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S B Harrap

Publications and source records attributed to S B Harrap.

84 records · Page 5Linked to original sources
PubMed1988

Causes and effects of high blood pressure: a longitudinal approach to genetic cosegregational analysis.

Numerous biochemical and physiological phenotypic differences exist between genetically normotensive and hypertensive rats. Only some of these differences, however, are likely to be related to the primary mechanisms causing high blood pressure. Others, and perhaps the majority, will be the result of either the secondary effects of hypertension or the result of incidental genetic differences between the strains that bear no relationship to the difference in blood pressure. Cosegregational analysis by cross-breeding normotensive and hypertensive strains permits the identification of phenotypes that are genetically linked to high blood pressure. However, cosegregational analyses are still prone to the confounding effects of hypertension per se, which can obscure important phenotypic traits and might even mimic Mendelian inheritance of phenotypes by producing qualitative shifts in gene expression. This paper discusses a longitudinal approach to genetic analysis designed to increase the sensitivity with which primary causes of high blood pressure are identified, by beginning the analysis during the development of high blood pressure. At this stage, phenotypic abnormalities causing blood pressure to rise are most likely to be present, and the blood pressure elevation is small so that the confounding effects of elevated arterial pressure are minimized.

Animals↗
PubMed1986

Pressor sensitivity to angiotensin I and angiotensin II during the development of experimental renal hypertension in the rat.

Treatment with the potent angiotensin converting enzyme inhibitor perindopril completely prevented any rise in blood pressure in the 2-kidney, 1-clip (2K1C) model of renal hypertension in rats. Withdrawal of this inhibitor was followed by a slow rise in blood pressure. In 2K1C rats treated with perindopril, pressor responses to angiotensin I fell during the treatment period, but returned to normal after the inhibitor was stopped. Pressor responses to angiotensin II (AII) increased during treatment with perindopril; this was presumably due to increased receptor sensitivity consequent on the falls in endogenous AII levels. Responses to AII fell to control levels after the inhibitor was stopped. It is concluded that an increased pressor sensitivity to AII is not the cause of the slowly developing hypertension in the 2K1C model of hypertension, and that the slow pressor response to AII must be due to other factors.

Angiotensin I↗
PubMed1986

Genetic analysis of blood pressure and sodium balance in spontaneously hypertensive rats.

Blood pressure and parameters of sodium balance were measured during the first 16 weeks of life in male Okamoto spontaneously hypertensive rats (SHR, n = 22), Wistar-Kyoto rats (WKY, n = 25), and the F1 (n = 27) and F2 (n = 81) hybrids of the SHR and WKY. Genetic analysis revealed that blood pressure in SHR was controlled by approximately four independent genetic loci and the degree of genetic determination was 64.5%. No difference in blood pressure was discernible before 12 weeks of age between those F2 rats that at 16 weeks had blood pressures either higher or lower than one standard deviation from the mean. Exchangeable sodium was measured sequentially in individual rats of all populations by determining their whole-body radioactivity while receiving 37.5 mM 22Na/23NaCl drinking fluid of constant specific activity as their sole source of sodium. The SHR had consistently higher exchangeable sodium levels than WKY and showed evidence of relative sodium retention during the early developmental phase of hypertension. Sodium intake was higher in SHR than WKY from 4 to 16 weeks of age, although saline preference was the same in both strains. None of these parameters of sodium balance were found to correlate with blood pressure in the F2 population. It is concluded that the heritable abnormalities of sodium balance in SHR appear to represent coincidental inbred characteristics controlled by genetic loci that are unrelated to those loci responsible for the expression of hypertension in this model.

Animals↗
PubMed1986

Renal haemodynamics and total body sodium in immature spontaneously hypertensive and Wistar-Kyoto rats.

We have investigated the renal haemodynamics and sodium metabolism in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats during the first 10 weeks of life. Using constant infusion clearance measurements of 51Cr-EDTA and 125I-hippuran in unrestrained, conscious, 4-week-old rats we found a significant reduction in glomerular filtration rate (GFR) and renal blood flow (RBF), respectively, in SHR compared with WKY. The arterial blood pressure (BP) and renal vascular resistance were also significantly elevated in SHR at this age. Acute oral treatment with hydralazine increased SHR GFR and RBF to equal that of WKY, but acute angiotensin converting enzyme inhibition with oral MK 421 caused the GFR and RBF of SHR to exceed that of WKY. In addition, the plasma renin activity of 4-week-old SHR was significantly elevated compared with WKY. Total body sodium was measured from 1 to 10 weeks of age by determining the whole-body radioactivity of rats equilibrated on 22Na-labelled NaCl of constant specific activity. Indirect blood pressure and sodium intake were measured from weeks 4 to 10 inclusive. Relative sodium retention was observed in SHR both before and during the early developmental phase of hypertension. The sodium intake and BP of SHR were consistently higher than WKY throughout weeks 4 to 10. We propose that increased renal vascular resistance in immature SHR alters the pressure natriuresis relationship to cause sodium retention, with the subsequent development of hypertension.

Animals↗
PubMed1984

Failure of psychosocial stress to induce chronic hypertension in the rat.

The effect of psychosocial stress produced by aggregation in a special cage designed by Henry was investigated in three separate experiments using Wistar-Kyoto (WKY), Sprague-Dawley (SD) and F1 hybrids of the Japanese spontaneously hypertensive and Wistar-Kyoto (SHR-WKY F1) rats. Each aggregated group displayed typical 'stressed' behavioural disturbances. Adrenal hypertrophy, elevation of plasma renin activity and gastric erosions were noted in male aggregated SD rats; while adrenal enlargement, elevation of plasma noradrenaline and gastric erosions were found in male aggregated SHR-WKY F1 rats. Sustained hypertension, however, did not develop in any strain nor in any subgroup within each strain. Gastric erosions were also noted in isolated SD and SHR-SKY F1 rats suggesting that long term isolation of rats also induces stress. Isolated rats also remained normotensive throughout. Reduced haematocrit was found in both aggregated and isolated male SHR-WKY F1 rats suggesting increased plasma volume. We conclude that neither stress due to psychosocial disturbances nor that due to isolation produces chronic hypertension in the three strains of rat studied.

Adrenal Glands↗
PubMedDate not supplied

Total body sodium in immature spontaneously hypertensive and Wistar Kyoto rats.

Total body sodium of male and female spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats was estimated weekly during the first 8 weeks of life by measuring exchangeable sodium (ENa). Blood pressure and sodium intake was measured from weeks 4 to 8. SHR had significantly higher blood pressure and sodium intake than WKY from 4 to 8 weeks of age. ENa was higher in SHR than WKY throughout the first 8 weeks of life. Relative sodium retention was observed in SHR during weeks 5 to 8 despite a significant rise in SHR blood pressure and fall in sodium intake. These findings suggest a change in the renal pressure/natriuresis relationship at this age in the SHR.

Age Factors↗
PubMedDate not supplied

Persistent effects on blood pressure and renal haemodynamics following chronic angiotensin converting enzyme inhibition with perindopril.

Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats aged 4 and 16 weeks were given an acute oral dose of either Perindopril (3 mg/kg) or vehicle. Direct blood pressure (BP), glomerular filtration rate (GFR) and renal blood flow (RBF) were measured, and renal vascular resistance (RVR) calculated. GFR and RBF were lower in vehicle-treated SHR than WKY at 4 weeks of age, but were not different at 16 weeks. Acute Perindopril increased GFR and RBF and reduced RVR in both strains at both 4 and 16 weeks. Total body sodium, sodium intake and blood pressure were measured in SHR and WKY from 1 to 28 weeks of age. Rats of both strains were treated daily between 4 and 16 weeks of age with either Perindopril (3 mg/kg per day) or vehicle. Chronic Perindopril treatment prevented the development of hypertension in the SHR. From 16 to 28 weeks of age, after stopping Perindopril, BP rose slowly in SHR, but remained lower than vehicle-treated SHR. No changes in total body sodium occurred during Perindopril treatment. GFR and RBF were measured in SHR and WKY chronically treated with either Perindopril or vehicle, 3 days or 12 weeks after stopping treatment. In WKY, GFR and RBF were not different between Perindopril-treated and untreated rats at either measurement. In SHR, GFR and RBF remained significantly higher in rats previously treated with Perindopril at both ages. These findings suggest that renal haemodynamic abnormalities may be important in the initiation of hypertension in the SHR. These renal circulatory abnormalities and the hypertension of the SHR depend, at least in part, on intact converting enzyme activity, yet appear to be independent of abnormalities of total body sodium. At a later age, hypertension seems to develop independently of renal vascular abnormalities.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

Renal medulla and bradykinin during the development of hypertension in SHR.

1. The long-term reduction in blood pressure following ACE inhibitor treatment in young spontaneously hypertensive rats (SHR) appears to depend on both the kidney and bradykinin. 2. The aim of this experiment was to examine the effects of ACE inhibition and bradykinin on renal morphology and blood pressure in SHR. 3. Between 6 and 10 weeks of age male SHR received one of four treatments: water (n = 26), ramipril (1 mg/kg per day; n = 24), ramipril (1 mg/kg per day) plus Hoe 140 (0.5 mg/kg per day; n = 25) or Hoe 140 (0.5 mg/kg per day; n = 25). 4. Renal medullary and cortical volumes were determined stereologically at 10 and 20 weeks of age. 5. After 4 weeks of treatment, ramipril reduced the size of the renal medulla while Hoe 140 increased medullary volumes compared to control. Ten weeks after treatment was stopped the renal medulla of the ramipril group had returned to normal, however, there was a persistent increase in medullary volume of both Hoe 140 treated groups. 6. Our results imply that bradykinin may influence the size of the renal medulla which may have important effects on the development of hypertension in SHR.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Low affinity nerve growth factor receptor gene co-segregates with decreased bodyweight and increased left ventricular weight in spontaneously hypertensive rats.

1. The sympathetic nervous system influences the cardiovascular and hormonal systems and sympathetic innervation is dependent on nerve growth factor (NGF). The NGF gene is linked genetically to high blood pressure in the spontaneously hypertensive rat (SHR) and there exists a mutation in the SHR low affinity NGF receptor (LNGFR) gene. 2. To determine whether the LNGFR mutation was linked genetically with cardiovascular phenotypes we studied an F2 population derived from SHR and normotensive Donryu (DRY) rats. 3. Mean arterial pressure (MAP), left ventricular mass (LVM) and related phenotypes were measured in 127 20 week old male F2 rats and correlated with the inheritance of the SHR mutation (S) and/or the DRY allele (D) of the LNGFR. 4. Analysis of variance revealed that the S mutation was associated with a significantly lower bodyweight in F2 rats (P < 0.0001). 5. The S mutation was associated with a significant (P < 0.007) increase in LVM:bodyweight ratio, but not with differences in right ventricular or kidney weights corrected for bodyweight. We found no association between MAP and LNGFR alleles or genotypes. 6. These results suggest that the mutation in the signal peptide of LNGFR may serve as a useful marker for the analysis of genetic factor(s) involved in the differential determination of body size and heart weight.

Alleles↗
PubMedDate not supplied

Erythrocyte cation cotransport and countertransport in essential hypertension.

We studied erythrocyte cation cotransport and countertransport systems in 21 and 27 patients with essential hypertension, respectively, all of whom were under 50 years of age, had a diastolic blood pressure level greater than 100 mm Hg, and had a family history of hypertension. The following parameters were normal in nearly all patients: total erythrocyte Na+ and K+ concentrations, the maximal rate (Vmax) of inward cotransport, the affinity of cotransport with Rb+ as the substrate, the net outward cotransport of Na+ ions, the passive "leak" influx of Rb,+ and the maximal rate of Li+-Na+ countertransport. Only four patients gave clearly abnormal results; in two the maximal rate of both cotransport and countertransport was double the normal values, while another two patients demonstrated a greater than twofold increase in passive "leak" influx to Rb+ ions. Most of the patients with moderate to severe essential hypertension in this Australian study were characterized by normal erythrocyte cation fluxes, but a few showed elevation of both cotransport and countertransport of cations.

Adult↗
PubMedDate not supplied

Cardiovascular hypertrophy does not predispose to genetic hypertension.

It has been proposed that cardiovascular hypertrophy precedes and contributes to the development of genetic hypertension. In a genetically segregating population we determined whether susceptibility to high blood pressure was associated with cardiovascular structural abnormalities in youth. In 9-week old male F2 rats derived from a cross of spontaneously hypertensive rats (SHR) and inbred normotensive Donryu (DRY) rats we determined left ventricular mass (LVM) by echocardiography and the media-lumen ratio (MLR) of mesenteric resistance vessels by biopsy. Direct mean arterial pressure was measured in the same rats at 20 weeks of age. The ranges of LVM and MLR in young F2 rats encompassed values seen SHR and DRY at this age. However, no correlation was observed between LVM or MLR and subsequent blood pressures at 20 weeks of age. The blood pressure of F2 rats with cardiovascular structural phenotypes within the SHR range was no higher than the remainder of the F2 population. These studies do not support the hypothesis that hypertrophy of the heart or mesenteric resistance vessels confer susceptibility to the development of genetic hypertension.

Animals↗