The inhibitor of human renin, H142, was studied in nine male volunteers. On three occasions, in random order, volunteers were infused with 5% dextrose or with H142 at 1.0 or 2.5 mg/kg per h for 30 min while supine and thereafter with dextrose for 1½ h. There was a marked reduction in plasma active renin concentration as assayed by an enzyme-kinetic method, with parallel falls in the circulating concentrations of angiotensins (ANG) I and II, all of which rebounded transiently to values above basal after the H142 infusion was stopped. In contrast, total renin concentration as measured by radio-immunoassay rose while ANG I and II fell, subsiding when H142 was discontinued. There was a slight but significant increase in plasma noradrenaline as renin became inhibited; plasma adrenaline was unchanged. H142 produced a slight fall in systolic blood pressure (SBP) and a clearer, highly significant, dose-related fall in diastolic blood pressure (DBP). There was a modest but significant increase in the heart rate. These studies confirm H142 as an effective inhibitor of human renin in vivo.
The renin inhibitor H77 and the angiotensin I converting enzyme (ACE) inhibitor captopril were compared in separate experiments with infusion of 5% dextrose as a control for the effects on plasma angiotensin II (Ang II) concentration, arterial pressure and cardiac function, measured by Swan-Ganz catheter, in conscious dogs. The effects of a high dose of H77 (10 mg/kg per h) were similar to those of high-dose captopril (6 mg/kg per h). Both reduced plasma Ang II concentration, systemic vascular resistance and arterial pressure; both increased the heart rate; both increased cardiac output but the change was significant only with captopril; neither affected stroke volume, pulmonary artery pressure or pulmonary vascular resistance; both reduced left and right atrial pressures. The similar pattern of effects for the two inhibitors suggests that the mechanism by which they act is the same--reduction in Ang II--and that the cardiovascular effects of H77 are not a specific action of the peptide that is unrelated to the reduction in plasma Ang II concentrations.
Corticosteroids are important in the regulation of normal physiology and are key factors in regulating cardiovascular physiology and disease, the development of which is known to have a genetic component. However, there is little information on the extent to which plasma and urine steroid levels are determined by familial and genetic factors. We have examined basal and ACTH-stimulated plasma steroid levels and 24-h corticosteroid metabolite excretion rates in 146 pairs of adult twins[ 75 monozygotic (MZ); 71 dizygotic (DZ)]. Intraclass correlation coefficients were measured for all variables; several plasma steroid measurements were strongly related in both (MZ) and (DZ) twins, consistent with a familial pattern. These included basal levels of 11-deoxycortisol and aldosterone. ACTH-stimulated plasma aldosterone levels were also significantly correlated, to a significant degree, in both MZ and DZ twins. The index of 11β-hydroxysteroid dehydrogenase activity (tetrahydrocortisol + allotetrahydrocortisol/tetrahydrocortisone) and of the more specific index of activity of the type 2 isoform of this enzyme (urine free cortisol/cortisone) also correlated, to a similar degree, in DZ and MZ twins. In contrast, for the basal and ACTH-stimulated plasma concentrations and 24-h urine excretion rates of several corticosteroids, there was evidence of significant heritability (H2), in that correlation in MZ twins was greater than in DZ. For example, basal plasma corticosterone concentrations (B) (H2 = 0.44), basal and stimulated 11-deoxycorticosterone concentrations (DOC) (H2 = 0.44 and 0.41, respectively), stimulated 11-deoxycortisol concentrations (H2 = 0.53), and the index of 11β-hydroxylase activity DOC/B (H2 = 0.49) were all significantly heritable. For the urinary variables, 24-h tetrahydrodeoxycortisol (H2 = 0.59) and free aldosterone (H2 = 0.56) were significantly heritable. Our data provide the first evidence that plasma and urine levels of important glucocorticoids and mineralocorticoids show a strong familial pattern, and in some instances, there is evidence of a genetic component to this. This suggests that corticosteroids have a plausible role in essential hypertension that has a similar heritable component.
The findings embodied in this thesis have been discussed in the following two sections. A. Comparative Serology The indirect fluorescent antibody test (IFA) and the enzyme-linked immunosorbent assay test (ELISA) have been investigated for their sensitivity in determining IgG antibody levels in human sera to Herpes simplex virus type 1, Coxsackievirus and Rotavirus, The results obtained have been correlated with those obtained from neutralisation or complement fixation tests in an attempt to evaluate the relevance of the antibodies detected by these serological procedures. B. Virus Antibody Profiling A novel technique for discriminating between human bloodstains has been developed and the suitability of the IFA and ELISA tests for use in this procedure has been investigated.
Background Increased activity of the sympathetic nervous system has been proposed as a cause of high blood pressure (BP) and may be related to diet and body weight. To determine the role of these factors in predisposition to high BP, we studied 100 young adults with high or low BP from families in which both parents had either high or low BP. Methods and Results Plasma catecholamine, glucose, and insulin levels were measured before and after an oral glucose load. There was a significant correlation between fasting plasma norepinephrine and mean arterial pressure ( P =.001). Subjects with high BP, irrespective of parental BP, were heavier ( P =.003) and fatter ( P =.002) and had a greater rise in plasma insulin ( P =.003) following glucose than those with low BP. Offspring with high BP whose parents also had high BP showed an unexpected rise in plasma epinephrine ( P =.004) following glucose. This adrenal medullary response was not the result of high parental or high personal BP alone as it was not seen in offspring with low BP whose parents had high BP or in offspring with high BP whose parents had low BP. Conclusions Irrespective of family history, high BP is associated with increased body weight and hyperinsulinemia and reflects personal environment and behavior. However, abnormal epinephrine release is characteristic of the combination of genetic, environmental, and behavioral factors that is associated with high personal BP and a familial predisposition to high BP.
1. Genetic analysis of five kindreds with glucocorticoid-suppressible hyperaldosteronism, four of whom had not been subjected to any previous genetic analysis, revealed three different crossover breakpoints within the five kindreds clustered in the exon 3-intron 4 region of the chimaeric gene. The site of the crossover point had no effect on blood pressure within the kindreds studied. 2. The gene causing glucocorticoid-suppressible hyperaldosteronism was in strong linkage disequilibrium with an allele of a newly described restriction enzyme polymorphism of the aldosterone synthase gene promoter region, suggesting a possible role for this allele in the development of the chimaeric gene. 3. A novel observation on subjects inheriting glucocorticoid-suppressible hyperaldosteronism from their mothers showed that they had significantly higher plasma aldosterone concentrations and mean arterial blood pressures than those inheriting glucocorticoid-suppressible hyperaldosteronism from their fathers. 4. These results raise the possibility that chronic exposure in utero to elevated plasma aldosterone concentrations may result in the permanent programming of mineralocorticoid-dependent blood pressure regulatory mechanisms, which is amplified in later life by the elevated plasma aldosterone concentrations found in glucocorticoid-suppressible hyperaldosteronism.
Glucocorticoid-suppressible hyperaldosteronism (GSH) is an uncommon form of dominantly inherited hypertension caused by the inheritence of a chimaeric 11 beta-hydroxylase/aldosterone synthase gene. Affected individuals appear to have an increased risk of premature morbidity and mortality from stroke, but treatment with low doses of dexamethasone can completely reverse the biochemical and clinical features. We assessed the clinical and genetic features of 5 British kindreds with GSH, the largest collection outwith the United States, and determined the location of the crossover regions in the chimaeric gene of all 5 kindreds. All of the kindreds were of celtic origin, another feature peculiar to GSH. In total 19 out of 60 individuals screened by genotyping were found to possess the chimaeric gene and sequencing of the chimaeric gene revealed that all the crossover regions were within the exon 3- exon 4 region of, in keeping with previous studies, and three kindreds possessed indistinguishable chimaeric genes.
OBJECTIVE Previous evidence suggests that the efficiency of 11β‐hydroxylase is at least partly heritable and also that it may be mildly impaired in essential hypertension. In both cases, assessment of activity was based on the response of 11‐deoxycorticosterone (DOC) and 11‐deoxycortisol to ACTH. The gene (CYP11B1) coding for this enzyme is highly homologous with and lies a relatively short distance downstream from the gene coding for aldosterone synthase (CYP11B2) on chromosome 8. Two polymorphisms of CYP11B2 have been described. The first involves a change of −344C to T in a putative steroidogenic factor‐1 (SF‐1) binding site and the other, the intron conversion, an exchange of intron 2 for that of CYP11B1. These polymorphisms are in linkage dysequilibrium. Their effects on 11β‐hydroxylation were studied. METHODS AND RESULTS Normal subjects ( n = 135) were genotyped and those homozygous for either or both the polymorphisms were given ACTH (250 µg, i.v.). Plasma was sampled before and 30 minutes after administration. Basal concentrations of DOC, corticosterone, 11‐deoxycortisol and cortisol and responses of corticosterone and cortisol to ACTH were not affected by genotype. However, the responses of DOC ( P = 0·002 and P = 0·001, respectively) and 11‐deoxycortisol ( P = 0·025 and P = 0·002, respectively) were significantly greater in subjects homozygous for SF‐1 T and/or intron conversion than in those homozygous for SF‐1 C and/or normal intron. CONCLUSIONS These results indicate different 11β‐hydroxylase efficiencies. Thus, variation in CYP11B2 appears to affect the product of CYP11B1. The mechanism is unclear. The close proximity of the two genes may lead to competition for transcription factors or specific differences in intron 2 may affect transcription. Alternatively, the polymorphisms may be acting as markers for adjacent functional genetic variations.
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