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Background: Left ventricular (LV) hypertrophy is a risk factor for cardiovascular death, but the genetic factors determining LV size and predisposition to hypertrophy are not well understood. We have previously linked the quantitative trait locus cardiac mass 22 (Cm22) on chromosome 2 with cardiac hypertrophy independent of blood pressure in the spontaneously hypertensive rat. From an original cross of spontaneously hypertensive rat with F344 rats, we derived a normotensive polygenic model of spontaneous cardiac hypertrophy, the hypertrophic heart rat (HHR) and its control strain, the normal heart rat (NHR)., Methods and Results: To identify the genes and molecular mechanisms underlying spontaneous LV hypertrophy we sequenced the HHR genome with special focus on quantitative trait locus Cm22. For correlative analyses of function, we measured global RNA transcripts in LV of neonatal HHR and NHR and 198 neonatal rats of an HHR × NHR F2 crossbred population. Only one gene within locus Cm22 was differentially expressed in the parental generation: tripartite motif-containing 55 (Trim55), with mRNA downregulation in HHR (P < 0.05) and reduced protein expression. Trim55 mRNA levels were negatively correlated with LV mass in the F2 cross (r = -0.16, P = 0.025). In exon nine of Trim55 in HHR, we found one missense mutation that functionally alters protein structure. This mutation was strongly associated with Trim55 mRNA expression in F2 rats (F = 10.35, P < 0.0001). Similarly, in humans, we found reduced Trim55 expression in hearts of subjects with idiopathic dilated cardiomyopathy., Conclusion: Our study suggests that the Trim55 gene, located in Cm22, is a novel candidate gene for polygenic LV hypertrophy independent of blood pressure.

The International Society of Hypertension and the World Hypertension League have developed a policy statement calling for reducing dietary salt. The policy supports the WHO and the United Nations recommendations, which are based on a comprehensive and up-to-date review of relevant research. The policy statement calls for broad societal action to reduce dietary salt, thus reducing blood pressure and preventing hypertension and its related burden of cardiovascular disease. The hypertension organizations and experts need to become more engaged in the efforts to prevent hypertension and to advocate strongly to have dietary salt reduction policies implemented. The statement is being circulated to national hypertension organizations and to international nongovernmental health organizations for consideration of endorsement. Member organizations of the International Society of Hypertension and the World Hypertension League are urged to support this effort.

Objective: To investigate the role of the renin gene in the hypertension of the spontaneously hypertensive rat (SHR) of the Okamoto strain., Methods: We determined whether the SHR renin allele was cosegregated with high blood pressure in 137 F2 rats derived from inbred SHR and Wistar-Kyoto rats. Systolic blood pressure in conscious rats was measured by the tail-cuff method, whereas mean arterial pressure was determined from an indwelling catheter in the left carotid artery. Renin genotypes of F2 rats were determined using a SHR-specific Bg/II restriction fragment length polymorphism that we have previously described., Results: The SHR renin allele was cosegregated significantly with higher systolic blood pressure in male F2 rats aged 8-24 weeks and in females aged 12-24 weeks. The greatest differences in blood pressure between SHR renin allele homozygotes and Wistar-Kyoto rat renin allele homozygotes were 35 mmHg for males and 17 mmHg for females aged 24 weeks. The SHR renin allele was also associated with a higher mean arterial pressure in rats aged 24 weeks and cosegregated with higher body weight of male F2 rats aged 12-24 weeks but not with that of the females. In contrast to the relationship with blood pressure, the SHR renin allele was segregated with lower plasma renin concentrations in rats aged 24 weeks., Conclusion: These results are consistent with the SHR renin gene being one of the loci determining high blood pressure in rats of this strain, possibly through action at some extra-renal site subserving control of blood pressure.

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.

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.

Aim: To assess the feasibility and utility of a new method to identify factors associated with increased predisposition to high blood pressure in young people., Subjects: Eight hundred and sixty-four people aged 16-24 years and their parents., Setting: Ladywell Medical Centre, Edinburgh, Scotland, UK., Method: Blood pressure was measured in 864 young adults and in both of their parents. Four groups of approximately 50 offspring were selected from the corners of a scatter diagram, with offspring blood pressure scores on one axis and combined parental blood pressure scores on the other. Blood and urine samples were taken for biochemical and genetic analyses., Results: Two groups of offspring had parents with high blood pressure and two groups had parents with low blood pressure. When parental blood pressure was low, comparison of offspring with high and low blood pressure revealed significantly higher mean body mass index in offspring with high blood pressure, but no significant elevation of biochemical or hormonal variables. When parental blood pressure was high, comparison of offspring with high and low blood pressure also revealed a significant difference in body mass index, but in addition, offspring with high blood pressure and high parental blood pressure had higher levels of angiotensinogen, cortisol and 18-OH corticosterone. Restriction fragment length polymorphism analysis revealed that 27% of offspring at the greatest genetic risk (high personal and parental blood pressure) were homozygous for the larger allele of the glucocorticoid receptor gene compared with only 9% of those at lowest genetic risk (low personal and parental blood pressure)., Conclusion: The combined biochemical and genetic findings suggest that abnormalities of glucocorticoid metabolism and the renin-angiotensin system may help to explain genetic predisposition to high blood pressure. The new sampling method is practicable and could be applied to the investigation of other continuously distributed variables which show familial aggregation.

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.