Temporary losartan or captopril in young SHR induces malignant hypertension despite initial normotension.

Racasan S, Hahnel B, van der Giezen DM, Blezer EL, Goldschmeding R, Braam B, Kriz W, Koomans HA, Joles JA.

Department of Nephrology, University Hospital, Utrecht, The Netherlands.

BACKGROUND: Exposure of normotensive rats to angiotensin-converting enzyme (ACE) inhibitors in early life causes hypertrophy of intrarenal arteries. Similar defects have been found in knockout mice lacking angiotensinogen, ACE, or angiotensin II type 1 (AT1) receptors. On the other hand, transient inhibition of the renin-angiotensin system from 2 weeks of age in spontaneously hypertensive rats (SHR), either with ACE inhibitors or with AT1 receptor antagonists partially prevents the increase in blood pressure. However, permanent treatment of SHR from conception onwards with ACE inhibitors completely prevents hypertension. Although these studies demonstrated protection from hypertension-induced changes in the heart and large arteries, renal arteries were not studied and follow-up did not extend beyond 6 months of age. We postulated that while brief exposure to ACE inhibitors or AT1 receptor antagonists in young SHR would temporarily decrease blood pressure, it would also be associated with development of intrarenal arterial malformation, and ultimately have deleterious effects. METHODS: Direct effects on intrarenal arterial morphology of an ACE inhibitor (captopril, 100 mg/kg/day) and an AT1 receptor antagonist (losartan, 50 mg/kg/day), administered from the last week of gestation until 8 weeks of age were examined in SHR. After stopping treatment at 8 weeks, we continued to monitor blood pressure until spontaneous death. RESULTS: Systolic blood pressure at 8 weeks was normalized by captopril and losartan (SHR control 187 +/- 8 mm Hg; captopril 118 +/- 5 mm Hg; and losartan 120 +/- 9 mm Hg). However, by 30 weeks, blood pressure had increased to control SHR levels. At 4 weeks, the media of renal arteries and arterioles was hypertrophied. Marked smooth muscle cell hyperplasia of cortical arteries resulted in significantly increased wall thickness by 8 weeks, despite similar external diameter. Arterial wall structure was disrupted, with fragmentation of elastic fibers and irregular distribution of collagen type I fibers. After stopping treatment, the rats gradually began to show poor health and all had died by 1 year of age, while all 1-year-old control SHR females were in good health. The cause of morbidity and mortality in the rats treated in early life was clearly malignant hypertension. Severe hypertrophy of renal arterioles was found, as well as cerebral hemorrhage. CONCLUSION: Despite initial normalization of blood pressure interference with the renin-angiotensin system during a crucial stage of development in SHR can initiate marked smooth muscle cell hyperplasia and disruption of the wall structure of the intrarenal arteries. Subsequent progression of this intrarenal process after cessation of treatment suggests an independent process that eventually results in malignant hypertension and early death.

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Is there an association between level of adult blood pressure and nephron number or renal filtration surface area?

Black MJ, Briscoe TA, Constantinou M, Kett MM, Bertram JF.

Department of Anatomy & Cell Biology, Monash University, Clayton, Victoria, Australia. Jane.Black med.monash.edu.au

BACKGROUND: Reductions in renal filtration surface area (FSA) have been linked to development of hypertension. This study investigated whether there are direct relationships, in the adult rat, between levels of blood pressure and nephron number or total renal FSA. METHODS: F1 and F2 offspring were generated from a spontaneously hypertensive rat (SHR)/Wistar Kyoto (WKY) rat cross. Tail-cuff systolic blood pressure was measured twice weekly from 5 to 15 weeks of age and mean arterial blood pressure determined prior to sacrifice. At 15 weeks of age, the rats were perfusion-fixed and glomerular (and thereby nephron) number, glomerular size, total length, and surface area of glomerular capillaries and total renal FSA were determined using unbiased stereologic techniques. RESULTS: In F1 offspring, blood pressure levels were midway between the SHR and WKY rats. Nephron number was significantly higher in the WKY rats compared to the SHR and F1 offspring. However, there was no difference in nephron number between the F1 rats and SHR and no difference in renal FSA between the three groups. In the F2 generation, where there is random segregation of the SHR and WKY genes, there was no significant correlation between either nephron number and adult blood pressure (r2= 0.16, P= 0.11) or total renal FSA and adult blood pressure (r2= 0.02, P= 0.58). There was a significant inverse correlation between nephron number and glomerular size (r2= 0.49, P= 0.0043). CONCLUSION: There is not a direct corollary between nephron number or renal FSA and level of blood pressure in this rat model.

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Nocturnal blood pressure is elevated with natriuresis and proteinuria as renal function deteriorates in nephropathy.

Fukuda M, Munemura M, Usami T, Nakao N, Takeuchi O, Kamiya Y, Yoshida A, Kimura G.

Department of Internal Medicine and Pathophysiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. m-fukuda med.nagoya-u.ac.jp

BACKGROUND: We reported that patients with sodium sensitive type of hypertension exhibited the lack of nocturnal fall in blood pressure with enhanced natriuresis during night. Sodium sensitivity is caused by diminished glomerular filtration capability and/or augmented tubular reabsorption of sodium, and seems tightly linked with glomerular capillary hypertension. In the present study, we investigated the relationship between glomerular filtration rate and circadian rhythms of these parameters in patients with glomerulopathy. METHODS: Twenty six patients (15 men and 11 women; aged 17 to 72 years; mean age 47 +/- 3 years), whose diagnosis was confirmed as glomerulopathy with renal biopsy, were studied during hospitalization. Ambulatory blood pressure for 24 hours was monitored, while urinary samples were collected for both daytime (6:00 a.m. to 9:00 p.m.) and nighttime (9:00 p.m. to 6:00 a.m.) to estimate circadian rhythms of urinary sodium and protein excretion rates (UNaV, UproV). Then night/day ratios of mean arterial blood pressure (MAP), UNaV, and UproV were analyzed in relation to 24-hour creatinine clearance as a marker of glomerular filtration rate. RESULTS: Serum creatinine and creatinine clearance were 1.1 +/- 0.1 mg/dL and 89 +/- 7 mL/min/1.73 m2. There were significant day-night differences in MAP (96 +/- 2 mm Hg vs. 92 +/- 2 mm Hg; P= 0.006), UNaV (6.7 +/- 0.9 mmol/hour vs. 3.6 +/- 0.3 mmol/hour; P= 0.003), and UproV (161 +/- 27 mg/hour vs. 128 +/- 28 mg/hour; P= 0.02). Creatinine clearance had significantly negative relationships with night/day ratios of MAP (r=-0.49; P= 0.01), UNaV (r=-0.43; P= 0.03,) and UproV (r=-0.41; P= 0.04). In addition, night/day ratio of MAP had significantly positive relationships with night/day ratios of UNaV (r= 0.49; P= 0.01) and UproV (r= 0.45; P= 0.02). CONCLUSION: Our results show that as renal function deteriorates in glomerulopathy the nocturnal dip in blood pressure is lost, resulting in enhanced urinary sodium and protein excretions during night. These findings are compatible with our proposal that impaired natriuresis during daytime makes nocturnal blood pressure elevated to compensate for diminished natriuresis by pressure natriuresis. We speculate that nocturnal glomerular capillary hypertension contributes, at least in part, to enhanced urinary sodium and protein excretions during night.

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Heterogeneity of cardiorenal characteristics in normotensive subjects.

Fesler P, du Cailar G, Ribstein J, Mimran A.

Department of Internal Medicine, Centre Hospitalier Universitaire Montpellier, France.

Blood pressure is a marker of elevated risk for cardiovascular disease, even within the normotensive range. The present study evaluates cardiorenal modifications observed in normotensive (<140/90 mm Hg) subjects. Using World Health Organization-International Society of Hypertension definitions, 265 normotensive subjects were categorized as having optimal (n=73), normal (n=84), and high-normal (n=108) blood pressure. Renal hemodynamics and function and cardiac morphology were evaluated by isotopic clearance techniques and ultrasonography, respectively. Urinary albumin excretion was measured in 24-hour urine collections. Body mass index and 24-hour urinary sodium (estimate of sodium intake), as well as left ventricular mass index, relative wall thickness, and glomerular filtration rate and filtration fraction, progressively increased in the optimal to high-normal groups. In contrast, effective renal plasma flow remained constant. Albuminuria was similar in all groups. Of interest, the proportion of subjects with concentric pattern of cardiac geometry (relative wall thickness > or =0.44) increased from 7% in optimal to 13% and 20% in normal and high-normal groups, respectively (P<0.05). Within this normotensive range of blood pressure, left ventricular mass index and relative wall thickness but not albuminuria were linearly correlated to systolic blood pressure; however, no correlation with diastolic blood pressure was found. In conclusion, changes in cardiac geometry and renal hemodynamics (increase in glomerular filtration rate and filtration fraction, an approximate index of glomerular pressure) that could predispose to cardiovascular morbidity and renal risk are already present in normotensive subjects with blood pressure higher than 120/80 mm Hg.

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An association between smoking habits and blood pressure in normotensive Japanese men: a 5-year follow-up study.

Okubo Y, Suwazono Y, Kobayashi E, Nogawa K.

Department of Occupational and Environmental Medicine (A2), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. ookubo med.m.chiba-u.ac.jp

BACKGROUND: There are few studies on the effects of smoking on blood pressure (BP) that consider confounding factors such as age, obesity, lifestyle and blood chemistry. As such, we conducted a 5-year follow-up study to clarify the effects of smoking habits on blood pressure in normotensive Japanese men. METHODS: The subjects were 2107 normotensive male steelworkers aged 40-54 years. They were classified using three indices: smoking habits in 1990, changes in smoking habits, and changes in amount of smoking. The associations between these indices and changes in blood pressure were evaluated using analysis of covariance (ANCOVA). As analyses, BMI, salt intake, physical activity, drinking habit, and results of blood chemistry in 1990 and their changes, age and blood pressure in 1990 were used as covariates. RESULTS: The cumulative incidence of hypertension in smokers was lower than in non- and ex-smokers. The adjusted mean of change in blood pressure of smokers was significantly lower than in non- and ex-smokers. No significant difference between non-smokers and ex-smokers, or among groups of smokers who varied their amount of smoking was observed. CONCLUSION: Chronic smoking reduces changes in blood pressure and 5-year cumulative incidence of hypertension. However, no significant dose-dependent effect of smoking on changes in blood pressure was observed.

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Low birth weight predicts higher blood pressure but not dermal capillary density in two populations.

Irving RJ, Shore AC, Belton NR, Elton RA, Webb DJ, Walker BR.

BHF Senior Research Fellow & Professor of Endocrinology, University of Edinburgh, Endocrinology Unit, Western General Hospital, Edinburgh, EH4 2XU, Scotland, UK. B.Walker ed.ac.uk

The association between low birth weight and high blood pressure is well established, but underlying mechanisms remain undefined. Vascular rarefaction, which may elevate peripheral vascular resistance, has been observed in capillaries of young men at risk for hypertension and men who had low birth weight. We looked for evidence that capillary rarefaction explains the association of low birth weight with high blood pressure in two cohorts. Participants in study 1 included 107 healthy boys aged 6 to 16 years recruited at random from a single school. Study 2 included 61 members of a cohort recruited at birth and studied at age 24 years. Measurements included indices of current size, blood pressure by automated sphygmomanometer, and dermal capillary density by video capillaroscopy of dorsal index finger skin after 10 minutes of venous occlusion. Lower birth weight predicted higher systolic blood pressure in both studies: in study 1, 3.57 mm Hg/kg birth weight (after adjustment for current height, 95% confidence interval 0.38 to 6.75, P<0.05); in study 2, 122+/-12 mm Hg in low birth weight (<2 kg) versus 115+/-9 in controls (P<0.05). Dermal capillary density was not associated in either group with birth weight or systolic blood pressure. We have found no evidence in these 2 cohorts that reduced capillary density explains the associations between lower birth weight and higher blood pressure.

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Study of policies on insured lives with elevated blood pressure known at time of issue.

Woodman H, Mast J, Milano A, Ingle D, Bergstrom R, Hart A, Hoffman NJ.

BACKGROUND: The mortality results of policies on insured lives with elevated blood pressure have been the subject of several studies since the early 20th century. This study, which began with issues of 1989, utilizes data from the Impairment Study Capture System (ISCS). Data are also compiled for impairments other than elevated blood pressure in the ISCS for the same study period. A comparison of these 2 sets of data shows the relative severity of elevated blood pressure compared to all other impairments combined. The determination of elevated blood pressure was made on the basis of risk classification due to lack of specific blood pressure readings. METHODS: Mortality results are actual to expected ratios based on the SOA 1990-95 Select Basic Table. The companies participating in this study have completed 3 steps: (1) agreement to have individual reports to the MIB included in the ISCS file; (2) submission of additional policy information, not on the MIB report; and (3) update of in-force status annually. Reports do not include personal identifying information. RESULTS: Based on the limited amount of data contributed by relatively few companies, there has been considerable improvement since earlier studies in mortality among insureds with elevated blood pressure. Some possible reasons for this include: (1) fewer smokers--there were fewer smokers in the population and hence applying for insurance during the period covered by this study as compared to earlier studies; (2) improved treatment, patient awareness and adherence to regimen--a wider variety of medications and current treatment practices compared to treatment in the 1970s and early 1980s may have influenced results. Compared to prior studies, it is likely that more insureds with elevated blood pressure first noted on the insurance examination subsequently have received treatment. In addition, those with elevated blood pressure have become more aware of the importance of adhering to their medication regimen and improving other adverse risk factors; (3) improvement in the treatment of related medical conditions. CONCLUSION: The results of this study must be interpreted with caution. The volume of data is not substantial, and the results may not be representative of non-contributing companies. Going forward, it is hoped that more companies will agree to participate such that future studies will produce data and results of greater utility.

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Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes.

Saydah SH, Fradkin J, Cowie CC.

US Centers for Disease Control and Prevention, National Center for Health Statistics, Hyattsville, Md, USA.

CONTEXT: Control of blood glucose levels, blood pressure, and cholesterol levels is proven to reduce the risk of vascular disease among individuals with diabetes mellitus; however, the current state of control of these risk factors among individuals in the United States is uncertain. OBJECTIVES: To examine 1999-2000 national data on control of risk factors for vascular disease among adults with previously diagnosed diabetes and to assess trends during the past decade. DESIGN, SETTING, AND PARTICIPANTS: Review of data from the Third National Health and Nutrition Examination Survey (NHANES III, conducted 1988-1994) and NHANES 1999-2000, cross-sectional surveys of a nationally representative sample of the noninstitutionalized civilian US population. Participants were adults aged 20 years and older with previously diagnosed diabetes who participated in both the interview and examination in either NHANES III (n = 1265) or NHANES 1999-2000 (n = 441). MAIN OUTCOME MEASURES: Levels of glycosylated hemoglobin (HbA1c), blood pressure, and total serum cholesterol in reference to target goals. RESULTS: Compared with NHANES III, participants with previously diagnosed diabetes in NHANES 1999-2000 were similar by age and sex, were less likely to be non-Hispanic white, were diagnosed at an earlier age, had a higher body mass index, and were more likely to use insulin in combination with oral agents. In NHANES 1999-2000, only 37.0% of participants achieved the target goal of HbA1c level less than 7.0% and 37.2% of participants were above the recommended "take action" HbA1c level of greater than 8.0%; these percentages did not change significantly from NHANES III (P =.11 and P =.87, respectively). Only 35.8% of participants achieved the target of systolic blood pressure (SBP) less than 130 mm Hg and diastolic blood pressure (DBP) less than 80 mm Hg, and 40.4% had hypertensive blood pressure levels (SBP > or =140 or DBP > or =90 mm Hg). These percentages did not change significantly from NHANES III (P =.10 and P =.56, respectively). Over half (51.8%) of the participants in NHANES 1999-2000 had total cholesterol levels of 200 mg/dL or greater (vs 66.1% in NHANES III; P<.001). In total, only 7.3% (95% confidence interval, 2.8%-11.9%) of adults with diabetes in NHANES 1999-2000 attained recommended goals of HbA1c level less than 7%, blood pressure less than 130/80 mm Hg, and total cholesterol level less than 200 mg/dL (5.18 mmol/L). CONCLUSION: Further public health efforts are needed to control risk factors for vascular disease among individuals with diagnosed diabetes.

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