Glomerular hyperfiltration, high renin, and low- extracellular volume in high blood pressure.

Abnormal renovascular resistance and glomerular filtration rate are characteristic of established hypertension and may also be involved in its pathogenesis. To determine renal and body fluid correlates of the predisposition to high blood pressure, we examined 100 healthy young adults with high or low blood pressure. Within each group, half had parents with high blood pressures, and half had parents with low blood pressures. Renal function and hemodynamics, body fluid volumes, and relevant hormones and genotypes were measured. Subjects with high personal and parental blood pressures had the highest levels of glomerular filtration rate (P<0.02) and plasma active renin concentration and low levels of exchangeable sodium and plasma volume (P<0.02). High glomerular filtration rate was not associated with differences in urinary kallikrein or prostaglandins. Polymorphisms of the renin, angiotensin-converting enzyme, and angiotensinogen genes were not associated with differences in glomerular filtration rate or renin. Subjects with high personal, but low parental, blood pressures had low exchangeable sodium and plasma volumes (P<0.02) but normal glomerular filtration rates. In this population, extracellular volume depletion and high renin are correlates of high blood pressure in early adulthood, and glomerular hyperfiltration is a feature of those who also have familial predisposition to high blood pressure.

Human alpha-adducin gene, blood pressure, and sodium metabolism.

The adducin genes contribute significantly to population variation in rat blood pressure and cell membrane sodium transport. The 460Trp mutation of the human alpha-adducin gene has been associated with hypertension, in particular hypertension sensitive to sodium restriction. We studied the relationship between the 460Trp mutation and population variation in blood pressure and sodium metabolism. From 603 Scottish families, we selected 151 offspring and 224 parents with blood pressures in either the upper (high) or bottom (low) 30% of the population distribution and measured the 460Trp mutation using allele-specific hybridization. In offspring, we also measured exchangeable sodium, plasma volume, and total body water. Plasma levels of components of the renin-angiotensin system, atrial natriuretic peptide, and cellular sodium and transmembrane sodium efflux were also estimated. The overall frequency of the 460Trp mutation was 27.1%. In offspring and parent groups, we found no difference in the genotype or allele frequencies of the 460Trp mutation between subjects with high or low blood pressure. There was no overall association between the alpha-adducin genotypes and blood pressure variation. In offspring, the 460Trp mutation was not associated with any significant differences in body fluid volumes or exchangeable sodium; levels of plasma renin, angiotensin II, aldosterone, or atrial natriuretic peptide; intracellular sodium; or ouabain-sensitive transmembrane sodium efflux. These findings suggest that in our Scottish population, the alpha-adducin 460Trp polymorphism is not related to blood pressure and does not affect whole body or cellular sodium metabolism.

Angiotensin II type 1 receptor gene polymorphism is associated with increase of left ventricular mass but not with hypertension.

A genetic epidemiologic approach is useful to elucidate the genes responsible for hypertension. Genetic analyses of the components of the renin-angiotensin system have succeeded in showing an association between their polymorphism and hypertension. Recently, two types of angiotensin II receptor were cloned and characterized. To examine the genetic contribution of angiotensin II type 1 receptor (AT1) and type 2 receptor (AT2) genes in human essential hypertension, a case-control study was performed in Japanese subjects. The study comprised 321 subjects with hypertension who satisfied the criteria for essential hypertension, together with 215 age and sex matched controls. The significance of the differences in genotype distribution between hypertensive and normotensive subjects was examined by chi2 analysis. Neither AT1 nor AT2 gene variants were associated with human essential hypertension in the Japanese subjects. However, the AT1 receptor gene polymorphism was associated with left ventricular mass index in normotensive subjects. The study results suggest that gene polymorphisms of both angiotensin II receptors are not directly involved in the increase of genetic risk for hypertension, but that the AT1 receptor gene might contribute genetically to the increase of left ventricular mass.

Upregulation of angiotensin-converting enzyme during the healing process after injury at the site of percutaneous transluminal coronary angioplasty in humans.

BACKGROUND: Balloon injury models in rat have shown enhanced expression of ACE in the developing neointima. However, neointimal lesions in human coronary arteries are complex due to atherosclerosis and different types of wall laceration. This study was designed to investigate whether ACE is present in the neointima of humans, including patients with restenosis after percutaneous transluminal coronary angioplasty (PTCA). METHODS AND RESULTS: Thirty-seven sites with angioplasty injury, obtained at autopsy, were studied using immunocytochemical techniques. Sites with injury limited to a fibrous plaque and those with injury extending into the media (<2 months after PTCA) showed fibrocellular repair tissue composed mainly of smooth muscle cells that were distinctly positive for ACE. In cellular reactions at the site of injury limited to the atheromatous plaque (<2 months after PTCA), the expression of ACE appeared first in accumulated macrophages; once smooth muscle cells appeared in the repair tissue, they also expressed ACE. At a later stage (3 months after PTCA), the number of cells with ACE expression decreased markedly; from 7 months on, ACE was no longer expressed within the repair tissue. Basically, there were no differences with regard to ACE expression during the healing process after PTCA between segments with and those without angiographic evidence of restenosis. CONCLUSIONS: These results show that PTCA injury in humans results in upregulation of ACE at sites of active repair and, therefore, ACE could play an important role as one of the mediators of the healing process after PTCA.

Absence of genetic linkage of chromosome 5q31 with asthma and atopy in the general population.

BACKGROUND: Clinical asthma is associated with increased serum total immunoglobulin E (IgE), atopy (skin prick test positivity to common aeroallergens), and bronchial hyperreactivity (BHR) to non-specific stimuli (positive methacholine challenge test). A region on chromosome 5q31-33 has been linked with increased total serum IgE and BHR. A study of the genetic linkage of this region with clinical asthma and atopy was therefore undertaken. METHODS: A polymorphic microsatellite marker in chromosome 5q31 (D5S399) was studied in 119 sibling pairs recruited from the general population who shared asthma, atopy, and/or BHR. Based on our population distribution of 13 different alleles, it was expected that by chance alone sibling pairs would share on average 1.24 alleles and that a significant excess would indicate genetic linkage. RESULTS: No evidence of linkage was found in 45 siblings concordant for asthma (shared alleles = 1.09, p = 0.95), in 103 sibling pairs with atopy (shared alleles = 1.18, p = 0.82), in 51 sibling pairs with BHR (shared alleles = 1.22, p = 0.62), or in 68 sibling pairs who shared atopy in the absence of BHR (shared alleles = 1.22, p = 0.61). A slight non-significant excess of shared alleles (1.44, p = 0.11) was observed in siblings who shared BHR without atopy. CONCLUSIONS: No evidence of genetic linkage of chromosome 5q31 with either clinical asthma or atopy was therefore detected in the population studied. Linkage between chromosome 5q and BHR needs further investigation.

Predominance of nocturnal sympathetic nervous activity in salt-sensitive normotensive subjects.

To assess the relation between salt sensitivity and autonomic nervous function by power spectral analysis of heart rate variability in normotensive subjects, low and high salt diets were given to 13 normotensive men (aged 25 to 39 years) for 4 days each. Autonomic function was assessed by power spectral analysis of R-R intervals based on an autoregressive algorithm from 24-h Holter electrocardiogram. Subjects whose mean blood pressure was increased more than 3 mm Hg by high salt diet were defined as salt sensitive (SS, n = 5), and the remainder as salt resistant (SR, n = 8). Using the low frequency (LF, 0.1 Hz) and high frequency (HF, 0.25 Hz) components, the LF to total power ratio (%LF) was used as a marker of sympathetic activity, and the HF to total power ratio (%HF) as a marker of parasympathetic activity. Compared to the daytime, SR revealed a decrease in %LF and an increase in %HF during the night on both diets. In SS, these circadian changes were observed only during low-salt diet. During the night, SS showed a higher %LF and a lower %HF than SR. Plasma catecholamines tended to be decreased by the high sodium diet in SR but not in SS subjects. These results suggest that the persistent nocturnal predominance of sympathetic nervous activity in a salt-sensitive men may contribute to the subsequent increase of blood pressure in these subjects.

Links between hypertension and myocardial infarction.

The mechanisms through which hypertension contributes to the occurrence of myocardial infarction should be discussed from two points of view: (1) common risk factors for the two diseases, such as genetic risk, insulin resistance, sympathetic hyperactivity, and vasoactive substances such as angiotensin K, and (2) linking factors that are induced by hypertension and contribute to the development of atherosclerosis and myocardial infarction, such as atherosclerosis and left ventricular hypertrophy. Mechanical stress on blood vessels because of high blood pressure is an especially important factor in endothelial dysfunction, the progression of atherosclerosis, and plaque rupture. This article concentrates on these factors from the perspective of their relationship with the renin-angiotensin system, because recent multicenter trials have demonstrated that angiotensin-converting enzyme inhibitors are effective for preventing recurrence of myocardial infarction.

Enhanced predictability of myocardial infarction in Japanese by combined genotype analysis.

To explore the genes responsible for myocardial infarction and restenosis after percutaneous transluminal coronary angioplasty, we performed association studies of the polymorphisms of the angiotensinogen and angiotensin-converting enzyme (ACE) genes. In the first study, normotensive myocardial infarction patients (n = 103) and control subjects (n = 103), who were matched for established risk factors with the myocardial infarction patients, were randomly selected. The angiotensinogen-TT genotype (T indicates threonine instead of methionine at position 235) was more frequent in the myocardial infarction group than in the control group (P < .05). The ACE-DD genotype (D indicates a deletion polymorphism in intron 16) was also more frequent in the myocardial infarction group (P < .0001). The odds ratio estimated by the combined analysis of the angiotensinogen-TT and ACE-DD genotypes (11.2) was markedly increased compared with that estimated separately from the angiotensinogen-TT (1.75) or ACE-DD (4.43) genotype. In the second study, we investigated 91 consecutive patients with acute myocardial infarction who underwent successful direct angioplasty. Combined analysis showed that the angiotensinogen-TT genotype did not enhance the predictability of myocardial infarction from the ACE-DD genotype. In conclusion, the angiotensinogen-TT genotype is a predictor for myocardial infarction, as well as the ACE-DD genotype, and the combined analysis of the angiotensinogen-TT and ACE-DD genotypes further enhanced the predictability of myocardial infarction in Japanese, suggesting its future clinical usefulness.

Association analysis of a polymorphism of the angiotensinogen gene with essential hypertension in Japanese.

An association study of the polymorphism of the angiotensinogen gene, consisting of T-->C transition at nucleotide 704 in exon 2, with essential hypertension in the Japanese population was performed by restriction fragment length polymorphism (RFLP). The allele which contained the Tth 111-I restriction site in the presence of C transition was designated 'a' and the allele that lacked restriction site was designated 'A'. The frequency of aa genotype in our normotensive group was higher than the previously reported values in Caucasians. In spite of the high frequency of the aa genotype in Japanese, the aa genotype was significantly more frequent in 108 hypertensives than in 104 normotensive subjects compared with the two other genotypes (P = 0.009). These results suggested that this molecular variant of the angiotensinogen gene may be a preserved inherited predisposition for essential hypertension in various ethnic groups, including Caucasians and Japanese.

The effects of central administration of angiotensin II type-1 receptor antagonist, CV-11974, in nephrectomized spontaneously hypertensive rats.

1. The role of the brain renin-angiotensin system in the pathogenesis of genetic hypertension was evaluated using a specific non-peptide angiotensin II type-1 receptor antagonist, TCV-116. 2. CV-11974 (active metabolite of TCV-116) was acutely injected either intravenously (i.v.) or intracerebroventricularly (i.c.v) in male spontaneously hypertensive rats (SHR; 12 week old). In separate groups of nephrectomized and sham-operated SHR, graded doses of CV-11974 were administered either i.v. or i.c.v. for 2 days using an osmotic minipump. In another group, the effects of nephrectomy on the depressor effect of chronic treatment with CV-11974 were investigated. Haemodynamics at three points: before infusion, before nephrectomy and 48 h after nephrectomy, were monitored. 3. Acute i.c.v. injection of CV-11974 decreased blood pressure in the presence of the kidney. Prolonged i.c.v. administration of the drug for 2 days decreased blood pressure even at the lowest dosage, which had no hypotensive effects when given i.v. The hypotensive effect of centrally administered CV-11974 was noted even 48 h after bilateral nephrectomy. 4. These results suggest that the brain renin-angiotensin system has a primary role in the maintenance of hypertension after eliminating the circulating renin-angiotensin system in SHR.

Association analysis of a polymorphism of the angiotensin converting enzyme gene with essential hypertension in the Japanese population.

An association study of the insertion/deletion (I/D) polymorphism located in intron 16 of the ACE gene with essential hypertension in the Japanese population was performed. The 287 bp I/D polymorphism was detected by polymerase chain reaction. Derived allele frequencies for insertion and deletion were not significantly different between 133 hypertensive and 104 normotensive subjects. A significant relationship between I/D polymorphism and plasma ACE activity was observed in the normotensive group, but not in hypertensives. These results suggest that I/D polymorphism of the gene is not implicated in Japanese hypertensive subjects, and that studies involving various ethnic groups are important.

Analysis of the apolipoprotein B3' hypervariable region in patients with essential hypertension.

1. The typing of the apolipoprotein B 3' hypervariable region was investigated in hypertensive and normotensive subjects using rapid typing of a variable number of tandemly repeated short DNA sequences (VNTR) by the polymerase chain reaction. 2. In the DNA samples of 89 normotensive and 99 hypertensive patients, 13 different-sized alleles were detected. The most frequent allele has 35 repeat units in both groups with frequencies of 0.624 and 0.596 in normotensive and hypertensive patients, respectively. Frequency distribution of 13 alleles was similar in both groups. 3. These results demonstrate no association between the apolipoprotein B gene polymorphism and essential hypertension.

[Case report of a patient with pseudohypoparathyroidism associated with slight increase in serum level of unconjugated bilirubin].

We treated a 29-year-old male patient with pseudohypoparathyroidism type I, who showed a slight increase in serum indirect bilirubin without any signs of liver dysfunction. Serum levels of total, direct and indirect bilirubins were 2.4, 0.7 and 1.7mg/dl, respectively (normal ranges: 0.2-0.8, 0-0.2 and 0.2-0.6mg/dl, respectively). The cause of the increases in serum bilirubin levels was not clear; however, hemolytic anemia, hereditary unconjugated hyperbilirubinemia or ineffective erythropoiesis were ruled out as causes for the increase, since 1) his serum level of haptoglobin was normal, 2) increase in serum level of indirect bilirubin 120 minutes after the infusion of 50mg nicotinic acid was within the normal range, and 3) severe anemia was not observed. Osmotic fragility of his circulating red blood cells was also within normal range. Three other patients with pseudohypoparathyroidism visiting our clinic also showed slightly high levels of serum indirect bilirubin, although four outpatients with idiopathic hypoparathyroidism showed no such abnormality. Abnormality in the responsiveness to parathyroid hormone and/or to that in the cyclic AMP productivity in this disease may cause the increase in the circulating unconjugated bilirubin.