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Biomedical subjects

S B Harrap

Publications and source records attributed to S B Harrap.

At least 55 records · Page 3Linked to original sources
PubMed1997

Behavioural and cardiovascular responses of rats to euthanasia using carbon dioxide gas.

Our results showed more rapid falls in pulse rate and blood pressure in rats euthanized in a chamber precharged with carbon dioxide (CO2), when compared with rats euthanized more slowly, but death still took over 5 min in the former group. There was no behavioural evidence of pain or distress in either group during euthanasia. Initial ataxia and dyspnoea was punctuated by a lag before death, thus separating euthanasia into three clearly defined phases. All visual signs of death preceded complete vascular collapse by about 1 min in both groups, so we recommend that gas flow be maintained for at least 1 min after apparent death.

Administration, Inhalation↗
PubMed1996

Plasma angiotensin II, predisposition to hypertension, and left ventricular size in healthy young adults.

BACKGROUND: We studied the correlates of left ventricular mass (LVM) in 84 healthy young adults aged 16 to 24 years from the general population. Subjects were selected according to predisposition to hypertension into four groups with either high or low personal blood pressures and either high or low parental blood pressures. METHODS AND RESULTS: LVM was measured by echocardiography, and measurements of blood pressure, heart rate, body dimensions, and plasma concentrations of components of the renin-angiotensin system were made under resting conditions. LVM was similar in individuals predisposed to hypertension (high personal and parental blood pressures) and those with contrasting predisposition (low personal and parental pressures). Regression analysis of the combined groups showed that LVM correlated closely with body size, particularly lean body mass (r=.69, P<.0001) and systolic (r=.35, P<.0001) but not diastolic blood pressure. Plasma angiotensin II (r=.39, P<.0001), renin (r=.302, P<.01), and angiotensin-converting enzyme (r=.22, P<.05) showed significant correlation with LVM. Multiple regression analysis revealed that plasma angiotensin II was the most important component of the renin-angiotensin system and that its effect was independent of systolic blood pressure and body size. CONCLUSIONS: These findings provide evidence in humans that angiotensin II exerts a direct on myocardial size. This association may have important implications for the complications and treatment of left ventricular hypertrophy.

Adolescent↗
PubMed1996

Nerve growth factor gene and hypertension in spontaneously hypertensive rats.

OBJECTIVE: High blood pressure in spontaneously hypertensive rat (SHR) is associated with increased sympathetic innervation of key tissues, possibly as the result of increased nerve growth factor (NGF). The aim of this study was to test for genetic linkage of the NGF gene to high blood pressure. DESIGN: We studied NGF gene expression in young SHR and examined linkage of the NGF locus to mean arterial pressure in genetically segregating crosses of SHR and normotensive Donryu (DRY) rats. METHODS: NGF mRNA was measured by Northern blot, and a restriction fragment length polymorphism of the NGF gene revealed after digestion with the NsiI restriction enzyme was used to study inheritance. RESULTS: Levels of NGF mRNA were detected easily in the kidneys of 2-, 4- and 10-week-old SHR but not in age-matched DRY rats. In an F2 population, the blood pressure of rats homozygous for the DRY NGF allele was 6 mmHg less than in heterozygotes and 8 mmHg less than in rats homozygous for the SHR NGF allele (analysis of variance, P < 0.004). In backcross rats the blood pressure of NGF heterozygotes was not significantly different from that of SHR homozygotes. CONCLUSION: These results indicate differences in renal NGF mRNA in SHR during the development of hypertension and suggest that a genetic locus in or near the NGF gene contributes in a Mendelian dominant pattern to a significant increment in blood pressure in SHR.

Animals↗
PubMed1996

Cardiac transplantation, perindopril, and left ventricular hypertrophy in spontaneously hypertensive rats.

Angiotensin-converting enzyme inhibitors reduce blood pressure and cardiac mass but may also have a direct effect on myocardial growth. To test this hypothesis, we studied the effects of perindopril on the weight of transplanted hearts in which the left ventricle does not pump blood. Hearts were transplanted between littermate 10-week-old male spontaneously hypertensive rats, and recipients were treated for 2 weeks with vehicle (n = 10), perindopril (3 mg/kg per day) (n = 9), perindopril (3 mg/kg per day) plus the selective bradykinin B2 receptor antagonist Hoe 140 (500 micrograms/kg per day) (n = 13), or angiotensin II (200 ng/kg per minute) (n = 12). Perindopril reduced blood pressure and native left ventricular weight and also caused a significant decrease in the weight of the transplanted left ventricle compared with controls. Hoe 140 did not significantly alter blood pressure or native left ventricular weight of perindopril-treated rats but caused a significant increase in the weight of the transplanted left ventricle compared with rats treated with perindopril alone. Angiotensin treatment resulted in a significant increase in blood pressure and native left ventricular weight but no significant change in the weight of the transplanted left ventricle. Blood pressure and left ventricular weight for native but not for transplanted hearts were positively correlated. Therefore, in the absence of mechanical load, the weight of the left ventricle of spontaneously hypertensive rats responds little to angiotensin II but can be reduced by angiotensin-converting enzyme inhibition. The effect of perindopril on transplanted hearts of spontaneously hypertensive rats appears to depend on bradykinin.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

An appraisal of the genetic approaches to high blood pressure.

BACKGROUND: The genetics of high blood pressure is a growing field. Remarkable discoveries have been made in the rare genetic causes of hypertension. However, if molecular biology is to achieve its full potential it must address more common forms of high blood pressure. The genetics of essential hypertension offers great potential but also presents special challenges. This review examines how genes might influence blood pressure, how we might organize the search for underlying genes, where we should look and the way in which genetic knowledge might be used. NEED FOR BROAD APPROACH: For reasons related to informative research design and the prevention of cardiovascular disease, genetic approaches need to address the variation of blood pressure from low to high levels, not only hypertension. NEED FOR GENETIC MARKERS: If there is to be a time when DNA testing will be routine, then it will depend on discovering genetic markers that are informative, reliable and cost-beneficial.

Animals↗
PubMed1995

Linkage of high-affinity IgE receptor gene with bronchial hyperreactivity, even in absence of atopy.

Asthma is a manifestation of bronchial hyperreactivity (BHR) and forms part of the spectrum of atopic disease. Some pedigree studies of atopy have suggested linkage with the high-affinity IgE receptor (Fc epsilon RI beta) gene on chromosome 11q13, but others find no linkage. The molecular genetics of asthma and BHR have not been studied in the general population. We examined the genetic linkage of the Fc epsilon RI beta gene with clinical asthma and the underlying phenotypes of BHR (to methacholine) and atopy (defined by skinprick testing) in 123 affected sibling-pairs recruited from the general population. We found evidence of significant linkage of a highly polymorphic microsatellite marker in the fifth intron of the Fc epsilon RI beta gene to a diagnosis of asthma (18.0% excess of shared alleles, p = 0.002) and to BHR (21.7% excess of shared alleles, p = 0.001). Significant linkage was also observed in siblings sharing BHR when those with atopy were excluded (32.8% excess of shared alleles, p = 0.004). Atopy in the absence of BHR did not show significant linkage to the Fc epsilon RI beta gene (7.2% excess of shared alleles, p = 0.124). These findings suggest that mutations in the Fc epsilon RI beta gene or a closely linked gene influence the BHR underlying asthma, even in the absence of atopy.

Adult↗
PubMed1995

The SA gene: predisposition to hypertension and renal function in man.

1. The SA gene is expressed in the kidneys and is associated with hypertension in man and experimental animal models. Predisposition to hypertension is associated with renal haemodynamic abnormalities and increased renal SA gene expression. 2. We studied the distribution of the SA gene alleles (A1, A2), defined by the PstI polymorphism, in young adults with contrasting predisposition to hypertension to determine whether genetic variation at the SA gene locus is associated with variations in renal haemodynamics, electrolyte metabolism and the renin-angiotensin system. 3. The frequency of the A2 allele was not significantly different between subjects with high personal and parental blood pressures and subjects with low personal and parental blood pressures. We detected no overall relationship between blood pressures and SA genotype, even after taking sodium intake into account. 4. Glomerular filtration rate, renal blood flow, renal vascular resistance, plasma volume, exchangeable sodium and total body water did not differ according to SA genotypes. Moreover, we detected no significant effect of SA genotype on circulating components of the renin-angiotensin system or atrial natriuretic peptide. 5. In our population, genetic variation at the SA gene locus defined by PstI polymorphism does not influence the renal characteristics that contribute to the development of hypertension.

Adult↗
PubMed1995

Converting enzyme inhibition and its withdrawal in spontaneously hypertensive rats.

When spontaneously hypertensive rats (SHR) treated at a young age with an inhibitor of angiotensin-converting enzyme (ACE) are withdrawn from treatment, their blood pressure (BP) remains below that of untreated rats. We examined the effects of ACE inhibitor treatment and its withdrawal on angiotensin-(1-7) [Ang-(1-7)], angiotensin II (Ang II) and angiotensin I (Ang I) in plasma, kidney, adrenal, heart, aorta, brown adipose tissue, lung, and brain of male SHR and normotensive Donryu rats. Rats were administered either vehicle or perindopril (3 mg/kg/day) from 6 to 10 weeks, from 6 to 20 weeks, and from 6 to 10 weeks, followed by perindopril withdrawal from 10 to 20 weeks. Angiotensin peptides and plasma levels of renin, angiotensinogen, ACE, and aldosterone were measured at 10 and 20 weeks of age. Perindopril reduced BP of both SHR and Donryu rats, although only SHR showed a reduction of BP of 19 mm Hg after perindopril withdrawal, associated with a reduction of 5% in heart weight/body weight ratio. Perindopril reduced the angiotensin II/angiotensin I ratio in all tissues by > 50%, with strain- and tissue-specific differences in the effects of perindopril on the levels of individual angiotensin peptides. None of the changes in Ang II levels persisted after perindopril withdrawal. In contrast to those of Donryu rats, plasma angiotensinogen levels of perindopril-withdrawn SHR were 14% lower than those of vehicle-treated SHR (p = 0.0356). Although the lower BP of perindopril-withdrawn SHR was not associated with an alteration in Ang II levels, the suppressed plasma angiotensinogen levels may have contributed to the lower BP of these rats. Alternatively, another action of perindopril, such as a change in cardiovascular structure, may have been responsible for the reduced BP of perindopril-withdrawn SHR.

Aldosterone↗
PubMed1995

Resetting blood pressure in spontaneously hypertensive rats. The role of bradykinin.

Brief angiotensin-converting enzyme (ACE) inhibition in young spontaneously hypertensive rats (SHR) causes a persistent reduction in blood pressure. Bradykinin accumulation may contribute to these long-term effects, and to test this hypothesis we studied the consequences of bradykinin B2 receptor antagonism during ACE inhibitor treatment in young SHR. Male SHR were treated from 6 to 10 weeks of age with water, ramipril (1 mg/kg per day), Hoe 140 (0.5 mg/kg per day), or both ramipril and Hoe 140. Systolic blood pressure and body weight were measured each week from 6 to 20 weeks of age. During treatment, Hoe 140 treatment resulted in lower blood pressures than in controls. Rampiril caused a larger fall in blood pressure over the same period. The ramipril plus Hoe 140 group had the lowest blood pressures of any group during treatment. After treatment, the blood pressure of Hoe 140-treated SHR was similar to that of untreated SHR. After ramipril, blood pressure rose but plateaued significantly below values in controls. In contrast, withdrawal of combined ramipril and Hoe 140 treatment caused a rapid rise of systolic blood pressure to levels significantly higher than in ramipril-treated SHR but less than in controls. The antihypertensive effects of Hoe 140 during the development of genetic hypertension may represent a direct effect of the drug or some alteration in the normal relation between bradykinin and blood pressure. The antagonism by Hoe 140 of the long-term blood pressure reduction after ramipril withdrawal indicates that the persistent effects of ACE inhibitors may in part be due to the accumulation of bradykinin during a critical stage of development.

Aging↗
PubMed1995

Angiotensin peptides in spontaneously hypertensive and normotensive Donryu rats.

The renin-angiotensin system has been implicated in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). Given that SHR may have normal or suppressed plasma levels of renin and angiotensin peptides, we examined whether the tissue levels of angiotensin peptides are elevated in these rats. We measured angiotensin-(1-7) [Ang-(1-7)], Ang II, and Ang I in plasma, kidney, adrenal, heart, aorta, brown adipose tissue, lung, and brain of male SHR and normotensive Donryu rats at 6, 10, and 20 weeks of age. SHR had higher blood pressures and ratios of heart weight to body weight at all ages. Plasma renin levels of SHR were 13% to 32% of the levels of Donryu rats. Although plasma angiotensin-converting enzyme activity was lower in SHR than in Donryu rats, lung was the only SHR tissue with a reduced Ang II-Ang I ratio. Ang II levels in SHR adrenal were 24% to 42% of the levels of Donryu adrenal, and for SHR plasma, aorta, brown adipose tissue, and lung, Ang II levels were 38% to 93% of the levels of Donryu rats. For kidney and heart, Ang II levels were similar in SHR and Donryu rats at 6 weeks of age although suppressed in SHR at 10 and 20 weeks. Moreover, brain Ang II levels were higher in SHR than Donryu rats at 6 weeks of age and similar at 10 and 20 weeks of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗
PubMed1995

Increased levels of bradykinin and its metabolites in tissues of young spontaneously hypertensive rats.

OBJECTIVE: To determine whether tissue kinin levels in spontaneously hypertensive rats (SHR) differ from those in normotensive rats. DESIGN AND METHODS: The tissue levels of bradykinin-(1-9) and its metabolites bradykinin-(1-7) and bradykinin-(1-8) were measured in kidney, and bradykinin-(1-9) and bradykinin-(1-7) were measured in adrenal, lung, heart, aorta, brown adipose tissue and brain of male SHR and the normotensive genetically homogeneous Donryu rat strain, at age 6, 10 and 20 weeks. RESULTS: In comparison with Donryu rats, bradykinin-(1-7), bradykinin-(1-8) and bradykinin-(1-9) levels were increased in kidney, and bradykinin-(1-7) and bradykinin-(1-9) levels were increased in adrenal, lung and heart of SHR aged 6 weeks. Bradykinin-(1-7) levels remained elevated in adrenal and lung of SHR aged 10 weeks. The bradykinin-(1-7): bradykinin-(1-9) ratio for kidneys of SHR was reduced at all ages and the bradykinin-(1-8):bradykinin-(1-9) ratio was reduced at age 10 and 20 weeks. Bradykinin peptide levels in aorta, brown adipose tissue and brain were similar for SHR and Donryu rats. CONCLUSION: The increased levels of bradykinin-(1-9) and its metabolites in kidney, adrenal, lung and heart tissues of young SHR suggest increased kallikrein activity in these tissues. Moreover, the reduced bradykinin-(1-7):bradykinin-(1-9) and bradykinin-(1-8):bradykinin-(1-9) ratios in kidneys of SHR indicate reduced endopeptidase- and carboxypeptidase-mediated metabolism of bradykinin-(1-9), which may have contributed to the increased bradykinin-(1-9) levels in this tissue. Together with the previously reported hypotensive effect of bradykinin-(1-9) antagonism in young SHR, and the cosegregation of the SHR kallikrein gene with blood pressure, the increased bradykinin-(1-9) levels in tissues of young SHR are consistent with a role for this peptide in the pathogenesis of hypertension in those rats.

Animals↗
PubMed1994

Public health, cardiovascular disease and molecular biology.

Rapid developments in molecular biology provide the tools to search for genetic markers of coronary heart disease. Already the angiotensin converting enzyme and the angiotensinogen genes have been implicated in myocardial infarction and hypertension. However, common conditions such as coronary disease raise special problems for genetics both in selection of suitable subjects and the use of informative genetic methods. Traditionally genetics has focused on the family; now it must broaden that view to identify markers that are relevant to the general community. The magnitude and complexity of the problem demands collaboration between epidemiologists, physicians, geneticists and laboratory scientists. This paper proposes a two stage approach to the genetics of coronary heart disease, beginning with affected relative pair linkage studies using the new generation gene maps to define chromosomal regions of interest. The thorough and systematic search using gene maps also offers the possibility of defining genetic markers of "hidden" coronary risk factors. In the second stage, candidate genes within these regions are examined in case-control association studies to identify simple markers that divide the population into groups with contrasting risk of coronary disease. It is important that families and cases are representative of the general population, otherwise the predictive value of the new genetic markers will be in doubt. In particular, genetic analyses should avoid the potential bias resulting from the exclusion of cases of sudden and unexpected coronary death.

Cardiovascular Diseases↗
PubMed1994

Hypertension and cardiac hypertrophy in growth hormone-deficient rats.

1. Growth hormone may influence cardiac growth during post-natal maturation or in response to hypertension, and the growth-hormone deficient dwarf rat model offers an opportunity to study this question. 2. We compared the blood pressure and heart weight of dwarf rats and Fischer (F344) control rats in early adulthood, after two hypertensive stimuli: unilateral renal ischaemia (two-kidney, one-clip) or the administration of deoxycorticosterone acetate and saline drinking fluid. 3. In untreated animals at 13 weeks of age the body weight of dwarf rats was significantly less than that of F344 rats, but the mean arterial pressure was similar. Although the hearts of dwarf rats were smaller than those of F344 rats, the heart weight/body weight ratio was significantly greater in dwarf rats. 4. Both dwarf and F344 rats developed similar hypertensive mean arterial pressures 5 weeks after left renal artery clipping or treatment with deoxycorticosterone acetate salt. The heart weights of hypertensive dwarf and F344 rats were equivalent, indicating a proportionally greater increase in cardiac size in dwarf rats for the same rise in blood pressure. 5. The plasma insulin-like growth factor-I level was markedly lower in dwarf than in F344 rats, and hypertension did not have any significant effects on these levels. 6. These findings indicate that the developmental increase in blood pressure and heart size in growing animals and the adaptive cardiac hypertrophy accompanying hypertension are not affected by growth hormone deficiency.

Animals↗
PubMed1994

Blood pressure and lifespan following brief ACE inhibitor treatment in young spontaneously hypertensive rats.

1. Brief treatment with angiotensin-converting enzyme (ACE) inhibitors in young spontaneously hypertensive rats (SHR) causes a reduction in blood pressure that persists into maturity. The lifetime effects of such treatment have not been studied. 2. Nineteen male SHR were treated with either water (n = 9) or perindopril (3 mg/kg per day) (n = 10) by daily gavage between 6 and 10 weeks of age and systolic blood pressure and bodyweight were measured each month until all animals died in old age. 3. Following treatment the systolic blood pressure of SHR treated with perindopril remained consistently lower than control SHR until about 82 weeks of age. After this age the blood pressure of control SHR fell spontaneously so that smaller differences were observed between the two groups in the last 4 months of the study. 4. Rats that received perindopril lived on average 1 month longer than control rats, but this difference was not statistically significant. 5. Thus, brief ACE inhibition in early life in SHR ameliorated the hypertension throughout life.

Angiotensin-Converting Enzyme Inhibitors↗