effective, with a peak at 20 min. This effect was similar in magnitude to that of frog skin angiotensin II (Ang II) and oxytocin but lower than that of human Ang II and arginine-vasotocin. The AT2 angiotensin receptor antagonist PD 123319 (1.0 ÁM) fully inhibited the response to 0.1 ÁM Ang-(1-7) but had no effect on the response to Ang II at the same concentration. The specific receptor antagonist of Ang-(1-7), A-779, was ineffective in blocking the response to Ang-(1-7) and to frog skin Ang II. The AT1 receptor subtype antagonist losartan, which blocked the response to frog skin Ang II, was ineffective in blocking the response to Ang-(1-7). The present results support the view of an antidiuretic action of Ang-(1-7) in the mammalian nephron

Synthesis and structural characterization of poly(LGGVG), an elastin-like polypeptide.

Poly(LGGVG) a potential elastin-like biomaterial has been synthesized and studied both in solution (by circular dicroism and nuclear magnetic resonance) and in the aggregated state (by transmission electron microscopy). For sake of comparison, also the conformation of the protected (Boc-LGGVG-OEt) and free (H(2)(+)-LGGVG-OH) 'monomers' has been investigated. While in the latter ones the presence has been evidenced of more or less stable type II beta-turns, the polymer showed a conformational ensemble, possibly comprising type II beta-turns, type I beta-turns and open (unordered) structures. At supramolecular level, twisted-rope aggregates were observed by transmission electron microscopy for the polymer. Thus, the title compound has shown to possess, at both molecular and supramolecular level, physico-chemical properties very similar to those of elastin, so to give some confidence that it could really constitute the precursor of an artificial substitute of elastin itself.

Losartan reduces the vasorelaxant effect of atrial natriuretic peptide on basal tone in aorta.

The Ca2+ -and receptor-dependencies of the basal tone seen in angiotensin II (Ang II)-conditioned rabbit thoracic aortic rings were investigated. Ca2+ -free Krebs significantly and partially reversibly reduced basal tone in aortic rings that had recovered from an earlier challenge with Ang II; rings not previously exposed to Ang II were unaffected. The effect of Ca2+ -free Krebs was similar to the reduction in basal tone evoked by atrial natriuretic peptide (ANP), but was smaller than that seen with exposure to Ca2+ -free Krebs+EGTA+sodium nitroprusside (SNP). Pretreating rings with Ca2+ free Krebs blocked the vasorelaxant effects of ANP and Ca2+ -free Krebs+EGTA+SNP. Losartan, an AT1 receptor antagonist, significantly attenuated ANP-induced relaxation, but did not otherwise alter basal tension in either unstimulated or Ang II-conditioned rings. The AT2 receptor antagonist, PD 123319, had no effect. These data suggest that transient exposure to Ang II induces prolonged, AT1-dependent increases in intracellular free Ca2+ which are antagonized by ANP.

Atrial natriuretic peptide relaxes arterial basal tone induced by coarctation hypertension.

We have investigated the vasorelaxant effect of atrial natriuretic peptide (ANP) on isolated non-contracted aorta from coarctation hypertensive rats (HR) and the role of endothelium in this vasorelaxant action. After 7-14 days of surgery, mean blood pressure was higher (P < 0.01) in HR compared with sham operated rats (SR), used as the control. ANP (10(-6) mol/l) significantly lowered basal tone in previously unstimulated HR thoracic aortic rings; however, it had no effect in HR abdominal aorta or in SR abdominal and thoracic aorta. Endothelial destruction potentiated the vasorelaxant effect of ANP on basal tone in HR thoracic aorta. A similar potentiation of the ANP-response was observed by pre-treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 3 x 10(-4) mol/l) or methylene blue (2 x 10(-5) mol/l) in unrubbed HR thoracic aorta. Treatment with calcium-free Krebs + EGTA (2 x 10(-3) mol/l) + sodium nitroprusside (10(-5) mol/l) or calcium-free Krebs significantly decreased basal tone and abolished ANP-response. These effects were observed only in HR thoracic aorta. Similarly, staurosporine (10(-7) mol/l) and calphostin C (10(-6) mol/l), inhibitors of protein kinase C (PKC), diminished basal tone and abolished the ANP-response in HR thoracic aorta. Acetylcholine (10(-6) mol/l) had a small but significant action on the basal tone of unrubbed HR thoracic aorta. These results demonstrate that ANP has a vasorelaxant effect on aortic basal tone when the vessel is exposed to high blood pressure. Inhibition of ANP effects on basal tone by calcium-free Krebs and PKC antagonists suggests that the HR aorta increases Ca2+-active tone, that modifies the response of vascular smooth muscle to the vasodilating hormone ANP.

Alcohol drinking and blood pressure among adolescents.

The purpose of this study was to evaluate alcohol consumption among adolescents from Tucuman, Argentina, and to determine its possible relationship with increased levels of blood pressure. Three hundred fifty-six students aged 13-18 included in the study were asked to answer questionnaires anonymously. Two blood pressures measures were then taken. Differences between both sexes were found in quantity and frequency of alcohol consumption. Enjoyment was determined to be the main reason for drinking. There was an association between frequency and alcohol-related problems, and smoking habits. There were also differences in blood pressure among males and females. A weak, but significant, relationship between quantity/frequency index and diastolic blood pressure was found. A greater prevalence of hypertension in male heavy drinkers was noted as well. Because this addiction implies multiple social problems and it also accounts for a hypertension risk factor, the importance of aiming at developing prevention strategies for alcohol abuse among adolescents is stressed.

Epidemiology of cholelithiasis in southern Italy. Part II: Risk factors.

OBJECTIVE: To determine behavioural, dietary and other common factors associated with new cases of gallstones, diagnosed by ultrasonography, in a prospective cohort study conducted in southern Italy. SUBJECTS AND METHODS: Between May 1985 and June 1986, systematic sampling from the electoral register of Castellana, a small town in southern Italy, yielded 2472 subjects who had had their gallbladder checked for gallstones by ultrasonography. Between May 1992 and June 1993, 1962 out of the 2235 (87.7%) subjects without gallstones at baseline agreed to a further ultrasound examination. At the first survey a standardized questionnaire was administered, inquiring about medical history, diet, cigarette smoking and other behavioural characteristics. Height and weight were also measured, and blood levels of glucose, cholesterol, HDL-cholesterol and triglycerides were determined by standard methods. The same variables were measured at the second survey. The diagnosis of gallstones was made with the same echograph by echographists working in the same department. Multiple logistic regression was used to determine which factors measured at the first survey were associated with the incident cases of gallstones. RESULTS: One hundred and four subjects had developed gallstones, an incidence of 9.7 per 1000 persons per year. Age, body mass index (BMI), weight change, a history of diabetes, constipation (shown by use of laxatives), cigarette smoking, years of schooling, consumption of fried foods and excessive oil, and pregnancy in females, were positively associated with the incidence of gallstones. Consumption of wine, coffee, fish and wholemeal bread was inversely associated. Sex, family history of cholelithiasis, use of oral contraceptives and serum lipids were not independent risk factors for gallstones. CONCLUSION: The results of this study confirm many gallstone-associated factors reported in previous cross-sectional and case-control studies, as well as in other cohort studies based on the clinical diagnosis of gallstones, such as BMI, ageing and wine consumption. Furthermore, use of laxatives, considered a proxy of constipation, appears to be another important independent risk factor for gallstones.