Severe paediatric ulcerative colitis: incidence, outcomes and optimal timing for second-line therapy.

BACKGROUND: Despite the predominance of extensive disease in children with ulcerative colitis, data concerning severe paediatric ulcerative colitis are sparse. We reviewed rates and predictors of response to intravenous-corticosteroid therapy in a single-centre cohort with long-term follow-up. METHODS: 99 children (49% males; age 2-17 years) were hospitalised (1991-2000) for treatment of severe ulcerative colitis (90% extensive; 49% new onset ulcerative colitis). Clinical, laboratory and radiographic data were reviewed. A population-based subset was used to assess incidence. Predictors of corticosteroid response were analysed using univariate and multivariate analyses at days 3 and 5 of therapy. Colectomy rates were calculated using Kaplan-Meier survival analyses. RESULTS: 28% (95% CI, 23 to 34%) of children with ulcerative colitis resident in the Greater Toronto Area required admission for intravenous corticosteroid therapy, of whom 53 (53%; 95% CI, 44 to 63%) responded. Several predictors were associated with corticosteroid failure, but in multivariable modelling only C-reactive protein [OR = 3.5 (1.4 to 8.4)] and number of nocturnal stools [OR = 3.2 (1.6 to 6.6)] remained significant at both days 3 and 5. The Pediatric Ulcerative Colitis Activity Index (PUCAI), Travis and Lindgren's indices strongly predicted non-response. Radiographically, the upper range of colonic luminal width was 40 mm in children younger than 11 years versus 60 mm in older patients. Cumulative colectomy rates at discharge, 1 year and 6 years were 42%, 58% and 61%, respectively. CONCLUSIONS: Children with ulcerative colitis commonly experience at least one severe exacerbation. Response to intravenous corticosteroids is poor. The PUCAI, determined at day 3 (>45 points) should be used to screen for patients likely to fail corticosteroids and at day 5 (>70 points) to dictate the introduction of second-line therapies.

Effect of aging on the prognostic significance of ambulatory systolic, diastolic, and pulse pressure in essential hypertension.

BACKGROUND: This study compared the relative prognostic significance of 24 hour intra-arterial ambulatory systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP) parameters in middle-aged versus elderly hypertensives. METHODS AND RESULTS: A total of 546 subjects aged <60 years and 142 subjects aged >/=60 years who had undergone baseline pretreatment 24-hour intra-arterial ambulatory blood pressure monitoring were followed for 9.2+/-4.1 years. Multivariate analysis showed that in younger subjects, 24-hour, daytime, and nighttime DBP, MAP, and SBP, when considered individually, were positively related to morbid events; DBP parameters provided the best predictive values. In the group >/=60 years (elderly group), 24-hour, daytime, and nighttime PP and SBP were the most predictive parameters, whereas ambulatory DBP and MAP measurements failed to provide any prognostic value. When 24-hour values of SBP and DBP were jointly included in the baseline model, DBP (z=2.02, P=0.04) but not SBP (z=-0.43, P=0.67) was related to outcome in younger subjects, whereas in the elderly group, SBP (z=3.33, P=0.001) was positively and DBP (z=-1.75, P=0.07) was negatively related to outcome. Clinic blood pressure measurements failed to provide any independent prognostic value in either age group. CONCLUSIONS: The relative prognostic significance of ambulatory blood pressure components depends on age; DBP parameters provided the best prognostic value in middle-aged individuals, whereas PP parameters were the most predictive in the elderly. This may reflect differing underlying hemodynamic mechanisms of hypertension in these age groups.

Prediction of coronary and cerebrovascular morbidity and mortality by direct continuous ambulatory blood pressure monitoring in essential hypertension.

BACKGROUND: The goal of this study was to assess the prognostic value of ambulatory versus clinic blood pressure measurement and to relate cardiovascular risk to ambulatory systolic and diastolic blood pressure levels. METHODS AND RESULTS: The study population consisted of 688 patients 51+/-11 years of age who had undergone pretreatment 24-hour intra-arterial ambulatory blood pressure monitoring on the basis of elevated clinic blood pressure. A total of 157 first events were recorded during a 9.2+/-4.1-year follow-up period. The predictive value of a regression model containing age, sex, race, body mass index, smoking, diabetes mellitus, fasting cholesterol level, and previous history of cardiovascular disease was significantly improved by the addition of any ambulatory systolic or diastolic blood pressure parameter (whether 24-hour, daytime, or nighttime mean) or pulse pressure, whereas inclusion of baseline clinic blood pressure variables did not enhance the prediction of events. The most predictive models contained the ambulatory systolic blood pressure parameters. In the model containing 24-hour mean ambulatory systolic blood pressure (P=0.001), age (P<0.001), male sex (P<0.001), South Asian origin (P=0.008), diabetes mellitus (P=0. 05), and previous cardiovascular disease (P<0.001) were additional independent predictors of events. Whereas 24-hour ambulatory systolic blood pressure was linearly related to the incidence of both coronary and cerebrovascular events, 24-hour ambulatory diastolic blood pressure exhibited a positive linear relationship with cerebrovascular events but a curvilinear relationship with coronary events. CONCLUSIONS: Ambulatory blood pressure is superior to clinic measurement for the assessment of cardiovascular risk; there is no reduction in coronary risk at lower levels of ambulatory diastolic blood pressure.

Continuous inhibition of 11ß-hydroxysteroid dehydrogenase type I in adipose tissue leads to tachyphylaxis in humans and rats but not in mice.

BACKGROUND AND PURPOSE: 11ß-hydroxysteroid dehydrogenase type I (11ß-HSD1), a target for Type 2 diabetes mellitus, converts inactive glucocorticoids into bioactive forms, increasing tissue concentrations. We have compared the pharmacokinetic-pharmacodynamic (PK/PD) relationship of target inhibition after acute and repeat administration of inhibitors of 11ß-HSD1 activity in human, rat and mouse adipose tissue (AT). EXPERIMENTAL APPROACH: Studies included abdominally obese human volunteers, rats and mice. Two specific 11ß-HSD1 inhibitors (AZD8329 and COMPOUND-20) were administered as single oral doses or repeat daily doses for 7-9 days. 11ß-HSD1 activity in AT was measured ex vivo by conversion of (3) H-cortisone to (3) H-cortisol. KEY RESULTS: In human and rat AT, inhibition of 11ß-HSD1 activity was lost after repeat dosing of AZD8329, compared with acute administration. Similarly, in rat AT, there was loss of inhibition of 11ß-HSD1 activity after repeat dosing with COMPOUND-20 with continuous drug cover, but effects were substantially reduced if a 'drug holiday' period was maintained daily. Inhibition of 11ß-HSD1 activity was not lost in mouse AT after continuous cover with COMPOUND-20 for 7 days. CONCLUSIONS AND IMPLICATIONS: Human and rat AT, but not mouse AT, exhibited tachyphylaxis for inhibition of 11ß-HSD1 activity after repeat dosing. Translation of observed efficacy in murine disease models to human for 11ß-HSD1 inhibitors may be misleading. Investigators of the effects of 11ß-HSD1 inhibitors should confirm that desired levels of enzyme inhibition in AT can be maintained over time after repeat dosing and not rely on results following a single dose.

Plasma renin and angiotensin II measurement in hypertensive and normal subjects: correlation of basal and stimulated states.

Plasma renin activity (PRA) and angiotensin II (AII) were measured in peripheral venous samples obtained from the following subgroups: normal ambulant subjects (n = 61): normal subjects after 7 days treatment with a thiazide diuretic (n = 27): hypertensive subjects before and after a thiazide diruretic (n = 35); severely hypertensive subjects after diazoxide treatment (n = 14) and untreated severely hypertensive subjects (n = 27). In addition aortic (n = 27) and renal vein (n =48) samples were taken from the latter group during investigation of possible renovascular hypertension. Values for PRA and AII were clearly correlated in all groups. Further, calculated regression lines of PRA upon AII did not differ significantly from that calculated for normal subjects, with the exception of the intercept of the diazoxide treated group. However, when the regression line for renal venous samples was compared with that calculated for peripheral venous samples of all other subjects (199), there was a relative increase in the ratio of PRA to AII at all values. Thus, except in the renal vein, measurement of AII and PRA appear to reflect changes in activity of the renin-angiotensin system equally well and there is no support for the view that there is a discrepancy between measured AII and PRA in peripheral venous blood in the clinical situations examined here.

Reversal of two-kidney one clip renovascular hypertension in the rat.

Attempted correction of two-kidney, one clip Goldblatt hypertension in the rat was carried out by three techniques; removal of the constricting clip, removal of the ischemic kidney, and converting enzyme blockade by oral captopril. Since duration of hypertension is said to be a critical factor, groups of rats were studied after short term (less than 6 weeks from clipping) and chronic (greater than 4 months) hypertension. Blood pressure, sodium balance, and plasma renin concentration (PRC) were followed before and after these correcting procedures. In a control group of animals, removal of a loose renal artery clip did not influence blood pressure and only caused trivial postoperative retention of sodium. Unclipping, however, normalized blood pressure in both short-term and chronic hypertension. After a major postoperative fall, blood pressure returned to somewhat elevated levels after nephrectomy in animals with chronic (but not short-term) hypertension. Sodium balance became markedly positive with the fall in blood pressure of operated hypertensive animals and was significantly correlated with the fall in blood pressure of operated hypertensive animals and was significantly correlated with the fall in blood pressure in these four groups at 7 days (r = 0.43). Captopril also produced a fall in blood pressure at 24 hours, with a positive sodium balance, although the relationship between blood pressure fall and sodium balance did not reach statistical significance (r = 0.30). The PRC was elevated in all hypertensive groups, although individual values overlapped with values from normal rats and nonhypertensive rats with a loose renal artery clip. The PRC fell to normal or subnormal values after either operative procedure and stabilized for at least 2 months independently of whether blood pressure fell or not. It is concluded that neither sodium retention nor renin hypersecretion maintains blood pressure in this model. Also, the rapidity of the blood pressure fall is not consistent with a role for vascular hypertrophy. The greater efficacy of unclipping suggests that the revascularized kidney after this procedure exerts a vasodepressor function independent of sodium excretion or the renin-angiotensin system.

Arterial wall uptake of renal renin and blood pressure control.

We have studied the contribution of circulating renin of renal origin to renin-like activity within the arterial wall and to blood pressure. Bolus injections of renin sufficient to elevate blood pressure by 44.7 mm Hg caused aortic renin to rise from 0.13 to 1.48 ng angiotensin I/100 mg/hr in nephrectomized rats. Elevation of aortic renin was still present at 6 hours, and this was associated with significant blood pressure elevation (p less than 0.05) which could be reversed by infusion of sarcosine, alanine, angiotensin II (saralasin). Prevention of the pressor effect by pretreatment with the converting enzyme inhibitor captopril did not reduce renin uptake. When kidneys were left in situ, although significant uptake of renin could be demonstrated 1 hour after injection, the increase at 3 hours was no longer significant (p greater than 0.05) and blood pressure returned to normal by 1 1/2 hours. This change in blood pressure may be related to the much more rapid clearance of circulating renin in the presence of normal kidneys or to other renal factors influencing the blood pressure response. The present studies demonstrate therefore that most of the renin-like activity within the aortic wall is derived from plasma renin and it seems probable that this component of the renin-angiotensin system plays an important role in blood pressure maintenance in the nephrectomized rats injected with renin. The relationship is less obvious in the presence of normal kidneys where additional influences may come into play.

Surgical reversal of two-kidney one clip hypertension during inhibition of the renin-angiotensin system.

Conscious rats with two-kidney one clip Goldblatt hypertension had the constricting clip removed during continuous infusion of either dextrose, saralasin, or captopril. Other dextrose-infused animals underwent removal of the ischemic kidney or a sham procedure. Direct arterial blood pressure (BP) was recorded throughout the 15-hour preoperative and subsequent 24-hour postoperative period. Rats were studied in the "early" phase (1-3 weeks duration) or "chronic" phase (greater than 4 months) of hypertension. Animals subjected to a sham procedure returned to preoperative BP values. The BP of animals unclipped or nephrectomized did not return to previous hypertensive levels. Instead, a biphasic response was seen where BP partially recovered from an operative fall and then slowly declined to normal at 24 hours; this effect occurred in both stages of hypertension. At 24 hours, removal of the ischemic kidney was as effective as removal of the constricting clip in the correction of both early and chronic phase hypertension. Rats infused with saralasin or captopril demonstrated an acute (within 2 hours) and sustained fall in BP, but not to normotensive levels. This fall was significant in all animals (p less than 0.01) apart from chronic phase rats infused with saralasin where no significant fall was seen. Although animals infused with saralasin or captopril commenced at a lower preoperative BP, the biphasic pattern of response to unclipping was identical to that of dextrose-infused unclipped rats. Thus, sustained inhibition of the renin-angiotensin system did not modify the correction of hypertension produced by removal of the constricting clip, and the response to surgical correction did not appear to be entirely mediated by changes in the activity of the renin-angiotensin system, particularly in the chronic stage. Equally, the rapidity of correction is not consistent with a role of vascular hypertrophy.

Vascular capacitance in rats subjected to chemical renal medullectomy.

Selective renal medullary destruction is produced in rats by a single injection of 2-bromoethylamine hydrobromide. The object of these studies was to investigate whether destruction of the renal medulla in normal rats would alter vascular capacitance. Conscious bromoethylamine-treated rats (n = 15) were compared with control saline-injected rats (n = 12). Mean circulatory filling pressure was measured during a brief circulatory arrest caused by inflation of a right atrial balloon. Blood volume was determined from plasma volume (iodine-125-labeled albumin) and hematocrit. Mean circulatory filling pressure was measured at resting blood volume and after rapid blood volume changes. Vascular compliance was derived from the mean circulatory filling pressure-blood volume curve. The bromoethylamine-treated rats were significantly hypertensive compared with control rats (mean arterial pressure 133 +/- 2 and 114 +/- 3 mm Hg, respectively, p less than 0.001) and had a significant tachycardia (475 +/- 8 and 443 +/- 10 beats/min, respectively, p = 0.02). Blood volume, plasma volume, hematocrit, and sodium excretion were no different. There was no significant difference in mean circulatory filling pressure (6.5 +/- 0.2 and 6.8 +/- 0.2 mm Hg, respectively, p = 0.4) or vascular compliance (3.64 +/- 0.20 and 3.53 +/- 0.12 ml/kg/mm Hg, respectively, p = 0.7). The position of the vascular pressure-volume curve was unchanged indicating no change in vascular capacity. This would suggest that the destruction of renal medullary vasodepressor mechanisms does not result in alterations in vascular capacitance.

Studies of isolated resistance vessels from offspring of essential hypertensive patients.

In order to investigate whether functional and morphological changes are present in the resistance vasculature before hypertension is established, isolated subcutaneous resistance vessels were studied from 21 young normotensive subjects with a family history of hypertension and 22 controls matched for age, sex, and weight. The vessels from the offspring of hypertensive patients displayed no morphological changes or differences in reactivity or sensitivity to the vasoconstrictor agonists norepinephrine, angiotensin II, serotonin, and vasopressin. In the presence of cocaine, however, vessels from offspring showed a significantly greater shift in sensitivity to norepinephrine, a phenomenon also observed in previous studies of vessels from hypertensive patients. The results suggest that in essential hypertension, while morphological and functional abnormalities of the resistance vasculature may develop as the blood pressure rises, a defect in neuroeffector activity is present before hypertension is established and may be a manifestation of abnormal sympathetic nervous system activity underlying the disease.

Leukocyte ionized calcium and sodium content and blood pressure in humans.

The relationship between leukocyte ionized calcium concentration, sodium content, and blood pressure was studied in normotensive subjects with (n = 17) and without (n = 21) a family history of hypertension and in untreated patients with essential hypertension (n = 22). There was a highly significant correlation between intracellular ionized calcium and mean supine blood pressure (measured on the same occasion) in normal subjects with no family history of hypertension (r = +0.73, p less than 0.01). This relationship was lost in normal subjects with a family history of hypertension, and in hypertensive patients there was a nonsignificant negative correlation between intracellular ionized calcium and blood pressure (r = +0.08 and -0.31, respectively). Intracellular ionized calcium was similar in the normotensive groups (both, 126 +/- 7 nmol/L) and slightly but nonsignificantly elevated in hypertensive patients (143 +/- 10 nmol/L; p = 0.09). There was no correlation between intracellular ionized calcium and sodium content in any group (r less than 0.1). These results indicate that while leukocyte ionized calcium in normotensive subjects with no family history of hypertension may reflect smooth muscle contractility resulting in the positive correlation between leukocyte ionized calcium and blood pressure, this relationship is lost in hypertensive patients and subjects predisposed to hypertension. This may be due to an altered relationship between leukocyte and smooth muscle calcium handling in these subjects or to non-calcium-mediated influences on blood pressure.

Effect of cold pressor test-induced stress on leukocyte sodium transport and norepinephrine.

The effects of stress on leukocyte membrane sodium efflux rate constant and plasma norepinephrine levels were studied before and during cold pressor test in normotensive subjects with and without a family history of hypertension. After 20 minutes of supine rest, no significant differences in total, ouabain-resistant or ouabain-sensitive sodium efflux rate constants were apparent between the two groups. In normotensive subjects with no family history, there was no significant change in any efflux rate constant during cold pressor test, although there was a highly significant negative correlation between change in total efflux rate constant and change in norepinephrine levels (r = -0.82, p less than 0.01, n = 12). During cold pressor test in subjects with a family history of hypertension, there was a significant rise in the ouabain-resistant efflux rate constant (1.5 +/- 0.1 vs 1.0 +/- 0.1 hr-1; p less than 0.01, n = 10); this level was also significantly higher than that in control subjects (p less than 0.002). In this group, the ouabain-sensitive efflux rate constant fell slightly but not significantly (1.8 +/- 0.2 vs 2.1 +/- 0.2 hr-1; n = 10). These results suggest that stress in the form of a cold stimulus produces qualitative differences in leukocyte cation transport in normotensive offspring of hypertensive patients as compared with subjects without such a family history.

Pulse pressure and resistance artery structure in the elderly.

There has been recent interest in the possibility that resistance vessel structural adaptation in hypertension may be more closely related to pulse pressure than to other blood pressure parameters. We investigated the relation between blood pressure and resistance vessel structure in a group of subjects from an age group (older than 60 years) in which a widening of pulse pressure is a typical finding and characterized blood pressure parameters using 24-hour ambulatory blood pressure monitoring. We studied resistance vessels retrieved from biopsies of skin and subcutaneous fat taken from the gluteal region of 32 subjects under local anesthesia (age, 70 +/- 1 years [mean +/- SEM], 21 of whom were hypertensive and 11 normotensive. Media-lumen ratio was higher in the hypertensive than the normotensive subjects (18.6 +/- 1.6% versus 12.8 +/- 1.2%, P < .01) and correlated with age (r = .44, P < .05), clinic systolic pressure (r = .35, P < .05), 24-hour systolic pressure (r = .40, P < .05), and 24-hour pulse pressure (r = .56, P < .001). Stepwise multivariate regression analysis identified clinic and 24-hour pulse pressure as the only significant predictors of media-lumen ratio independent of age, other parameters of clinic blood pressure, and blood pressure variability (R2 = 41%, P < .05). These findings confirm those from animal models of hypertension in demonstrating the importance of pulse pressure in relation to cardiovascular structural adaptation and have important implications for the goals of treatment of hypertension in the elderly.

Rat thymocyte sodium transport. Effects of changes in sodium balance and experimental hypertension.

The wide range of membrane electrolyte transport abnormalities associated with experimental, genetic, and essential hypertension may either reflect an underlying global change in the cell membrane or may be directly related to the underlying disturbance that causes hypertension or to changes in sodium balance. To investigate this further, we studied sodium transport and intracellular electrolyte composition in the thymocytes of normal rats undergoing salt loading or depletion, and in rats with renovascular, mineralocorticoid, or spontaneous hypertension compared to appropriate age-matched normotensive control rats. In normotensive rats, although there was no significant difference between the blood pressures at the two extremes of sodium balance, sodium loading caused a nonsignificant rise in sodium transport, whereas sodium depletion was associated with a significant fall in sodium transport and intracellular sodium. When cells from salt-loaded or normal animals were incubated in a medium containing their own serum, sodium transport was slightly stimulated in both, but there was no significant difference in the sodium efflux-rate constant of thymocytes obtained from rats on the normal as opposed to the high salt intake. Compared to normotensive rats, there was no significant change in the sodium efflux-rate constant in any of the hypertensive rat models studied. However, the sodium efflux-rate constant fell with age in both the spontaneously hypertensive and Wistar-Kyoto normotensive rats. The present studies show that dietary sodium intake and aging had considerable effects on rat thymocyte sodium transport, but neither of these changes was related to a change in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in leucocyte sodium transport in normotensive relatives of hypertensive subjects. Dissociation from blood pressure.

It has been postulated that depressed membrane sodium transport is a necessary step in blood pressure elevation in essential hypertension. Accordingly, leucocyte sodium efflux-rate constants were estimated in 14 normotensive subjects who had one or more first-degree relatives with essential hypertension, and also in 14 matched control subjects with no such family history, before and after taking bendrofluazide for 7 days. Efflux rates in the controls did not change after the diuretic. However, in the relatives, mean total sodium efflux-rate constant was at first significantly depressed but later rose to normal with the diuretic. This was due almost entirely to an increase in glycoside-sensitive sodium pump activity. Blood pressure remained unchanged in both groups. Thus, assuming that perturbations in leucocytes reflect similar abnormalities in other cell lines, major changes in sodium transport in the normotensive individual without accompanying changes in blood pressure suggest that, while these changes may be a marker for later hypertension, they do not participate directly in blood pressure control.

Chemical renal medullectomy. Effect on urinary prostaglandin E2 and plasma renin in response to variations in sodium intake and in relation to blood pressure.

We have studied the possible vasodepressor role of the renal medulla by chemical medullectomy. Bromoethylamine hydrobromide (200 mg/kg) was injected to induce selective renal medullary necrosis in rats. The acute effects on sodium balance and long-term effects on blood pressure, plasma renin concentration (PRC) and urinary prostaglandin E2 (PGE2) were studied and compared with saline injected controls. There was an immediate and sustained increase in urine volume of low osmolality. Direct blood pressure in conscious free-moving animals was higher at 2 and 10 weeks after injection in medullary-damaged rats, although this was only significant at 10 weeks (136 +/- 3.3 vs 118 +/- 4.5 mm Hg, p less than 0.01). An initial negative sodium balance returned to normal by 7 days and rats with established medullary damage tolerated a wide range of sodium intakes. Although there was no evidence of sodium retention on the normal diet, with very high sodium loads some sodium retention was apparent since PRC was suppressed and body weight increased. Plasma creatinine and creatinine clearance were normal. PRC in rats with medullary damage was unchanged on normal diet and rose to similar levels as in control rats on low sodium intake. Urinary PGE2 was markedly reduced (148 +/- 54 vs 536 +/- 71 ng/day, p less than 0.01) in medullary damaged rats, consistent with the renal medulla being the major source of urinary PGE2. High salt intake increased urinary PGE2 in normal and proportionally in medullary damaged rats, whereas on a low sodium intake, urinary PGE2 was not different from that on the normal diet in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence-based medicine and hypertension.

BACKGROUND: Evidence-based medicine (EBM) has been propagated as a revolutionary development which will improve the quality of clinical decision-making and guideline development Historically it follows an early 19th-century French attempt to introduce mathematical analysis into clinical practice. This met with resistance from both clinicians and scientists and was only accepted in more recent times with the development of clinical epidemiology and clinical trials. NATURE OF EBM: EMB claims to utilize the best available evidence to reach scientific conclusions, rejecting the appeal to expert authority. This involves a hierarchy of sources which places large controlled trials at the apex. Less value is attributed to arguments from clinical observation or pathophysiology. Systematic reviews and meta-analyses of trials therefore provide the strongest evidence for clinical decisions. THE CONCEPT OF EVIDENCE: The approach advocated in EBM is an over-simplification of the process of clinical thinking which involves interpretation and synthesis of relevant evidence from all sources and extrapolation to the clinical situation. In this process, there is no hierarchy of evidence. The relative value given to any particular evidence depends more upon its relevance and persuasiveness than the category to which it belongs. Discussion and debate amongst informed 'experts' is an integral feature of this process at each stage. IMPACT OF EBM: Although advocates of EBM acknowledge the contribution of all forms of evidence, the differential value attached to different sources has led to naïve and simplistic attempts to omit the traditional processes of interpretation, synthesis and extrapolation and to draw wide-ranging conclusions from trial data without adequate scientific discussion.

A major structural abnormality in the renin gene of the spontaneously hypertensive rat.

The renin genes of the spontaneously hypertensive rat (SHR) and Wistar-Kyoto (WKY) rat were compared by Southern blotting using cDNA and oligonucleotide probes. A 'deletion' of approximately 650 base pairs was found in the first intron (intron A) of the SHR gene compared with the WKY gene. Our studies strongly suggest that this is due to a decrease in the number of copies of the tandemly repeated sequence present within intron A of the rat renin gene. In both SHR and WKY, this region of the gene was found to be different from that of the parent Wistar rat and those of other Wistar-based inbred strains. The functional significance of the abnormality and any role it may have in hypertension in the SHR remain to be determined.

The effects of coarctation hypertension upon vascular inositol phospholipid hydrolysis in Wistar rats.

In order to examine the effects of imposing an acute pressure load upon vascular structure and phosphoinositide hydrolysis, aortic medial thickness, cross-sectional area, cell nuclear counts and inositol phosphate accumulation were measured in Wistar rats with experimental coarctation and sham-operated controls at 3, 9 and 20 days after surgery. Compared to sham-operated animals, rats with coarctation had significantly higher carotid artery pressures throughout the study. Below the ligature, femoral arterial pressure was significantly lower in animals with coarctation. Proximal to the coarctation, there was an increase in aortic medial cross-sectional area and medial thickness but no increase in nuclear counts, suggesting the induction of hypertrophy; statistically significant changes were present at 9 and 20 days. Distal to the ligature only small structural changes were observed indicating some atrophy had occurred. Inositol phosphate accumulation had increased slightly at 3 days in proximal aortae from ligatured rats, and was significantly raised at 9 and 20 days; no such changes were recorded below the coarctation. These data indicate that the increased load upon the proximal aorta initiates increased inositol phosphate production through local mechanisms. Whilst a causal link has not been conclusively established between phosphoinositide turnover and hypertrophy, the association between the two in these studies is consistent with the hypothesis that the induction of increased cell phosphoinositide metabolism contributes, at least in part, to the proximal aortic structural changes observed in this model.

Kidney renin mRNA levels in the early and chronic phases of two-kidney, one clip hypertension in the rat.

The effect of clipping the left renal artery on left and right kidney renin mRNA levels during the early and chronic phases of two-kidney, one clip Goldblatt hypertension in the rat was studied. Renin mRNA levels were determined using northern and dot blotting. Four weeks after clipping, renin mRNA levels were sixfold higher in the left kidney and eightfold lower in the right kidney of the Goldblatt rats compared with the left kidney of the sham-operated rats. Similar analysis at 20 weeks after clipping showed a fourfold increase in the left kidney and a 16-fold suppression in the right kidney compared with age-matched sham-operated control rats. The study demonstrates the profound changes that occur in renin gene expression in the clipped and contralateral kidneys in this model of hypertension and shows that these changes persist into the chronic phase of the hypertension.