EFFECTS OF LOSARTAN ON THE CARDIOVASCULAR SYSTEM, RENAL HAEMODYNAMICS AND FUNCTION AND LUNG LIQUID FLOW IN FETAL SHEEP

1. The angiotensin type 1 (AT₁) receptor antagonist, losartan (10 mg/kg) was infused intravenously into nine chronically catheterized fetal sheep (125–132 days gestation). Losartan reduced the fetal systolic (P < 0.01) and diastolic (P < 0.01) pressor response to 5 μg angiotensin II (AngII) i.v. from 27.4 ± 1.5 to 7.4 ± 0.9 and from 17.5 ± 1.3 to 5.4 ± 0.6 mmHg, respectively, after 1h and to 6.1 ± 0.5 and 4.4 ± 0.5 mmHg, respectively, after 2h. Maternal pressor responses to 5 μg AngII i.v. were unchanged. Fetal mean arterial pressure decreased (P < 0.05) after losartan administration, but fetal heart rate did not change. 2. Fetal haematocrit increased (P < 0.05), fetal PO₂ decreased (P < 0.01), PCO₂ did not change and pH decreased (P < 0.01), as did plasma bicarbonate levels (P < 0.01) following administration of losartan. Thus, losartan induced a fetal metabolic acidosis. 3. Fetal placental blood flow did not change following administration of losartan. In the fetal kidney, losartan caused a decrease in vascular resistance (P < 0.01) and an increase in blood flow (P < 0.05). Glomerular filtration rate decreased (P < 0.05); thus, filtration fraction decreased (P < 0.01). There was no change in the fractional reabsorption of sodium and glomerulotubular balance was maintained. Free water clearance decreased (P < 0.01) and became negative. Urine flow decreased (P < 0.01), the excretion rates of sodium, potassium and chloride did not change, but the urinary sodium:potassium ratio decreased (P < 0.05). There was a decrease in lung liquid flow (P < 0.05) following losartan. 4. It is concluded that the fetal renin-angiotensin system (RAS) is important in the maintenance of fetal arterial pressure, the regulation of fetal renal blood flow and is essential in the maintenance of fetal glomerular function. Further, these actions of AngII are mediated via functional AT₁ receptors. These effects of losartan on the fetal cardiovascular system, renal blood flow and function are similar to those observed following captopril administration. Thus, the effects of angiotensin converting enzyme (ACE) inhibition in the foetus are due to the blockade of the fetal RAS and are independent of any direct effects on bradykinin or prostaglandin levels.     

Solubility of neurofibrillary tangles and ultrastructure of paired helical filaments in sodium dodecylsulphate

Summary Temporal cortex from 14 cases of Alzheimer-type dementia and 6 cases of Down's syndrome, all selected for severe Alzheimer pathology, was homogenised in distilled water, NaOH, or sodium dodecylsulphate (SDS) containing 0.1% -mercaptoethanol. The homogenates were stained with Congo red, and the neurofibrillary tangles and plaque cores were counted under crossed-polarisation microscopy. The number of tangles and plaque cores in the water-treated extracts was not related to age, sex, postmortem interval or duration of dementia. The number of tangles after extraction in SDS or NaOH, as a percentage of tangles in water-treated extracts, was 57±25 (mean±SD) for 1% SDS, 43±17 for 5% SDS and 37±22 for 0.2 M NaOH. Plaque cores were essentially insoluble in all three agents. The percentage of tangles insoluble in 1% SDS did not correlated with age or post-mortem interval but decreased with increasing duration of dementia. Enhanced tangle solubility with increasing duration of dementia suggests that the nature of tangles changes with time; one possibility is that this reflects transformation of intracellular to extracellular tangles. Paired helical filament (PHF) length and the number of repeats per PHF were measured in electron micrographs of PHF prepared with and without treatment by 1% SDS. There was no significant multimodality of PHF length to suggest that PHF broke at regular intervals. The mean repeat length (PHF length/number of repeats) was greater for PHF isolated in the presence of 1% SDS than in its absence, showing that SDS affects ultrastructure by untwisting PHF. An untwisting process may also occur in vivo producing the straight filaments found, together with PHF, in tangles and neurites.Supported by Miss E. Buchan (to the MRC Brain Metabolism Unit) and the British Foundation for Age Research and the Wellcome Trust (to P. A. M. Eagles). S. Hussey was in receipt of an MRC Partnership Award.     

Relation of third and fourth heart sounds to blood velocity during left ventricular filling.

To investigate the relation between changes in left ventricular inflow velocity and the timing of third and fourth heart sounds, simultaneous phonocardiograms and continuous wave Doppler traces were recorded in 48 patients (aged 17-78) with heart disease and in 21 normal children. The onset of the first vibration of the third heart sound coincided with peak left ventricular inflow blood velocity to within 5 ms in all but two of the patients. The mean (SD) difference between the two events was 5 (5) ms, which did not differ significantly from zero. The relation was similar in patients with primary myocardial disease (11), and in those with valve disease (26), hypertension (five), and coronary artery disease (four). In the normal children, the mean interval was 2.5 (5) ms--not significantly different from zero. By contrast, the first deflection of the fourth heart sound consistently preceded the timing of peak atrial inflow velocity by 55 (10) ms. Agreement was much closer between the onset of atrial flow and the onset of the atrial sound (mean difference 1 (5) ms, not significantly different from zero). Gallop sounds seem to be closely related to changes in ventricular inflow velocity, and thus to the effects of forces acting on blood flow. The forces underlying the third sound seem to arise within the ventricle and are responsible for sudden deceleration of flow during rapid ventricular filling. The fourth sound, occurring at the onset of the "a" wave, is more likely to arise from dissipation of forces causing acceleration of blood flow--that is, atrial systole itself.     

Quantitative effects of speckle reduction on cross sectional echocardiographic images.

Speckle is prominent on all cross sectional echocardiograms. In order to assess its effects on image quantification, frames from a sector scanner with a six bit grey scale were stored and processed off line to identify and smooth the speckle by means of an adaptive filter based on fully developed speckle. In 14 controls, 12 patients with hypertrophic cardiomyopathy, and 12 with secondary left ventricular hypertrophy, filtering significantly reduced the standard deviation of echo intensity, which was used as a measure of the scatter of pixel amplitude, in all three groups (by 52%, 46%, and 46% respectively). The mean value of back-scattered echo intensity itself, however, was reduced by only 7%, 5%, and 8% respectively, and median values were not affected at all. Mean (SD) left ventricular cavity areas on the apical four chamber view were significantly increased from 26 (15) to 30 (17) cm2. The valve dimensions in the parasternal minor axis in 10 patients with mitral stenosis were significantly increased by 11% laterally, but were unaffected anteroposteriorly. Subjective image quality was appreciably modified: endocardial boundaries in apical views were enhanced and the septal "ground glass" appearance was lost in hypertrophic cardiomyopathy. Speckle reduction therefore greatly reduced the scatter of pixel values, with little effect on the mean regional back scattered echo amplitude. It also modified the perceived image texture. Improved boundary definition consistently increased the area estimates, particularly when these depended on lateral rather than range resolution.     

Subsynaptosomal distribution of calcium during aging and 3,4-diaminopyridine treatment

Since previous studies showed that calcium uptake by synaptosomes from rodents declines with aging [30], the subsynaptosomal distribution of calcium was determined with the disruption method of Scott et al. [37]. Calcium uptake by the mitochondrial (digitonin-resistant) and non-mitochondrial (digitonin-labile) compartments, as well as total uptake, were determined at 2, 5 and 10 min. After a 10 min incubation under resting conditions (5 mM-KCl), total calcium uptake decreased at 10 months (−14.6%) and 30 months (−33.0%) of age; mitochondrial calcium uptake increased by 10 months (+11.2%) but declined by 30 months (−17.5%); the nonmitochondrial calcium compartment declined at 10 (−34.7%) and 30 (−43.4%) months when compared to the 3 month old control. With potassium depolarization (31 mM-KCl), total calcium uptake declined from 100% (3 months) to 73.8% (10 months) or 53.0% (30 months); mitochondrial calcium uptake declined from 100% (3 months) to 85.6% (10 months) or 68.4% (30 months); non-mitochondrial calcium uptake decreased at 10 (−34.3%) and 30 (−57.7%) months of age when compared to 3 months (100%). The deficits in calcium homeostasis are not due to changes in synaptosomal volumes or to diminished membrane potentials, as assessed by tetraphenylphosphonium ion accumulation. 3,4-Diaminopyridine partially reversed the alterations in total, mitochondrial and non-mitochondrial calcium uptake by synaptosomes from aged mice.     

Analysis of the coxsackievirus B-adenovirus receptor gene in patients with myocarditis or dilated cardiomyopathy

Myocarditis and dilated cardiomyopathy (DCM) are common causes of morbidity and mortality in children and adults, most commonly due to infection with coxsackievirus B or adenovirus. Increased expression of the common human coxsackievirus B-adenovirus receptor (CAR) has been reported in patients with DCM. We investigated the CAR gene in patients with acquired or familial myocarditis/DCM for mutations/polymorphisms. Several polymorphisms or intronic substitutions, distant from the intron-exon boundaries, were identified but no mutations. Based upon these data it appears that CAR gene mutations are not a major host determinant in the development of myocarditis and DCM.     

Congenital abnormalities in a Vermont County. Detection and medical care.

A retrospective cohort study of congenital abnormalities was undertaken on all the 1813 children born in 1952 to the residents of Chittenden County, Vermont. Multiple screening procedures were utilized and included questionnaires to parents, review of hospital charts, hospital pediatric-consultant records, death certificates, hospital pathological files and agencies for crippled and retarded children. Information was obtained for 1775 of the 1813 children (89 per cent). Two hundred and thirty-eight children with 270 malformations were discovered, and the incidence of malformations was 152.1 per 1000 live births; 42.6 per cent of the defects were discovered in the perinatal period. An additional 16.3 per cent were detected between the ages of one month and one year, and 36.3 per cent were discovered initially after one year of age. An assessment of the level of professional care required for the abnormalities discovered indicated that 33.6 per cent required no care, 42.9 per cent required short-term care, and 23.5 per cent required long-term continuing care. The early discovery of congenital defects in this study was accomplished less frequently than in many prospective studies in which screening was likely to be more comprehensive and less representative of reality. The only method of improving early medical care for children handicapped by congenital defects is by serial observation of families over long periods by trained personnel.     

A twin study of ethanol metabolism

Blood alcohol measurements were obtained for 206 pairs of twins who had ingested a standard dose of alcohol (0.75 g/kg body weight) and repeat measurements were obtained for 40 of these pairs on a second occasion. The repeatability of the peak blood alcohol concentration (BAC) was 0.66, that of the rate of elimination was 0.39, and that of the time to peak BAC was 0.27. Only a small portion of the nonrepeatable variance could be explained by measurement error or drinking experience. It is concluded that short-term environmental factors exercise considerable influence on alcohol metabolism, particularly in the absorption phase. All of the repeatable variance in peak BAC and rate of elimination was due to genetic factors. Only a small proportion of any of the genetic variance could be explained by individual differences in weight, adiposity, or lung function. Likewise, these three factors were unable to account for the fact that females had higher BACs than males during both absorption and elimination.This work was supported by a grant in aid from the Australian Associated Brewers.     

Prestress Due to Dimensional Changes Caused by Demineralization: A Potential Mechanism for Microcracking in Bone

Microcracking in bone due to internal strains caused by mineralization is a possible mechanism of damage. Similar damage can be seen in other biological composites such as trees experiencing growth-related prestresses. Dimensional changes in cortical bone due to demineralization and experimental glycation were studied to test whether mineralization-related prestrains are consistent with observed microcracking patterns in bone. A microscopy technique that enables wet measurements of length and angle of milled bone specimens was used. Demineralization of bovine and human bones caused significant anisotropic changes in tissue size. Dimensional changes due to demineralization in bovine bone were prevented or reduced when collagen cross linking was increased by glycation. The dimensional changes of bone caused by demineralization are consistent with the hypothesis that mineralization-caused stresses in remodeling tissue can cause microcracks. © 2002 Biomedical Engineering Society. PAC2002: 8719Rr