The effect of variable CYP3A5 expression on cyclosporine dosing, blood pressure and long-term graft survival in renal transplant patients.

Kreutz R, Zurcher H, Kain S, Martus P, Offermann G, Beige J.

Abteilung Klinische Pharmakologie, Charite - Universitatsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. Kreutz medizin.fu-berlin.de

OBJECTIVE: Cyclosporine is extensively metabolized by cytochrome-P450 3A (CYP3A) enzymes in the liver and intestine including the CYP3A5 isoenzyme. CYP3A5 is also expressed in the kidney and has been implicated in blood pressure regulation. Appreciable expression of CYP3A5 occurs in carriers of the CYP3A5*1 allele, while the CYP3A5*3 allele is associated with low expression. We tested whether the presence of the CYP3A5*1 allele in renal transplant recipients and in donor kidneys influences cyclosporine dose requirements, blood pressure and long-term graft survival in renal transplant patients during chronic treatment with a cyclosporine-based immunosuppressive regimen. METHODS: We studied 399 Caucasian patients from our single-center registry with stable graft function for more than 10 weeks after transplantation. The genotypes for CYP3A5*1/*3 were determined by a TaqMan PCR method. Cyclosporine dose requirements, blood pressure and graft survival were analyzed in relation to the presence or absence of the CYP3A5*1 allele in recipients and donor kidneys. RESULTS: The CYP3A5*1 allele was found in 15.5% of the recipients and in 11.8% of the donor kidneys. The recipient CYP3A5*1 allele had no effect on cyclosporine dose and blood concentrations at trough with and without dose-adjustment. Blood pressure, number of antihypertensive compounds used for treatment and graft survival evaluated by Kaplan-Meier curves and Cox regression analysis were also not affected by the CYP3A5*1 allele either in recipients or donor kidneys. CONCLUSIONS: Cyclosporine dose requirements, blood pressure and long-term renal graft survival are not influenced by the CYP3A5*1 allele in Caucasian patients.

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Blood pressure differences between northern and southern Chinese: role of dietary factors: the International Study on Macronutrients and Blood Pressure.

Zhao L, Stamler J, Yan LL, Zhou B, Wu Y, Liu K, Daviglus ML, Dennis BH, Elliott P, Ueshima H, Yang J, Zhu L, Guo D; INTERMAP Research Group.

Department of Epidemiology, Fu Wai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.

Blood pressure and prevalence of high blood pressure are greater for northern than southern Chinese. Reasons for these differences are unclear. Relationships of north-south blood pressure differences with multiple dietary factors were investigated in 839 Chinese participants, International Study on Macronutrients and Blood Pressure (INTERMAP), 561 northern, 278 southern, aged 40 to 59 years. Daily nutrient intakes were determined from four 24-hour dietary recalls and 2 timed 24-hour urine collections. Average systolic/diastolic pressure levels were 7.4/6.9 mm Hg higher for northern than southern participants. Southern participants had lower body mass index, sodium intake, sodium/potassium ratio, and higher intake of calcium, magnesium, phosphorus, and vitamins A and C. Considered singly, with control for age and gender, several dietary variables (eg, body mass index, urinary sodium/potassium ratio, urinary sodium, dietary phosphorus, and magnesium) reduced north-south blood pressure differences by > or =10%. Controlled for age and gender, nondietary variables had little effect on north-south blood pressure differences. With inclusion in regression models of multiple dietary variables (sodium, potassium, magnesium or phosphorus, body mass index), north-south blood pressure differences became much smaller (systolic -1.1, diastolic 1.6 mm Hg) and statistically nonsignificant. In conclusion, multiple dietary factors accounted importantly for north-south blood pressure differences. Efforts are needed to improve nutrition in China, especially in the north, as well as in other populations including those in the United States, for prevention and control of adverse blood pressure levels and major adult cardiovascular disease.

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Effect of 90 decibel noise of 4000 hertz on blood pressure in young adults.

Mahmood R, Khan GJ, Alam S, Safi AJ, Salahuddin, Amin-ul-Haq.

Department of Physiology, Khyber Medical College, Peshawar. drrashidmahmood2002 yahoo.com

BACKGROUND: Almost every individual dislikes excessive and unnecessary noise. Noise exerts various adverse psychological and physiological effects, on human body including a rise in blood pressure. METHODS: 117 volunteer medical students, aged 18-23 years were exposed to 90 decibel noise of 4000 hertz for 10 minutes, produced by audiometer in a sound-proof room. Blood pressure was recorded every three minutes. RESULTS: Blood pressure increased during exposure to noise. Average rise in systolic blood pressure was 2.462+/-0.532 mm Hg and average rise in diastolic blood pressure was 3.064+/-1.047 mm Hg. Blood pressure came to resting value within two minutes after stopping exposure to noise in more than 50% of the subjects. CONCLUSION: Systolic and diastolic blood pressure increases due to noise exposure.

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Hypertension and impaired glycine handling in mice lacking the orphan transporter XT2.

Quan H, Athirakul K, Wetsel WC, Torres GE, Stevens R, Chen YT, Coffman TM, Caron MG.

Department of Cell Biology, Howard Hughes Medical Institute Laboratories, Duke University Medical Center, Durham, North Carolina 27710, USA.

A family of orphan transporters has been discovered that are structurally related to the Na(+)-Cl(-)-dependent neurotransmitter transporters, including the dopamine transporter. One member of this family, the mouse XT2 gene, is predominantly expressed in the kidney and has 95% homology to rat ROSIT (renal osmotic stress-induced Na(+)-Cl(-) organic solute cotransporter). To study the physiological functions of this transporter, we generated XT2-knockout mice by gene targeting. XT2(-/-) mice develop and survive normally with no apparent abnormalities. To attempt to identify potential substrates for XT2, we screened urine from XT2-knockout mice by high-pressure liquid chromatography and mass spectrometry and found significantly elevated concentrations of glycine. To study glycine handling, XT2(+/+) and XT2(-/-) mice were injected with radiolabeled glycine, and urine samples were collected to monitor glycine excretion. After 2 h, XT2(-/-) mice were found to excrete almost twice as much glycine as the XT2(+/+) controls (P = 0.03). To determine whether the absence of the XT2 transporter affected sodium and fluid homeostasis, we measured systolic blood pressure by computerized tail-cuff manometry. Systolic blood pressure was significantly higher in XT2(-/-) mice (127 +/- 3 mmHg) than in wild-type controls (114 +/- 2 mmHg; P < 0.001). This difference in systolic blood pressure was maintained on high and low salt feeding. To examine whether the alteration in blood pressure and the defect in glycine handling were related, we measured systolic blood pressure in the XT2(-/-) mice during dietary glycine supplementation. Glycine loading caused systolic blood pressure to fall in the XT2(-/-) mice from 127 +/- 3 to 115 +/- 3 mmHg (P < 0.001), a level virtually identical to that of the wild-type controls. These data suggest that the XT2 orphan transporter is involved in glycine reabsorption and that the absence of this transporter is sufficient to cause hypertension.

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The association of caffeinated beverages with blood pressure in adolescents.

Savoca MR, Evans CD, Wilson ME, Harshfield GA, Ludwig DA.

Georgia Prevention Institute, Department of Pediatrics, Medical College of Georgia, Augusta 30912-3715, USA. msavoca mail.mcg.edu

OBJECTIVE: To assess the association between the consumption of caffeinated beverages and blood pressure in African American and white adolescents. DESIGN: This study was part of ongoing research examining stress-induced hemodynamic responses in adolescents. African American and white adolescents (n = 159) selected foods and beverages for a 3-day sodium-controlled diet. Caffeine in these foods was used to stratify participants into 3 categories (0-50 mg/d, >50-100 mg/d, and >100 mg/d). Before menu selection, blood pressure readings were obtained. STATISTICAL ANALYSIS: A general linear model (multiple regression with both categorical and continuous variables) was developed to assess the effects of race, category of caffeine intake, and interaction of race and caffeine intake on systolic and diastolic blood pressure controlling for sex and body mass index (calculated as weight in kilograms divided by height in meters squared). RESULTS: The association between systolic blood pressure and caffeine category varied by race (P =.001). African Americans consuming more than 100 mg/d of caffeine had higher systolic blood pressure readings than the groups consuming 0 to 50 mg/d (mean difference, 6.0 mm Hg; 95% confidence interval [CI], 2.3 to 9.7) or more than 50 to 100 mg/d (mean difference, 7.1 mm Hg; 95% CI, 3.4 to 10.7). The effect on diastolic blood pressure was less pronounced (P =.08). The diastolic blood pressure of the group consuming more than 100 mg/d was 3.7 mm Hg (95% CI, 0.41 to 7.0) higher than the group consuming more than 50 to 100 mg/d and was not statistically different from the group consuming 0 to 50 mg/d (mean difference, 2.4 mm Hg; 95% CI, -0.9 to 5.8). There was no evidence that the association between diastolic blood pressure and caffeine intake varied by race (P =.80). CONCLUSIONS: For adolescents, especially African American adolescents, caffeine intake may increase blood pressure and thereby increase the risk of hypertension. Alternatively, caffeinated drink consumption may be a marker for dietary and lifestyle practices that together influence blood pressure. Additional research is needed owing to rising rates of adolescent hypertension and soft drink consumption.

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Role of angiotensin II in the pressor response to cortisol in fetal sheep during late gestation.

Forhead AJ, Fowden AL.

Department of Physiology, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. ajf1005 cam.ac.uk

Glucocorticoids increase blood pressure in utero, but the mechanisms responsible are unclear. This study investigated the hypothesis that the hypertensive effects of cortisol depend upon a functional renin-angiotensin system (RAS). The study examined, in the sheep fetus, whether blockade of the Ang II type 1 (AT(1)) specific receptor prevented the cortisol-induced increase in blood pressure. From 124 +/- 1 days of gestation (term 145 +/- 2 days), 27 chronically catheterized sheep fetuses were infused i.v. for 5 days with one of the following: (1) saline (0.9% NaCl at 2.5 ml day(-1), n= 6); (2) cortisol (3-5 mg kg(-1) day(-1), n= 7); (3) AT(1) receptor antagonist (GR138950, 1-3 mg kg(-1) day(-1) in saline, GRS, n= 7); or (4) cortisol and GR138950 (GRC, n= 7). On all days of infusion, plasma cortisol was greater in both groups of cortisol-treated fetuses than in the respective control fetuses (P < 0.05), and GR138950 prevented the pressor response to exogenous Ang II. Over 5 days of infusion, blood pressure increased by a maximum of 7.6 +/- 1.4 mmHg (mean +/-s.e.m., P < 0.05) in the cortisol-, but not saline-infused, fetuses. Blockade of the AT(1) receptor caused significant reductions in blood pressure in both GRS- and GRC-treated groups (P < 0.05); in the GRS-treated fetuses, the fall in blood pressure was significant from the first day of infusion, while in GRC-treated fetuses the decrement was not significant until the second day (P < 0.05). Over the period of the infusion, decreases in arterial blood pH andP(a,O(2)), and an increase inP(a,CO(2)), were observed in the fetuses treated with the AT(1) receptor antagonist (P < 0.05). Therefore, in the sheep fetus, 5 days of AT(1) receptor antagonism suppresses the cortisol-induced rise in blood pressure. These results suggest that cortisol may increase blood pressure within 24 h of administration by a mechanism that is independent of the fetal RAS. Thereafter, Ang II, via the AT(1) receptor, may mediate, in part, the hypertensive effects of cortisol in utero.

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Trends in blood pressure among children and adolescents.

Muntner P, He J, Cutler JA, Wildman RP, Whelton PK.

Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, La 70112, USA. pmuntner tulane.edu

CONTEXT: The prevalence of overweight among children and adolescents increased between 1988 and 2000. The change in blood pressure among children and adolescents over that time and the role of overweight is unknown. OBJECTIVE: To examine trends in systolic and diastolic blood pressure among children and adolescents between 1988 and 2000. DESIGN, SETTING, AND POPULATION: Two serially conducted cross-sectional studies using nationally representative samples of children and adolescents, aged 8 to 17 years, from the third National Health and Nutrition Examination Survey (NHANES III) conducted in 1988-1994 (n = 3496) and NHANES 1999-2000 (n = 2086). MAIN OUTCOME MEASURES: Systolic and diastolic blood pressure levels. RESULTS: In 1999-2000, the mean (SE) systolic blood pressure was 106.0 (0.3) mm Hg and diastolic blood pressure was 61.7 (0.5) mm Hg. After adjustment for age, mean systolic blood pressure was 1.6 mm Hg higher among non-Hispanic black girls (P =.11) and 2.9 mm Hg higher among non-Hispanic black boys (P<.001) compared with non-Hispanic whites. Among Mexican Americans, girls' systolic blood pressure was 1.0 mm Hg higher (P =.21) and boys' was 2.7 mm Hg higher (P<.001) compared with non-Hispanic whites (P<.001). With further adjustment for body mass index, these differences were attenuated. After age, race/ethnicity, and sex standardization, systolic blood pressure was 1.4 (95% confidence interval [CI], 0.6-2.2) mm Hg higher (P<.001) and diastolic blood pressure was 3.3 (95% CI, 2.1-4.5) mm Hg higher in 1999-2000 (P<.001) compared with 1988-1994. With further adjustment for differences in the body mass index distribution in 1988-1994 and 1999-2000, the increase in systolic blood pressure was reduced by 29% and diastolic blood pressure was reduced by 12%. CONCLUSIONS: Blood pressure has increased over the past decade among children and adolescents. This increase is partially attributable to an increased prevalence of overweight.

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Cellular adhesion molecules and blood pressure: interaction with sex in a multi-ethnic population.

Miller MA, Kerry SM, Cook DG, Cappuccio FP.

Department of Community Health Sciences, St George's Hospital Medical School, London, UK. mmiller sghms.ac.uk

OBJECTIVE: To clarify the association between blood pressure and four different adhesion molecules, adjusting for potential confounders, in men and women from different ethnic origins. DESIGN AND METHODS: The soluble (s) plasma adhesion molecules sP-selectin, sE-selectin, intracellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) were measured in 261 white (120 women), 188 African origin (99 women) and 215 South Asian (99 women) individuals living in England. All were free from coronary heart disease, stroke, other cardiovascular disease and diabetes, and were not receiving drug treatment for hypertension or high lipids, hormone replacement therapy or oral contraceptives. RESULTS: After adjustment for age, only sE-selectin concentrations were significantly associated with blood pressure. There was a significant interaction of sex with systolic (P = 0.013), diastolic (P = 0.042) and pulse (P = 0.015) pressures. After adjustment for age, ethnicity, body mass index and smoking, the significant interaction of sex persisted and in women the associations with systolic (P < 0.001), diastolic (P < 0.001) or pulse (P = 0.004) pressure were unchanged, but in men the association with diastolic blood pressure was abolished. Finally, the association appeared to be present in women younger than 50 years, who were likely to be premenopausal. CONCLUSIONS: The relationship between adhesion molecules and blood pressure is adhesion molecule specific and varies with sex and age, which may partially explain previous inconsistencies in the literature. The mechanisms relating blood pressure to adhesion molecule concentrations are unknown, but they are likely to be modified by the menopause. These differences may relate to the production, clearance or cell-surface shedding of the adhesion molecules.

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