Activation of angiotensin-generating systems in the developing rat kidney

The present study was designed to determine the developmental changes in intrarenal angiotensin (Ang) peptides in the rat. Kidney Ang I and II levels were threefold and sixfold higher in newborn than adult kidneys, respectively (Ang I, 678 +/- 180 versus 243 +/- 38 fmol/g, P < .01; Ang II, 667 +/- 75 versus 103 +/- 6 fmol/g, P < .001). Intrarenal Ang II levels correlated positively with the temporal changes in renin gene expression (r = .93, P < .001). However, no correlation was found between renal Ang II content and angiotensin-converting enzyme (ACE) expression during development, which prompted us to evaluate whether renal enzymes, other than renin and ACE, contribute to Ang II formation in the developing kidney. Angiotensin peptide levels were measured in newborn and adult kidney homogenates incubated with human angiotensinogen (a poor rat renin substrate) for 30 minutes at 37 degrees C. Inhibitors of aspartyl proteases and metalloproteases were ineffective in preventing the formation of Ang II in either newborn or adult kidneys. However, addition of the serine protease inhibitors soybean trypsin inhibitor and phenylmethylsulfonyl fluoride inhibited Ang II generation in the newborn kidneys only. In contrast, Ang I generation was not affected by inhibition of serine proteases in either newborn or adult kidneys. We conclude that Ang I and II synthesis is activated in the developing rat kidney. In addition to renin and ACE, the newborn rat kidney expresses serine protease activity that is capable of generating Ang II directly from angiotensinogen. This putative enzyme is induced in the newborn kidney and may cooperate with renin in the activation of Ang II synthesis during early development.     

Combination chemotherapy using intravenous nedaplatin (254-S) and intraarterial cisplatin (CDDP) with transcatheter arterial embolization (TAE) for a patient with uterine cervical cancer: a case report

1. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are important in the control of body fluid homeostasis, blood pressure (BP) regulation and vascular remodelling. The genes for these peptides may, therefore, be involved in the pathogenesis of genetic hypertension. We have previously described a quantitative trait locus (QTL) for BP in the ANP gene region on rat chromosome 5. We have now assessed the possibility that this QTL lies at the closely linked BNP locus. 2. Intra-arterial BP and heart weight were measured in 12-week-old (n = 207) and 24-week-old (n = 88) F2 rats derived from crosses between Wistar-Kyoto normotensive rats and spontaneously hypertensive rats. We designed polymerase chain reaction primers to amplify a microsatellite in the BNP gene from genomic DNA. Analysis of variance was used for cosegregation analysis. Linkage mapping and localization of QTL was performed using the Mapmaker computer package. 3. A significant correlation was found between genotype for the BNP gene and systolic BP (P < 0.001) in 12-week-old rats. The ANP gene, but not the BNP gene, was associated with systolic BP in 24 week rats. There was no segregation of heart weight with BNP genotype at 12 or 24 weeks of age. The BNP gene mapped approximately 20 cM from the ANP gene in our rat hybrids, away from the previously described QTL. There was evidence for a second BP locus near to but distinct from the BNP gene. 4. These results suggest that BP QTL are present in the natriuretic peptide gene region but that the ANP and BNP genes themselves have no major effect on BP in this cross.     

Fetal growth retardation and increased placental weight in the spontaneously hypertensive rat

Epidemiological studies have linked low birth weight and increased placental weight with increased risk of hypertension in adult life. It has been proposed that the cardiovascular changes which lead to hypertension are initiated in utero by processes associated with intrauterine growth retardation. The alternative possibility, that hypertension may result from genetic influences which also determine fetal and placental size, has had less support because birth weight is not determined genetically in humans. However, in the spontaneously hypertensive rat (SHR) essential hypertension is known to be transmitted genetically. Fetal and placental weights were, therefore, measured at Day 20 gestation in SHRs and compared with those in the normotensive Wistar Kyoto (WKY) control strain. Fetal weight (1.93 +/- 0.04 g) was significantly (P < 0.001) reduced in SHRs compared with WKY fetuses (2.23 +/- 0.01 g) but placental weight was heavier (P < 0.001) in SHRs (0.347 +/- 0.005 g) than in WKY rats (0.300 +/- 0.006 g) although litter size was not different. As expected, maternal blood pressure recorded under 1% halothane anaesthesia was higher (126 +/- 2.7 mm Hg) in SHR than WKY rats (100 +/- 2.1 mm Hg; 1 mm Hg = 133 Pa). In addition the concentration of maternal blood glucose in SHR was significantly (P < 0.001) higher (4.8 +/- 0.32 mM v. 3.7 +/- 0.11 mM) and the concentration of plasma insulin was significantly (P < 0.05) lower in SHRs (18.8 +/- 3.0 ng mL-1) than in WKY dams (29.4 +/- 3.1 ng mL-1). Thus, the data support human population studies which show an association between adult hypertension and a reduced fetal:placental weight ratio at birth. However, because hypertension in the SHR is genetically determined, these data suggest that fetal growth retardation and increased placental weight may also be determined genetically.     

HSP27 locus cosegregates with left ventricular mass independently of blood pressure

Left ventricular hypertrophy remains a significant clinical problem and a predictor of fatal outcome in hypertension. Blood pressure per se and environmental modifiers including stress affect cardiac mass. Heat shock proteins are involved in the stress response as well as in the regulation of cardiac growth and cytoprotection. The present study evaluates heat shock protein 27 as a locus marker or candidate gene of cardiac hypertrophy in hypertension. The spontaneously hypertensive rat allele of heat shock protein 27 was associated with about a 6% increase in relative left ventricular weight (P = .0112) in 30 recombinant inbred strains from crosses of Brown Norway and spontaneously hypertensive rats. In 336 F2 crosses of spontaneously hypertensive and Wistar-Kyoto rats, the hypertensive allele was dominant and cosegregated with a similar 6% increase in the ratio of left ventricular weight to body weight (P = .0058) in rats fed a normal salt diet, but its contribution to left ventricular weight decreased in rats kept on a high salt diet. The contribution of the heat shock protein 27 allele was independent of blood pressure. We suggest that heat shock protein 27 represents a candidate gene/locus marker of cardiac hypertrophy in hypertension.     

Can health care assistants replace student nurses?

Quantitative trait loci (QTLs) affecting body weight were investigated in the backcross population derived from diabetic BB/OK and spontaneously hypertensive rat (SHR). The F1 hybrids were backcrossed onto BB/OK rats, and QTL analysis was performed with the resulting backcross population on chromosomes 1, 3, 4, 10, 13 and 18. According to the stringent threshold for a lod score of 3.0, markers on chromosomes 1 and 4 were found to be linked with body weight. The QTL with a peak lod score (3.3) on chromosome 1 for a male population was located within the region flanked by loci Igf2 and D1Mgh12. On chromosome 4, linkage between the body weight and the region around the Npy locus was observed (lod score 3.1). The existence of the QTL on chromosome 4 affecting body weight was confirmed by congenic BB.LL rats, carrying chromosomal region of SHR (D4Mit6-Npy-Spr) on the genetic background of the BB/OK rat.     

The changes in plasma arginine-vasopressin in patients with essential hypertension and the correlation with patient's condition

The levels of plasma arginine-vasopressin (AVP) in 80 patients with essential hypertension were measured, and its impact on the disease and its clinical significance were studied. The results showed that: (1) The levels of plasma AVP in patients with essential hypertension were significantly higher than that in normotensive subjects (P < 0.001). It dropped to normal level after antihypertensive drugs. (2) The concentrations of plasma AVP in both hypertensive subjects and normotensive subjects were not correlated with age and sex (P < 0.05). (3) The concentration of plasma AVP in patients with essential hypertension was the highest in stage III, the lowest in stage I, and middle in stage II. (4) The levels of plasma AVP in patients with malignant hypertension were significantly higher than that in patients with benign hypertension (P < 0.05). A positive correlation was found between the levels of plasma AVP and blood pressure (r = 0.3398, P < 0.01). (5) The concentrations of plasma AVP in hypertensive subjects with ventricular hypertrophy were higher than that in hypertensive subjects with out ventricular hypertrophy (P < 0.05). (6) The concentrations of plasma AVP in hypertensive subjects with heart failure were significantly higher than that in hypertensive subjects with out heart failure (P < 0.001). The results suggest that AVP has a role in the pathogenesis of hypertension, hypertension complicated with ventricular hypertrophy and hypertension complicated with heart failure. The levels of plasma AVP may be viewed as an index of the patient's condition in hypertensive subjects.     

Effects of antihypertensive therapy on left atrial function

OBJECTIVES: To investigate left atrial (LA) function as a reservoir, as a conduit and as a booster pump in essential hypertension (EH). LA volumes were echocardiographically measured in 28 untreated hypertensive patients and in 20 control subjects. BACKGROUND: LA makes a large contribution in left ventricular filling, especially in patients with impaired diastolic function. LA function is fundamental in left ventricular filling in hypertensive patients as hypertension results in left ventricular diastolic dysfunction. METHODS: Diagnosis of EH (blood pressure > 140/90 mm Hg) was based on three repeated readings of blood pressure (BP). Patients with myocardial infarction, cardiomyopathy, valvular or congenital heart disease were excluded. Doppler diastolic early (E) and late (A) velocity of mitral inflow were measured. The following indexes were calculated: left ventricular mass index (LVMI) using the Penn convention; left ventricular stroke volume (LVSV); LA reservoir volume (LARV = LA maximal volume at mitral valve opening minus minimal volume); LA conduit volume (LACV = LVSV-LARV). Atrial systolic function was assessed by calculating the active emptying fraction (volume at onset of atrial systole minus minimal volume/volume at onset of atrial systole, the E/A ratio and the LA ejection force (0.5 rho A2 MOA, where rho = the density of blood, MOA = mitral orifice area from the parasternal short axis view). Measurements were obtained in all hypertensive patients before and after 16 weeks administration of either enalapril (10 or 20 mg) or enalapril +/- chlorthalidone (20/25 mg) once a day. RESULTS: After 16 weeks of treatment, BP was reduced significantly (from 172/110 to 137/86 mm Hg, P < 0.001). LVMI decreased significantly as well (from 141 to 123 g/m2) although it was higher compared to controls (94 g/m2, P < 0.001). LARV decreased significantly (from 35.4 to 29.3 cm3, P < 0.05) while LACV increased significantly (from 43.8 to 51.3 cm3, P < 0.05), LA active emptying fraction and E/A ratio did not change. LA ejection force decreased significantly (from 20.9 to 18.1 kdynes, P < 0.05) but it was greater than controls (16.7 kdynes, P < 0.01). There was a positive relationship of LVMI to LARV (P < 0.01) in controls (r = 0.77) which held true in hypertensive patients, before (r = 0.72) and after treatment (r = 0.69). There was a negative relationship of LVMI to LACV (P < 0.01) in controls (r = -0.65), and in hypertensive patients untreated (r = -0.74) and after treatment (r = -0.72). CONCLUSIONS: Our results showed that in hypertensive patients, LA reservoir function increases and LA conduit function decreases, while LA ejection force increases. Antihypertensive treatment with enalapril and/or thiazide, induces normalisation of the LA function in parallel to left ventricular hypertrophy regression.     

The scimitar syndrome: clinical spectrum and surgical treatment

The stretch-induced myogenic response (MR) of large-capacitance pulmonary arteries were studied in normal and pulmonary hypertensive fetuses as well as normal newborn and adult sheep. Pulmonary hypertension in the fetus was induced by ligation of the ductus arteriosus for 12 d. The MR was obtained by stretching the vessel segments in vitro from their resting diameter (no load) to the diameter at which the muscle fibers were at optimal length (Lo), and the response was measured as a percentage of force obtained after supramaximal electrical stimulation (Po). In five control and four pulmonary hypertensive fetuses, the MR was also obtained after a stretch of 140% of Lo. The pulmonary hypertensive fetal arteries had a lower stress (1.3 +/- 0.4 versus 4.0 +/- 0.5 mN/mm2; p < 0.001) and shortening capacity compared with the fetal control (5.1 +/- 1.6 versus 9.9 +/- 0.8% of Lo; p < 0.01). The MR was observed in 21% of the control and 30% of the experimental fetuses, and it was of greater magnitude in the latter (14.8 +/- 1.9 of Po versus 34.3 +/- 2.5%, respectively; p < 0.01). When stretched to 140% of Lo, the MR was also greater in the experimental (514 +/- 148% of Po) than the control fetuses (142 +/- 68; p < 0.05). Postnatally, the MR was present in 67% of the newborn and 15% of the adult pulmonary artery segments, and the response was greatest in the newborn (23.1 +/- 4.2% of Po) compared with the adult (2.3 +/- 0.8; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Suppression of transformed phenotypes of Ha-ras-transformed NIH3T3 cells by caspase-2

Cardiac hypertrophy is a common but not inevitable complication of hypertension. Variation in heart size in hypertensives may reflect independent genetic susceptibility to cardiac hypertrophy. Using an experimental genetic model, we determined the location of quantitative trait loci responsible for cardiac hypertrophy and/or hypertension. We studied 182 F2 male animals derived from a cross of the spontaneously hypertensive rat and normotensive Donryu rats. Direct mean arterial pressure (MAP) and left ventricular (LV) mass were measured at 20 weeks of age, and DNA was obtained for linkage analysis. The estimated heritability of MAP was 62% and for LV mass expressed per unit of body weight (relative LV mass) was 76%. We used 185 polymorphic markers, with an average intermarker distance of 12.3 centimorgans for a genome-wide scan in a representative subgroup of 46 animals to identify preliminary quantitative trait loci, which were then mapped in all 182 male F2 rats. Two loci showed logarithm of the odds scores of > 4.0. One on chromosome 2, Lvm-1, was linked to relative LV mass but showed no evidence of linkage to MAP. Another locus on chromosome 1, Map-1, was linked to MAP. In the same region, a locus Lvm-2 was linked with relative LV mass. These data indicate the existence of a genetic locus on chromosome 2 of the spontaneously hypertensive rat that affects relative LV mass independently of blood pressure.     

The effects of an outpatient practice guideline at a teaching hospital: a prospective pilot study

BACKGROUND: Platelet-activating factor (PAF) is a bioactive phospholipid which is a potent hypotensive agent. To investigate the role of PAF in renovascular hypertension, we determined the PAF concentration and its production level assessed by the activity of cholinephosphotransferase (CPT) in renal tissue and examined the effect of a PAF antagonist on the mean arterial pressure (MAP) in control and two-kidney with one clipped (2K1C) hypertensive rats. MATERIALS AND METHODS: The concentration of PAF and CPT in the renal medulla and cortex were determined by radioassay. Also, the effect of a PAF antagonist, CV-6209, on MAP was also examined in both 2K1C hypertensive and normal control rats. RESULTS: The PAF concentration and CPT activity were significantly higher in the medulla than in the cortex in both 2K1C hypertensive and normal control rats, and both values in the medulla were also significantly higher in the clipped kidney than in the contralateral unclipped kidney or in control rat kidneys. We also observed a significant negative correlation between the PAF concentration in the medulla, and the medulla weight in the clipped kidney of 2K1C hypertensive rats. Infusion of the PAF antagonist, CV-6209, did not affect MAP in 2K1C hypertensive rats, but was significantly increased (P < 0.05) in control rats. CONCLUSIONS: These findings suggest that PAF, whose production is induced by renal ischemia due to renal artery stenosis, plays an important role in the renomedullary vasodepressor system, but the effect of PAF as a vasodilator in the peripheral vessels is limited in 2K1C hypertension.     

Perinatal growth disturbance in the spontaneously hypertensive rat

Disproportionate fetal and placental growth are associated with the development of hypertension in the rat and human. Here we report differences in fetal, neonatal, and placental growth, and in metabolism and endocrinology, between the spontaneously hypertensive rat (SHR), a genetic model for human essential hypertension, and the control Wistar-Kyoto (WKY) strain. Gestation in SHR (23 d) was longer than in WKY by 20 h. Body weights were lower in the SHR from fetal d 16 to 20 and on postnatal d 15. However, on fetal d 22 and postnatal d 1, there was no significant difference in body weight between SHR and WKY. SHR placentas were larger than those of WKY at d 20, and by term there was a difference of 30% (p < 0.01). Other indices of disproportionate growth were hypertrophy of the fetal heart and kidney and decreased ponderal index in the SHR neonate. Blood glucose in SHR fetuses was lower than in WKY fetuses (p < 0.05), whereas blood lactate was higher (p < 0.05) and fetal hematocrit was reduced (p < 0.001). These findings suggest undernutrition and placental insufficiency may occur in SHR fetuses. Plasma IGF-II was increased on the last day of gestation in both strains, whereas IGF-I was unaltered. Fetal liver IGFBP-2 mRNA and plasma IGFBP-2 levels were reduced in SHR on fetal d 20 and 22 (p < 0.01). Differences in growth and endocrine and metabolic parameters suggest abnormal perinatal physiology in the SHR, which may influence the later development of hypertension.     

Quantitative trait loci affecting body weight and fatness from a mouse line selected for extreme high growth

Quantitative trait loci (QTL) influencing body weight were mapped by linkage analysis in crosses between a high body weight selected line (DU6) and a control line (DUKs). The two mouse lines differ in body weight by 106% and in abdominal fat weight by 100% at 42 days. They were generated from the same base population and maintained as outbred colonies. Determination of line-specific allele frequencies at microsatellite markers spanning the genome indicated significant changes between the lines on 15 autosomes and the X chromosome. To confirm these effects, a QTL analysis was performed using structured F2 pedigrees derived from crosses of a single male from DU6 with a female from DUKs. QTL significant at the genome-wide level were mapped for body weight on chromosome 11; for abdominal fat weight on chromosomes 4, 11, and 13; for abdominal fat percentage on chromosomes 3 and 4; and for the weights of liver on chromosomes 4 and 11, of kidney on chromosomes 2 and 9, and of spleen on chromosome 11. The strong effect on body weight of the QTL on chromosome 11 was confirmed in three independent pedigrees. The effect was additive and independent of sex, accounting for 21-35% of the phenotypic variance of body weight within the corresponding F2 populations. The test for multiple QTL on chromosome 11 with combined data from all pedigrees indicated the segregation of two loci separated by 36 cM influencing body weight.     

Insulin resistance and essential hypertension in Vietnamese subjects

Several epidemiological and experimental studies suggest that essential arterial hypertension is associated with hyperinsulinism and insulin resistance in obese subjects and also in subjects with normal body weight. Undernutrition remains frequent in adult Vietnamese people and mean body mass index is around 18.5 kg/m2 in Vietnam. The aim of this study was to look for insulin resistance in hypertensive Vietnamese subjects, despite a markedly lower BMI in Vietnam than in occidental countries. One hundred and eight hypertensive patients (51 men and 57 women) over 40 years (mean = 65.4 years) were compared with 36 healthy subjects (23 men and 13 women) over 40 years (mean = 63.8 years). Hypertensive patients had significantly higher BMI (20.5 +/- 0.3 (SEM) kg/m2 vs 18.4 +/- 0.4 kg/m2; p < 0.01), thicker triceps skinfold (1.26 +/- 0.07 cm vs 0.71 +/- 0.07 cm; p < 0.001) and not significantly different waist/hip ratio (0.88 +/- 0.01 vs 0.85 +/- 0.01). Blood glucose at fasting and 2 hours after 75 g glucose taken orally were similar in hypertensive and normotensive subjects. Plasma insulin at fasting and 2 hours after glucose were significantly higher in hypertensive patients (44.4 +/- 5.1 pmol/L vs 21.6 +/- 3.2 pmol/L; p < 0.05 and 271.1 +/- 21.6 pmol/L vs 139.1 +/- 15.2 pmol/L; p < 0.001). Thus, despite under-nutrition, hypertensive Vietnamese patients have a moderate but significant increase in BMI and fat mass without predominant abdominal localization, and a state of insulin-resistance, compared with normotensive healthy subjects.     

Balloon valvuloplasty for the treatment of pulmonary stenosis in dogs

OBJECTIVE: To measure the effect of hypertension on neointima formation after balloon injury of rat aorta and its association with the local angiotensin converting enzyme (ACE) concentration. Balloon angioplasty of the thoracic aorta using a 2 French Fogarty catheter was performed in spontaneously hypertensive rats (SHR) and normotensive Sprague-Dawley (SD) rats. RESULTS: The injured aortic wall of SHR had already significantly higher ACE concentrations than did the uninjured aortic wall of normotensive SD rats (media: 729 +/- 37 dpm/mm2 in SHR versus 496 +/- 38 dpm/mm2 in SD rats, P < 0.01; intima: 83 +/- 5 dpm/mm2 versus 68 +/- 6 dpm/mm2 in SD rats, P < 0.01). Fourteen days after injury of the aorta the hypertensive rats had significantly higher neointima: media ratios than did the normotensive rats (0.83 +/- 0.09 versus 068 +/- 0.01, P < 0.01). This was associated with a significant increase in vascular media and neointima ACE concentrations in SHR (media 965 +/- 25 dpm/mm2, neointima 614 +/- 48 dpm/mm2) compared with those in normotensive SD rats after balloon angioplasty (media 669 +/- 23 dpm/mm2, neointima 287 +/- 33 dpm/mm2, P < 0.01). ACE inhibitor treatment with 10 mg/kg body weight lisinopril daily for 14 days by gavage reduced neointima proliferation in hypertensive and normotensive rats (neointima: media ratio: 0.35 +/- 0.02 for SHR, P < 0.01, versus untreated SHR with balloon injury; 0.28 +/- 0.01 for SD, P < 0.01, versus untreated SD rats with balloon injury). This was associated with significant vascular media ACE inhibition (SHR 149 +/- 9 dpm/mm2; SD rats 118 +/- 7 dpm/mm2; P < 0.01 versus untreated controls with balloon injury) and neointima ACE inhibition (SHR 73 +/- 4 dpm/mm2, SD rats 63 +/- 7 dpm/mm2, P < 0.01, versus untreated controls with balloon injury), but also lowered the blood pressure in SHR significantly (to 148 +/- 5 mmHg, P < 0.01, versus untreated SHR with balloon injury). When this drop in blood pressure was prevented by feeding the rats a high-salt diet (SHR with ACE inhibitor plus high salt-diet group blood pressure 193 +/- 3 mmHg, P = 0.57, versus untreated SHR) hypertension per se without the local ACE increase (ACE concentration in SHR with ACE inhibitor high-salt diet rats' media 167 +/- 10 dpm/mm2 and neointima 81 +/- 9 dpm/mm2) had only a mild effect on neointima formation after balloon angioplasty (neointima: media ratio 0.4 +/- 0.01 for SHR with ACE inhibitor plus high-salt diet versus 0.35 +/- 0.02 for SHR with ACE inhibitor plus normal-salt diet P < 0.05). Treatment with 10 mg/kg body weight angiotensin II subtype 1 receptor antagonist losartan potassium daily for 14 days by gavage was associated with a reduction in neointima formation similar to that observed with the ACE inhibitor both for SHR and for SD rats (neointima: media ratio 0.32 +/- 0.04 for SHR with losartan, 0.27 +/- 0.03 for SD rats with losartan; P < 0.01, versus untreated controls with balloon injury) suggesting that ACE inhibitor prevented neointima formation, at least in part by, reducing the local production of angiotensin II. CONCLUSION: Neointima formation after balloon angioplasty in SHR is increased compared with that in normotensive SD rats. This is due mainly to there being a higher degree of activation of the renin-angiotensin system in the aorta of the SHR before and after balloon injury compared with that in normotensive SD rats measured in terms of the increased vascular ACE concentrations. Blood pressure alone had only a moderate effect on neointima formation.     

Changes in cerebrospinal fluid and cerebrovascular endothelin concentrations during hypotension and hypertension in newborn piglets with induced sterile meningitis

The effects of sterile meningitis on endothelin-1 (ET-1) and big ET-1 concentrations during hypotension and hypertension were studied in the cerebrospinal fluid and plasma of newborn piglets. Cerebrospinal fluid was obtained via cisterna magna puncture, and blood was obtained from the sagittal sinus vein and left subclavian artery. The study group consisted of 14 newborn piglets injected with 0.5 mL heat-killed group B streptococcus (GBS) (10(9) colony forming unit (cfu) equivalents), into the right cerebral lateral ventricle; the control group consisted of 10 newborn piglets injected with sterile normal saline, in a similar fashion. Hypotension (mean arterial blood pressure (MABP) 20-59 mmHg; 1 mmHg = 133.3 Pa) and hypertension (MABP 110-140 mmHg) were induced 1.5-2 h apart in random sequence in each animal, by inflating balloon-tipped catheters placed at the aortic root and descending aorta, respectively. Cerebral blood flow (CBF) was measured using radiolabeled microspheres, 15 min before and after injection of GBS or saline (normotension), during the hypotension and hypertension episodes, and during recovery normotension, immediately prior to cerebrospinal fluid and blood sampling. ET-1 and big ET-1 concentrations (pg/mL) were measured using radioimmunoassay kits. The combined effect of induced sterile meningitis and induced hypotension resulted in a significant rise in the concentration of cerebrospinal fluid ET-1 (control, 5.1 +/- 0.1; GBS, 9.3 +/- 0.2 pg/mL; p < 0.01), cerebrospinal fluid big ET-1 (control, 0; GBS, 18.1 +/- 2.7 pg/mL; p < 0.01), and sagittal sinus (cerebrovascular) big ET-1 (control, 15.5 +/- 4.2; GBS, 47.5 +/- 9.6 pg/mL; p < 0.01). In contrast, the combined effect of induced sterile meningitis and induced hypertension resulted in a marked elevation in cerebrovascular ET-1 concentrations (control, 9.5 +/- 0.9; GBS, 28.5 +/- 6.1 pg/mL; p < 0.01), with no significant change in cerebrospinal fluid concentrations. In addition, cerebrovascular production of ET-1 increased dramatically during hypertension in the GBS group (control, 0; GBS, 161.7 +/- 13.2 pg.min-1.100 g-1; p < 0.001), and was maintained during the recovery period (133.7 +/- 10.8 pg.min-1.100 g-1). Cerebrovascular ET-1 concentrations correlated significantly with total CBF and MABP in both groups of animals (control, r = 0.49, p < 0.002; GBS, r = 0.64, p < 0.0001), but the response was of a much greater magnitude in the GBS group. There was an inverse relationship between cerebrovascular big ET-1 concentrations and total CBF (r = -0.53, p < 0.0001) and MABP (r = -0.71, p < 0.0001) in the GBS group. In the MABP range of 60-110 mmHg a positive relationship was observed between cerebrovascular ET-1 concentrations and cerebral vascular resistance, in the control group only (r = 0.59, p < 0.002). The combined insult of induced sterile meningitis and induced hypotension or hypertension may be associated with increased cerebrovascular ET-1 and (or) big ET-1 concentrations. Changes in these vasoactive agents may contribute to pressure passivity of CBF in the newborn with meningitis.     

Congenic strain confirms putative quantitative trait locus for body weight in the rat

Quantitative trait loci (QTLs) affecting body weight were investigated in the backcross population derived from non-diabetic BB/OK and spontaneously hypertensive rat (SHR) strains. The F1 hybrids were backcrossed onto SHR rats, and QTL analysis was performed separately with the resulting backcross populations for each sex on Chromosomes (Chrs) 1, 3, 4, 10, 13, and 18. The body weight was determined at the age of 14 weeks, and the statistical analysis was performed with MAPMAKER/QTL 1.1b computer program. According to the stringent threshold for a lod score of 3.0, markers on Chr 1 were found to be linked with body weight. The QTL with a peak lod score (5.1) on Chr 1 for a male population was located within markers Igf2 and D1Mgh12. In contrast, in the female population the body weight affecting QTL (lod = 5.7) on Chr 1 was located between the D1Mit3 and Lsn markers. The existence of QTLs on Chr 1 affecting body weight in the male population was confirmed by congenic BB.Sa rats, carrying chromosomal region of SHR (Sa-Igf2) on the genetic background of BB rat.     

Left ventricular concentric remodelling and carotid structural changes in essential hypertension

AIM: Left ventricular concentric remodelling defines a modified left ventricular geometry in the presence of a normal left ventricular mass; it is an early and frequent adaptation in arterial hypertension. The present study was designed to evaluate the extent of carotid structural changes in essential hypertensives with left ventricular remodelling. PATIENTS AND METHODS: Two groups of hypertensive patients, who had never previously received anti-hypertensive treatment, 14 with left ventricular concentric remodelling (group I, relative wall thickness 0.48 +/- 0.02) and 48 with normal left ventricular geometry (group II, relative wall thickness 0.37 +/- 0.04) underwent clinical and laboratory examination, echocardiography, carotid artery ultrasonography and 24 h ambulatory blood pressure monitoring (ABPM). The left ventricular dimensions and mass were obtained according to the Penn convention. The intima-media thickness (IMT) of the posterior wall of both common carotid arteries was measured 5, 10 and 20 mm caudally to the bulb and the average value was used for analysis. RESULTS: In both groups age (group I 44 +/- 9 years; group II 40 +/- 9 years), body surface area (group I 1.85 +/- 0.2 m2; group II 1.80 +/- 0.2 m2), duration of hypertension (group I 4.4 +/- 4; group II 3.8 +/- 3.9 years), metabolic parameters and smoking habits were similar. Both clinic and 24 h ABPM values were higher in group I (clinic 157 +/- 12/102 +/- 5; 24 h ABPM 145 +/- 10/95 +/- 7 mmHg) than they were in group II (clinic 146 +/- 11/97 +/- 5; 24 h ABPM = 134 +/- 10/87 +/- 8 mmHg, P < 0.01). The left ventricular mass index (LVMI) and IMT were found to be slightly but significantly greater in group I than they were in group II (LVMI 106 +/- 7 versus 98 +/- 12 g/m2, P < 0.05; IMT 0.68 +/- 0.13 versus 0.61 +/- 0.10 mm, P < 0.05). A significant correlation was found between LVMI and common carotid IMT in the whole group of hypertensive patients (r = 0.43, P < 0.01). CONCLUSIONS: Our results indicate that left ventricular concentric remodelling does not represent the only early cardiovascular change in arterial hypertension but rather is associated often with carotid intima-media thickening.     

Concomitant chemoradiotherapy for incompletely resected supratentorial low-grade astrocytoma in children: preliminary report

Interval mapping was used to identify putative quantitative trait loci (QTL) for blood pressure and cardiac mass on Chromosome (Chr) 3 in F1(S x R) x S population of 150 rats raised on an 8% NaCl diet. Two genetic markers 95.7 cM apart, D3Wox3 and D3Mco5 (tightly linked to Edn3), showed "suggestive" linkage to blood pressure (LOD = 2.0 and 1.8 respectively). In addition, D3Wox3 showed "suggestive" linkage to heart weight (LOD = 2.5), and D3Mco5 showed "suggestive" linkage to body weight-adjusted heart weight (LOD = 2.1). Congenic rats (designated S.R-Edn3) were constructed by introgressing the R-rat Edn3 allele (and flanking loci) into the S strain. On a 2% NaCl diet, S.R-Edn3 rats had lower blood pressure (21.4 mm Hg, P = 0. 0005) and heart weight (59 mg, P = 0.0038) compared with S rats, confirming the existence of a blood pressure QTL on Chr 3 near Edn3 even though QTL linkage analysis of blood pressure did not achieve stringent statistical criteria for significance. The results of the congenic experiment and the large distance between the two putative QTL suggest the presence of at least two independent blood pressure/cardiac mass QTL detectable on Chr 3 in the Dahl rat model of genetic hypertension.     

Polymorphism of gamma-adducin gene in genetic hypertension and mapping of the gene to rat chromosome 1q55

Adducin (ADD) is a heterodimeric protein involved in cellular signal transduction. A mutation in the alpha subunit affects ion transport and blood pressure in primary hypertension of Milan rats (MHS) and humans. In rats this effect is modulated by another mutation in the beta subunit. The recently described gamma subunit is a new member of the ADD family that should take the place of beta subunit in cells and tissues expressing alpha but not beta-Add. A missense mutation (Q572K) has been found in the gamma subunit of the Milan rats. Nineteen normotensive and five hypertensive inbred rat strains were genotyped for the polymorphisms in alpha, beta and gamma-Add genes. A disequilibrium was evident in the distribution of MHS-like Add genotype, being more frequent between the hypertensive than the normotensive strains (Chi-Square = 13.03, p = 0.0003). In kidney, brain, spleen, liver and heart a cDNA differing from gamma subunit by an in-frame insertion of 96 nucleotides, was found by PCR amplification and confirmed by RNase protection analysis. The rat gamma-Add gene was localized to chromosome 1q55 by fluorescence in situ hybridization.