Ultrafiltration volume is associated with changes in blood pressure in chronically hemodialyzed patients.

Kovacic V, Roguljic L, Kovacic V, Bacic B, Bosnjak T.

Hemodialysis Department, Medical Center Trogir, Trogir, Croatia. vedkovac inet.hr

INTRODUCTION: Volume overload is a main factor in development of hypertension in hemodialysis patients. In order to demonstrate impact of ultrafiltration volume on blood pressure during 15-months period in a group of patients undergoing chronic hemodialysis therapy, we conducted this study. We hypothesized that ultrafiltration volume different affects the pre/postdialysis systolic pressure, diastolic pressure, mean arterial pressure (MAP), and pulse pressure (PP) values. SUBJECTS AND METHODS: Study subjects were 23 anuric chronically hemodialyzed patients. The overall study time was 15 months, and 136 single hemodialysis treatments were analyzed. RESULTS: Ultrafiltration was negatively correlated with predialysis systolic blood pressure (r = -0.169, p = 0.025), postdialysis systolic blood pressure (r = -0.292, p < 0.001), postdialysis MAP (r = -0.186, p = 0.015), predialysis PP (r = -0.290, p < 0.001), and postdialysis PP (r = -0.370, p < 0.001). Ultrafiltration/dry body mass (UF/W) ratio was negatively correlated with predialysis PP (r = -0.222, p = 0.005), postdialysis PP (r = -0.340, p < 0.001), and postdialysis systolic blood pressure (r = -0.243, p = 0.002). We found significant difference in postdialysis PP between dialyses with UF/W ratio < or = 0.05 an dialyses with UF/W ratio > 0.05 (63.49 +/- 20.76 vs. 56.27 +/- 16.33 mmHg, p = 0.033). CONCLUSION: The ultrafiltration volume strongly affects postdialysis PP values. Evaluation of elevated blood pressure treatment in patients undergoing chronic hemodialysis therapy must be considered in respect of postdialysis PP values, not just depending on pre/postdialysis systolic and diastolic pressur or MAP values.

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A method for determining whether hypotension caused by novel compounds in preclinical development results from histamine release.

Blom JD, Yang PC, Nicholson NS, Case BL, Parlow JJ, South MS, Wegner CD.

Department of Discovery Biology, Pfizer Global Research and Development, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. jason.d.blom pfizer.com

INTRODUCTION: Many therapeutic agents stimulate histamine release from mast cells, which results in a decrease in blood pressure. The purpose of this study is to establish a method to determine if the mechanism of action, or one of the mechanisms, of hypotensive compounds is related to the release of histamine. The method was developed using a novel hypotensive compound, SC-372. METHODS: In Inactin anesthetized rats, after intravenous administration of SC-372 (0.3-7 mg/kg), the 2 and 7 mg/kg resulted in a dose-dependent decrease in blood pressure. Histamine (0.1 and 1 mg/kg) was injected intravenously to establish whether histamine release was the mechanism of action for the hypotension induced by SC-372. Compound 48/80 (0.1 mg/kg, promotes histamine release) and Cromolyn (1 mg/kg/min, [5 min], prevents histamine release from mast cells) were characterized and used intravenously in combination with/or compared to SC-372. RESULTS: Histamine resulted in a decrease in blood pressure that was unaffected by Cromolyn (1 mg/kg). Administration of Compound 48/80 resulted in a rapid reduction of systemic blood pressure. Intravenous infusion of Cromolyn prior to the injection of Compound 48/80 significantly attentuated the hypotensive response and the increase in histamine levels in the plasma. Intravenous administration of SC-372 resulted in a rapid reduction in blood pressure with a profile similar to that of Compound 48/80. When the rats were treated with Cromolyn prior to the administration of SC-372, both the blood pressure and plasma histamine levels were maintained at their pretreatment control levels. DISCUSSION: These data indicate that Compound 48/80 and Cromolyn can be used in rats to screen for histamine release-dependent drug-induced hypotension and suggest that the rapid decrease in blood pressure caused by SC-372 may result from histamine release from mast cells.

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Blood pressure, serum total cholesterol and contraceptive pill use in 17-year-old girls.

Nawrot TS, Den Hond E, Fagard RH, Hoppenbrouwers K, Staessen JA.

Studiecoordinatiecentrum, Hypertensie en Cardiovasculaire Revalidatie Eenheid, Departement Moleculair en Cardiovasculair Onderzoek, Katholieke Universiteit Leuven, Leuven, Belgium. tim.nawrot med.kuleuven.ac.be

BACKGROUND: Many studies have analysed the relation between cardiovascular risk factors and oral contraceptive use in adult women, whereas information on the possible health effects of oral contraceptive use during adolescence is lacking. DESIGN: The effect of current contraceptive pill use on blood pressure and serum total cholesterol concentration was studied in a cross-sectional sample of 120 adolescent girls with a mean age of 17.4 years. METHODS: After the girls had rested for 5 minutes in the sitting position, trained study nurses measured blood pressure three times consecutively using a mercury sphygmomanometer. The nurses also administered a questionnaire gathering information on the use of oral contraceptives, smoking and parental social class. In the morning blood samples were taken for the measurement of serum total cholesterol. RESULTS: Mean age (+/-SD) was 17.4+/-0.8 years. Blood pressure averaged (+/-SD) 108.7+/-9.9 systolic and 68.0+/-8.2 mmHg diastolic. Serum total cholesterol was 4.5+/-0.7 mmol/l. Forty-nine girls (41%) were taking the contraceptive pill. Of these, 44 (90%) were on a combination of ethinyloestradiol (20-35 microg) and a progestogen, four (8%) on anti-androgens (35 microg) and one (2%) only on a progestogen. After adjustment for age, body mass index, smoking and alcohol status systolic blood pressure was 4.6 mmHg higher (95% CI 1.2-8.1; P<0.001) in current pill users than in girls not currently on the pill (111.4 versus 106.8 mmHg). Adjusted for the aforementioned covariates, diastolic blood pressure was not related to pill use (68.2 versus 67.8 mmHg; P=0.7). Serum total cholesterol was 0.43 mmol/l (95% CI 0.18-0.60; P=0.001) higher among girls using oral contraceptives (4.7 versus 4.3 mmol/l), irrespective of whether or not the model was adjusted for age, body mass index, smoking and alcohol status. CONCLUSIONS: In 17-year-old girls, the use of oral contraceptives was associated with a nearly 5 mmHg higher systolic blood pressure and a 0.4 mmol/l higher level of serum total cholesterol. The long-term prognostic implications of our findings remain to be elucidated.

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Salt-induced hypertension in WKY rats: prevention by alpha-lipoic acid supplementation.

Vasdev S, Gill V, Longerich L, Parai S, Gadag V.

Department of Medicine and Laboratory Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John's Newfoundland, Canada. svasdev mun.ca

There is strong evidence that points to excess dietary salt as a major factor contributing to the development of hypertension. Salt sensitivity is associated with glucose intolerance and insulin resistance in both animal models and humans. In insulin resistance, impaired glucose metabolism leads to elevated endogenous aldehydes which bind to vascular calcium channels, increasing cytosolic [Ca2+]i and blood pressure. In an insulin resistant animal model of hypertension, spontaneously hypertensive rats (SHRs), dietary supplementation with lipoic acid lowers tissue aldehydes and plasma insulin levels and normalizes blood pressure. The objective of this study is to examine the effects of a high salt diet on tissue aldehydes, cytosolic [Ca2+]i and blood pressure in WKY rats and to investigate whether dietary supplementation with lipoic acid can prevent a salt induced increase in blood pressure. Starting at 7 weeks of age, WKY rats were divided into three groups of six animals each and treated for 10 weeks with diets as follows: WKY-normal salt (0.7% NaCl); WKY-high salt (8% NaCl); WKY-high salt + lipoic acid (8% NaCl diet + lipoic acid 500 mg/Kg feed). At completion, animals in the high salt group had elevated systolic blood pressure, platelet [Ca2+]i, and tissue aldehyde conjugates compared with the normal salt group and showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary alpha-lipoic acid supplementation in high salt-treated WKY rats normalized systolic blood pressure and cytosolic [Ca2+]i and aldehydes in liver and aorta. Kidney aldehydes and renal vascular changes were attenuated, but not normalized.

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Blood pressure lability and glomerulosclerosis after normotensive 5/6 renal mass reduction in the rat.

Griffin KA, Picken MM, Bidani AK.

Department of Internal Medicine, Loyola University Medical Center and Hines VA Hospital, Maywood, Illinois 60153, USA. Martha.Prado med.va.gov

BACKGROUND: Hypertension plays a major role in the progression of both experimental and clinical chronic renal disease. However, the pathogenesis of the more slowly developing glomerulosclerosis that is seen even in the absence of overt hypertension, both in renal mass reduction models and in humans with chronic renal disease, remains controversial. METHODS: The relationship of such glomerulosclerosis to the ambient blood pressure profiles was examined in the normotensive approximately 5/6 surgical excision rat remnant kidney model. Blood pressure was radiotelemetrically monitored at 10-minute intervals for 15 to 16 weeks ( approximately 15,000 blood pressure readings) in untreated rats (N= 13), or those treated with enalapril (N= 8), amlodipine (N= 9), or a combination of hydralazine, reserpine, and hydrochlorothiazide (N= 10). RESULTS: Even in these normotensive rats (systolic blood pressure <140 mm Hg), % glomerulosclerosis was significantly correlated with the overall average systolic blood pressure (r= 0.62, P < 0.0001; N= 40). However, much stronger correlations were observed between glomerulosclerosis and the % systolic blood pressure readings >150 mm Hg (r= 0.77, P < 0.0001) and the standard deviation of the average systolic blood pressure (r= 0.87, P < 0.0001). CONCLUSION: These data indicate that pressure dependent injury mechanisms continue to contribute to glomerular injury even within the "normotensive" blood pressure range in rats with reduced renal mass. This most likely represents the consequence of the impairment of protective renal autoregulation and enhanced glomerular transmission of the blood pressure fluctuations into the hypertensive range characteristic of the conscious state in both experimental animals and in humans. Such pathophysiology supports the need for more aggressive and around-the-clock blood pressure control in chronic renal disease.

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Cosegregation analysis of natriuretic peptide genes and blood pressure in the spontaneously hypertensive rat.

Ye P, West MJ.

Department of Medicine, The University of Queensland, Prince Charles Hospital, Brisbane, Queensland, Australia. s004734 yahoo.com

1. The natriuretic peptide precursor A (Nppa) and B (Nppb) genes are candidate genes for hypertension and cardiac hypertrophy in the spontaneously hypertensive rat (SHR). The purpose of the present study was to determine the role of the Nppa and Nppb genes in the development of hypertension in the SHR. 2. A cohort (n = 162) of F2 segregating intercross animals was established between strains of hypertensive SHR and normotensive Wistar-Kyoto rats. Blood pressure and heart weight were measured in each rat at 12-16 weeks of age. Rats were genotyped using 11 informative microsatellite markers, distributed in the vicinity of the Nppa marker on rat chromosome 5 including an Nppb marker. The phenotype values were compared with genotype using the computer package mapmaker 3.0 (Whitehead Institute, Boston, MA, USA) to determine whether there was a link between the genetic variants of the natriuretic peptide family and blood pressure or cardiac hypertrophy. 3. A strong correlation was observed between the Nppa marker and blood pressure. A quantitative trait locus (QTL) for blood pressure on chromosome 5 was identified between the Nppa locus and the D5Mgh15 marker, less than 2 cM from the Nppa locus. The linkage score for the blood pressure QTL on chromosome 5 was 3.8 and the QTL accounted for 43% of the total variance of systolic blood pressure, 54% of diastolic blood pressure and 59% of mean blood pressure. No association was found between the Nppb gene and blood pressure. This is the first report of linkage between the Nppa marker and blood pressure in the rat. There was no correlation between the Nppa or Nppb genes or other markers in this region and either heart weight or left ventricular weight in F2 rats. 4. These findings suggest the existence of a blood pressure-dependent Nppa marker variant or a gene close to Nppa predisposing to spontaneous hypertension in the rat. It provides a strong foundation for further detailed genetic studies in congenic strains, which may help to narrow down the location of this gene and lead to positional cloning.

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Effect of cross-fostering on blood pressure and renal function in the New Zealand genetically hypertensive rat.

Ashton N, Kelly P, Ledingham JM.

School of Biological Sciences, University of Manchester, Manchester, UK. nick.ashton man.ac.uk

1. The severity of hypertension displayed by adult spontaneously hypertensive rats (SHR) and Dahl (SS/Jr) rats can be reduced by 20-30 mmHg if the hypertensive pup is cross-fostered to a normotensive mother within the first 2 weeks of birth. In the SHR, at least, this blood pressure-lowering effect arises through programming of the neonatal kidney to excrete sodium more effectively. Thus, cross-fostering may only be effective in lowering pressure in salt-sensitive hypertensive strains. Accordingly, the aim of the present study was to determine whether cross-fostering is effective in lowering adult blood pressure in the salt-resistant New Zealand genetically hypertensive (GH) rat. 2. Genetically hypertensive and control normotensive (N) rat pups were reared by either their natural mothers or a foster mother of the opposite strain (NX and GHX). Blood pressure was tracked from the age of 6-18 weeks, at which time renal function was assessed using standard clearance techniques in anaesthetized rats. Renal function was also assessed in a separate group of young rats at 5-6 weeks of age. 3. Cross-fostered GHX rats had lower blood pressure than GH rats, but this difference was only apparent until 9 weeks. The NX rats had higher blood pressures than N rats, but again pressure converged at 10 weeks. Basal renal function did not differ between GH and GHX rats or between N and NX rats at either age. However, young GH rats had lower renal blood flow, glomerular filtration rate, urine output and sodium excretion than N rats. 4. These data show that cross-fostering is effective in lowering blood pressure in GH rats, albeit transiently. The kidneys do not appear to play a role, because renal function did not differ under the current experimental conditions between GH and GHX rats. However, the kidney may play a greater role in the onset of hypertension in the GH rat than previously thought.

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Effects of passive smoking on blood pressure and aortic pressure waveform in healthy young adults--influence of gender.

Mahmud A, Feely J.

Department of Pharmacology and Therapeutics, Trinity College Dublin and Hypertension Clinic, St James's Hospital, Dublin 8, Ireland.

AIMS: Passive smoking impairs the elasticity of the aorta in patients with coronary heart disease. We therefore studied the effect of passive smoking on wave reflection in the aorta, a marker of arterial stiffness, in healthy subjects. METHOD: We examined the effects of acute exposure to passive smoking on blood pressure and the aortic pressure waveform in healthy young men (n = 10) and women (n = 11), aged 26 +/- 5 years (mean +/- SEM) compared with 12 healthy controls, aged 24 +/- 2 years (six female) who were exposed to room air. The aortic pressure waveform was derived with radial applanation tonometry (SphygmoCor, AtCor Medical, version 6.2) and the augmentation index, a measure of arterial wave reflection in the aorta, calculated. Blood pressure (Omron Model HEM-705 CP, Omron Corporation, Tokyo, Japan) and augmentation index were measured at baseline, 15, 30 and 60 min after exposure to environmental tobacco smoke (carbon monoxide 25-30 p.p.m. for 60 min) or room air. RESULTS: Passive smoking was associated with an increase in brachial (124 +/- 4-137 +/- 3 mmHg, P < 0.01) and aortic systolic blood pressure (110 +/- 3-123 +/- 4 mmHg, P < 0.01) at 60 min in the male subjects only. The augmentation index increased from -1.7 +/- 5 to 14 +/- 5 at 60 min (P < 0.001) only in the male subjects. The transit time of the pulse did not change significantly. The change in augmentation index was independent of the increase in blood pressure. Brachial and aortic diastolic blood pressure and heart rate did not change significantly in either male or female subjects. No haemodynamic changes were observed in the control group. CONCLUSIONS: Acute exposure to passive smoking has a deleterious effect on the arterial pressure waveform in healthy young males but not in females, suggesting a possible protection of female gender from functional changes in arteries.

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