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Aims: Prevention of human hypertension is an important challenge and has been achieved in experimental models. Brief treatment with renin-angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this fascinating phenomenon, but relevant changes in gene expression are unknown., Methods and Results: In SHR, we studied the effect of treatment between 10 and 14 weeks of age with the angiotensin receptor blocker, losartan, or the angiotensin-converting enzyme inhibitor, perindopril [with controls for non-specific effects of lowering blood pressure (BP)], on differential RNA expression, DNA methylation, and renin immunolabelling in the kidney at 20 weeks of age. RNA sequencing revealed a six-fold increase in renin gene (Ren) expression during losartan treatment (P < 0.0001). Six weeks after losartan, arterial pressure remained lower (P = 0.006), yet kidney Ren showed reduced expression by 23% after losartan (P = 0.03) and by 43% after perindopril (P = 1.4 × 10-6) associated with increased DNA methylation (P = 0.04). Immunolabelling confirmed reduced cortical renin after earlier RAS blockade (P = 0.002). RNA sequencing identified differential expression of mRNAs, miRNAs, and lncRNAs with evidence of networking and co-regulation. These included 13 candidate genes (Grhl1, Ammecr1l, Hs6st1, Nfil3, Fam221a, Lmo4, Adamts1, Cish, Hif3a, Bcl6, Rad54l2, Adap1, Dok4), the miRNA miR-145-3p, and the lncRNA AC115371. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS, and the kidneys., Conclusion: Early RAS inhibition in SHR resets genetic pathways and networks resulting in a legacy of reduced Ren expression and BP persisting for a minimum of 6 weeks., Competing Interests: Conflict of interest: There are no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported., Methods and Results: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis., Conclusion: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Whether part of the blood pressure lowering effects of glyceryl trinitrate (GTN) is the result of centrally mediated reduction in sympathetic activity is debated. In humans, baroreflex activity potentially obscures the central sympatholytic effects of GTN. We examined this in a routine clinical tilt test in a patient with baroreflex failure secondary to previous neck radiotherapy. With reduced baroreflex function we observed an exaggerated fall in blood pressure and reduced sympathetic activity with GTN, supporting a peripheral vasodilation and central sympatholytic effect., (© 2020 Royal Australasian College of Physicians.)

Background: Renin-angiotensin-aldosterone system genes have been inconsistently associated with blood pressure, possibly because of unrecognized influences of sex-dependent genetic effects or gene-gene interactions (epistasis)., Methods and Results: We tested association of systolic blood pressure with single-nucleotide polymorphisms (SNPs) at renin ( REN ), angiotensinogen ( AGT ), angiotensin-converting enzyme ( ACE ), angiotensin II type 1 receptor ( AGTR1 ), and aldosterone synthase ( CYP11B2 ), including sex-SNP or SNP-SNP interactions. Eighty-eight tagSNPs were tested in 2872 white individuals in 809 pedigrees from the Victorian Family Heart Study using variance components models. Three SNPs (rs8075924 and rs4277404 at ACE and rs12721297 at AGTR1 ) were individually associated with lower systolic blood pressure with significant ( P <0.00076) effect sizes ≈1.7 to 2.5 mm Hg. Sex-specific associations were seen for 3 SNPs in men (rs2468523 and rs2478544 at AGT and rs11658531 at ACE ) and 1 SNP in women (rs12451328 at ACE ). SNP-SNP interaction was suggested ( P <0.005) for 14 SNP pairs, none of which had shown individual association with systolic blood pressure. Four SNP pairs were at the same gene (2 for REN , 1 for AGT , and 1 for AGTR1 ). The SNP rs3097 at CYP11B2 was represented in 5 separate pairs., Conclusions: SNPs at key renin-angiotensin-aldosterone system genes associate with systolic blood pressure individually in both sexes, individually in one sex only and only when combined with another SNP. Analyses that incorporate sex-dependent and epistatic effects could reconcile past inconsistencies and account for some of the missing heritability of blood pressure and are generally relevant to SNP association studies for any phenotype., (© 2017 American Heart Association, Inc.)

Background: The role of copy number variation (CNV) has been poorly explored in essential hypertension in part due to technical difficulties in accurately assessing absolute numbers of DNA copies. Droplet digital PCR (ddPCR) provides a powerful new approach to CNV quantitation. The aim of our study was to investigate whether CNVs located in regions previously associated with blood pressure (BP) variation in genome-wide association studies (GWAS) were associated with essential hypertension by the use of ddPCR., Methods: Using a "power of extreme" approach, we quantified nucleic acids using ddPCR in white subjects from the Victorian Family Heart Study with extremely high (n = 96) and low (n = 92) SBP, providing power equivalent to 1714 subjects selected at random., Results: A deletion of the CNVs esv27061 and esv2757747 on chromosome 1p13.2 was significantly more prevalent in extreme high BP subjects after adjustment for age, body mass index and sex (12.6% vs. 2.2%; P = 0.013)., Conclusions: Our data suggests that CNVs within regions identified in previous GWAS may play a role in human essential hypertension.

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.

The relative importance of various blood pressure indices on cardiovascular risk in people with type 2 diabetes mellitus has not been established. This study compares the strengths of the associations between different baseline blood pressure variables (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse pressure [PP], and mean arterial pressure) and the 4.3-year risk of major cardiovascular events in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-Modified Release Controlled Evaluation Study. Mean (SD) age for the 11 140 participants was 65.8 years (6.4 years). During follow-up, 1000 major cardiovascular events, 559 major coronary events, and 468 cardiovascular deaths were recorded. After adjustment for age, sex, and treatment allocation, the hazard ratios (95% CIs) associated with 1 increment in SD for the risk of major cardiovascular events were 1.17 (1.10 to 1.24) for SBP; 1.20 (1.13 to 1.28) for PP; 1.12 (1.05 to 1.19) for mean arterial pressure; and 1.04 (0.98 to 1.11) for DBP. The areas under the receiver operating characteristic curve were slightly higher for SBP and PP compared with mean arterial pressure and DBP for major cardiovascular and coronary events. Using achieved instead of baseline blood pressure values marginally improved the effect estimates for SBP, DBP, and mean arterial pressure, with no significant differences in the areas under the receiver operating characteristic curve between models with SBP and those with PP. In conclusion, SBP and PP are the 2 best and DBP is the least effective determinant of the risk of major cardiovascular outcomes in the relatively old patients with type 2 diabetes mellitus participating in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-Modified Release Controlled Evaluation Study. However, SBP may be the simplest and most useful predictor across a wider range of age groups and populations.

Systolic blood pressure is determined in large part by genes. Six independent studies have reported evidence of linkage between systolic pressure and chromosome 16p12 that incorporates SCNN1G, the gene encoding the gamma-subunit of the epithelial sodium channel. We undertook the first comprehensive association analysis of SCNN1G and systolic pressure. To achieve genetic contrast, we sampled unrelated subjects within the upper (mean: 166 mm Hg; n=96) and lower (mean: 98 mm Hg; n=94) 10% of the systolic pressure distribution of 2911 subjects from the Victorian Family Heart Study. We examined genotypes and haplotypes related to 26 single nucleotide polymorphisms across SCNN1G and its promoter. Each of 3 single nucleotide polymorphisms (rs13331086, rs11074553, and rs4299163) in introns 5 and 6 showed evidence of association with systolic pressure in logistic regression analyses adjusted for age, sex, and body mass index. Considered as a haplotype block, these single nucleotide polymorphisms were significantly associated with systolic pressure (haplo.score global: P=0.0001). In permutation analyses to account for multiple testing, a result such as this was observed only once in 10,000 permutations. The estimated frequency of 1 haplotype (TGC) was substantially greater in high (13.3%) than low (0.6%) systolic pressure subjects (P=0.0001). Three other haplotypes (TGG, TAC, and GGC) showed associations with high or low systolic pressure consistent with the observed associations of their composite alleles. These findings identify relatively common polymorphisms in the SCNN1G gene that are associated with high systolic blood pressure in the general Australian white population.

We have previously reported a quantitative trait locus associated with pressure-independent cardiac hypertrophy in the spontaneously hypertensive rat (SHR) of the Okamoto strain. This locus (Lvm1; left ventricular mass locus 1) contains the gene Fgf2 that codes for the potent cardiac growth factor, Fibroblast Growth Factor 2 (FGF2). Given that FGF2 appears essential for the induction of certain forms of cardiac hypertrophy in the rat, we proposed this gene as a candidate for the cardiac enlargement seen in the SHR. Previous reports of elevated FGF2 mRNA levels in the SHR, led us to hypothesise that nucleotide sequence variations occurring in the coding regions or in putative transcriptional factor binding sites within the Fgf2 promoter might play a role in cardiac hypertrophy in this strain. Given that we have also recently derived from the SHR a rat strain that develops spontaneous cardiac hypertrophy in the absence of hypertension (the Hypertrophic Heart Rat; HHR), we also took the opportunity to examine the sequence of its Fgf2 promoter and coding region. However, extensive sequence analysis of the promoter and coding regions of the SHR and HHR Fgf2 genes failed to reveal any nucleotide variations between strains. Thus, we conclude that variations in the nucleotide sequence of the promoter and coding region of the SHR Fgf2 gene do not play a role in the cardiac hypertrophy of the SHR and HHR strains.

The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene might have consequences for the risks of vascular diseases. We examined the ACE genotype and the effects of a perindopril-based blood pressure-lowering regimen on macrovascular events, dementia, and cognitive decline among hypertensive and nonhypertensive patients with a history of cerebrovascular disease. ACE I/D genotypes were measured in 5688 of 6105 individuals with previous stroke or transient ischemic attack who participated in the PROGRESS trial. The DD genotype was significantly (P<0.0001) less frequent in Asian subjects (Chinese and Japanese, 14.7%) than in non-Asian subjects (32.0%). Controlling for racial background, there were no associations between ACE genotypes and cerebrovascular disease history or cardiovascular risk factors, including baseline blood pressure. The ACE genotype was not associated with the long-term risks of stroke, cardiac events, mortality, dementia, or cognitive decline; neither did the ACE genotype predict the blood pressure reduction associated with the use of the ACE inhibitor perindopril. Similarly, there was no evidence that the ACE genotype modified the relative benefits of ACE inhibitor-based therapy over placebo. This study provides no evidence that in patients with cerebrovascular disease, knowledge of ACE genotype is useful for predicting either the risk of disease or the benefits of perindopril-based blood pressure-lowering treatment.

Context: The potential for discovery of underlying genetic causes for common conditions, such as hypertension, is a major justification for the human genome project. Hopes have been raised that personalised molecular prognostic and therapeutic strategies will result from genomic studies., Starting Point: The largest and most recent searches of the genome (Mark Caulfield and colleagues, Lancet 2003; 361: 2118-23; Michael Province and colleagues, Am J Hypertens 2003; 16: 144-47) have found limited evidence of genes that determine hypertension, and even less evidence for the existence of causative DNA variants (alleles) within these genes. Previous genomic studies did not reach a consensus on the likely location of blood-pressure genes. The difficulty in identifying genetic causes for common conditions might be because the causative alleles are numerous, with small individual impact, and are distributed unevenly between populations. WHERE NEXT?: Without comprehensive and reliable description of the alleles associated with hypertension, using genetics for diagnosis remains tenuous. However, the discovery of a single allele proven to be associated with control of blood pressure could lead to the discovery of relevant and novel physiological targets for the prevention and treatment of hypertension.

We describe a new line of rats with inherited cardiomyocyte and ventricular hypertrophy. From a second-generation cross of spontaneously hypertensive and Fischer 344 rats, we selected for low blood pressure and either high or low echocardiographic left ventricular (LV) mass over four generations to establish the hypertrophic heart rat (HHR) and normal heart rat (NHR) lines, respectively. After 13 generations of inbreeding, HHR had significantly greater (P < 0.0001) LV mass-to-body weight ratio (2.68 g/kg, SE 0.14) than NHR matched for age (1.94 g/kg, SE 0.02) or body weight (2.13 g/kg, SE 0.03). The isolated cardiomyocytes of HHR were significantly (P < 0.0001) longer and wider (161 microm, SE 0.83; 35.6 microm, SE 2.9) than NHR (132 microm, SE 1.2; 29.5 microm, SE 0.35). Telemetric 24-h recordings of mean arterial pressure revealed no significant differences between HHR and NHR. The HHR offers a new model of primary cardiomyocyte hypertrophy with normal blood pressure in which to examine genotypic causes and pathogenetic mechanisms of hypertrophy and its complications.

Genetic variation in the Y chromosome has significant effects on male blood pressure in experimental animals, but the effects in humans are unknown. We examined the relationship between blood pressure and a polymorphic HINdIII restriction site in the nonrecombining region of the Y chromosome in 409 randomly selected men from the general population. Carefully standardized measures of systolic and diastolic blood pressures were made. The HINdIII restriction site was significantly more common (43.2%) in men in the lowest decile of the diastolic blood pressure distribution than men in the highest decile (15.9%, P=0.007). No significant difference in genotype frequency was observed between the lowest and highest deciles for systolic pressure (32.4% versus 27.8%, P=0.66). In the entire group, men with the HIN:dIII restriction site had significantly lower diastolic blood pressures (81.2 mm Hg, SD:8.3, versus 83.2 mm Hg, SD:8.7, P=0.03). No significant differences in systolic blood pressure (130.6 mm Hg, SD:14.7, versus 128.3 mm Hg, SD:13.6) were observed in relation to genotypes. Our results indicate that genetic variation in the human Y chromosome is associated with high blood pressure and contributes significantly to the quantitative variation of male diastolic blood pressure in the general population.

Models of human disease have long been used to understand the basic pathophysiology of disease and to facilitate the discovery of new therapeutics. However, as long as models have been used there have been debates about the utility of these models and their ability to mimic clinical disease at the phenotypic level. The application of genetic studies to both humans and model systems allows for a new paradigm, whereby a novel comparative genomics strategy combined with phenotypic correlates can be used to bridge between clinical relevance and model utility. This study presents a comparative genomic map for "candidate hypertension loci in humans" based on translating QTLs between rat and human, predicting 26 chromosomal regions in the human genome that are very likely to harbor hypertension genes. The predictive power appears robust, as several of these regions have also been implicated in mouse, suggesting that these regions represent primary targets for the development of SNPs for linkage disequilibrium testing in humans and/or provide a means to select specific models for additional functional studies and the development of new therapeutics.

Abnormal renovascular resistance and glomerular filtration rate are characteristic of established hypertension and may also be involved in its pathogenesis. To determine renal and body fluid correlates of the predisposition to high blood pressure, we examined 100 healthy young adults with high or low blood pressure. Within each group, half had parents with high blood pressures, and half had parents with low blood pressures. Renal function and hemodynamics, body fluid volumes, and relevant hormones and genotypes were measured. Subjects with high personal and parental blood pressures had the highest levels of glomerular filtration rate (P<0.02) and plasma active renin concentration and low levels of exchangeable sodium and plasma volume (P<0.02). High glomerular filtration rate was not associated with differences in urinary kallikrein or prostaglandins. Polymorphisms of the renin, angiotensin-converting enzyme, and angiotensinogen genes were not associated with differences in glomerular filtration rate or renin. Subjects with high personal, but low parental, blood pressures had low exchangeable sodium and plasma volumes (P<0.02) but normal glomerular filtration rates. In this population, extracellular volume depletion and high renin are correlates of high blood pressure in early adulthood, and glomerular hyperfiltration is a feature of those who also have familial predisposition to high blood pressure.

Short-term treatment of young spontaneously hypertensive rats (SHR) with angiotensin-converting enzyme (ACE) inhibitors reduces systolic blood pressure. Renal medullary neutral lipids (RMNLs) have vasodilator properties that may explain the effects of ACE inhibition. We measured RMNL levels of SHR treated between 6 and 10 weeks of age with (1) vehicle, (2) ramipril 1 mg. kg-1. d-1, (3) the bradykinin B2 receptor antagonist icatibant 0.5 mg. kg-1. d-1, or (4) icatibant 0.5 mg. kg-1. d-1 plus ramipril 1 mg. kg-1. d-1. RMNLs were quantified by oil red O fluorescence at 10 and 20 weeks of age. Systolic blood pressure (BP) was measured by tail-cuff plethysmography. Ramipril reduced BP at 10 weeks of age and increased RMNLs compared with controls (0.99+/-0.07% versus 0.56+/-0. 06%, P<0.01). Icatibant alone had no significant effect on RMNLs (0.55+/-0.04%) but attenuated the increase in RMNLs by ramipril (0. 81+/-0.05%). In control SHR, the increase in BP between 10 and 20 weeks of age was associated with a significant increase in RMNLs (0.79+/-0.09%). SHR that had received ramipril had significantly lower BP than controls at 20 weeks of age, but RMNL was not significantly different (0.92+/-0.10%). Therefore, in young SHR, ACE inhibition increases RMNLs and reduces blood pressure, an effect that appears to depend on bradykinin. The changes in RMNLs at the age of 10 weeks paralleled long-term BP effects and may be involved in setting the BP track in SHR.

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.

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.

Nerve growth factor (NGF) determines sympathetic innervation of target tissues, and NGF levels are increased in young spontaneously hypertensive rats (SHR). Angiotensin can affect NGF levels, and the persistent reduction in blood pressure after brief angiotensin-converting enzyme inhibition in young SHR may involve long-term changes in NGF and sympathetic innervation. We measured the relative abundance of renal NGF mRNA by reverse transcription-polymerase chain reaction in SHR during and after treatment from 6 to 10 weeks of age with vehicle, perindopril (3 mg/kg per day), the bradykinin B2 antagonist Hoe 140 (0.5 mg/kg per day), both perindopril and Hoe 140, or angiotensin II (Ang II; 200 ng/kg per minute). Glomerular filtration rates were estimated at 10 and 20 weeks of age. At 10 weeks of age, Ang II caused a significant (P<.01) increase and perindopril caused a significant (P<.01) decrease in renal NGF mRNA levels. Blockade of the bradykinin B2 receptor during perindopril treatment attenuated (P<.05) the reduction in NGF mRNA levels. Renal NGF mRNA (P=.005) and blood pressure (P<.001) remained significantly lower than control 10 weeks after perindopril treatment was stopped. The partial reduction in blood pressure at 20 weeks of age in rats that had received perindopril and Hoe 140 was not associated with any difference in renal NGF mRNA. Perindopril-induced long-term reduction in renal NGF mRNA levels may decrease sympathetic innervation and thereby contribute to the long-term posttreatment blood pressure reduction.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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)

Phenotypic abnormalities of the renin-angiotensin system have been associated with the predisposition to high blood pressure. The angiotensin I converting enzyme (ACE) gene has been implicated as a candidate gene. We examined the distribution of common alleles of the ACE gene and measured circulating components of the renin-angiotensin system and urinary sodium excretion in 170 young Caucasian adults with contrasting genetic predisposition to high blood pressure. Predisposition was defined on the basis of personal and parental blood pressure levels by using the four corners sampling method. Young adults with greatest predisposition who had high blood pressure and two parents with high blood pressure did not show any significant difference in the distribution of the markers of the ACE gene, either as genotype or allele frequencies, when compared with young adults with least predisposition who had low blood pressure and two parents with low blood pressure. Offspring with urinary sodium excretion above the median (143.4 mmol per day) also showed no significant differences in the distribution of ACE alleles or genotype between groups. Different genotypes were associated with different average serum ACE concentrations (p < 0.0001), but plasma angiotensin II and aldosterone showed no significant variation with ACE genotype. These results suggest that in a group of Caucasians selected from the general population, the ACE gene is not associated with genetic predisposition to high blood pressure. In this population common ACE gene allelic markers would not be useful indexes of susceptibility to hypertension.

Angiotensin II (Ang II) may cause cardiovascular hypertrophy as a consequence of increased blood pressure or possibly by direct trophic actions. To dissociate Ang II and blood pressure in young spontaneously hypertensive rats (SHR), we used sodium loading during angiotensin converting enzyme inhibitor treatment. Animals were treated between 6 and 10 weeks of age with perindopril to lower Ang II and blood pressure, or with perindopril and 1% saline drinking fluid or perindopril and aldosterone infusion to lower Ang II but maintain high blood pressure. Blood pressure, heart weight, and media/lumen ratio of mesenteric resistance arteries were studied while rats were on treatment at 10 weeks of age and 15 weeks after treatment at 25 weeks of age. Perindopril lowered blood pressure and inhibited the development of cardiovascular hypertrophy. Saline or aldosterone restored high blood pressure during perindopril treatment and resulted in increased heart weight/body weight and resistance artery media/lumen ratios in direct proportion to the elevation of blood pressure. Because increased structure occurred despite perindopril treatment, we conclude that direct trophic actions of Ang II are not essential for the development of cardiovascular hypertrophy in young SHR and that the antitrophic actions of angiotensin converting enzyme inhibitors depend more on changes in blood pressure than on Ang II. However, restoration of blood pressure and structure by sodium during perindopril treatment raises the possibility that the design of the cardiovascular system and blood pressure may depend indirectly on Ang II through effects on sodium metabolism.

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 higher blood pressures of male compared with female spontaneously hypertensive rats (SHR) are the result of the inheritance of different sex chromosomes, although the pathophysiology has not been defined clearly. The reported hypertensive effect of kidneys transplanted from male SHR raises the possibility of a sex-specific renal abnormality, but the effects of transplanting female SHR kidneys have not been studied. To test this hypothesis, single kidneys were transplanted from male SHR into female SHR recipients and vice versa, followed by removal of the native kidneys of the recipients. Male and female SHR that had undergone uninephrectomy were used as controls. After surgery at 14 weeks of age, systolic blood pressures were measured each week until 30 weeks of age. The replacement of a SHR female kidney with a SHR male kidney was not associated with any significant rise in blood pressure, and the replacement of a SHR male kidney with a kidney from a female SHR was not associated with any reduction in blood pressure. These results indicate that the sexual dimorphism of SHR blood pressure is not the result of intrinsic renal differences between males and females and that nonrenal factors would be more likely to explain the blood pressure differences between the sexes.

1. Certain genes drive the blood pressure of young spontaneously hypertensive rats (SHR) to stable hypertensive levels in adulthood. 2. Relatively brief blockade of the renin-angiotensin system in young SHR can reset the track of SHR pressure to a lower level for the life of the animal. This effect appears to be a characteristic of the SHR strain. 3. It is proposed that the expression of a particular SHR hypertensive gene depends on angiotensin and is limited to young animals. This hypothesis explains some of the phenotypic abnormalities observed in young SHR and the decremental long-term blood pressure effects following ACE inhibitor treatment. 4. The identity of the gene is unclear, but information from biochemical, physiological and pharmacological studies may direct attention to distinct candidate genes within specific chromosomal regions of interest. 5. Understanding these genetic mechanisms may have important implications for future preventive strategies.

During the development of hypertension in young spontaneously hypertensive rats (SHR) vascular resistance is increased, particularly in the renal circulation, and, to a lesser extent, in the splanchnic bed. Treatment with angiotensin converting enzyme inhibitors in young SHR reverses the renovascular abnormalities more effectively than simple vasodilators, suggesting that the resistance changes may depend on angiotensin II. Perindopril treatment during the development of hypertension causes a reduction in blood pressure as a result of a fall in total peripheral resistance, which persists long after treatment is stopped. These long-term effects can be prevented by replacing angiotensin during perindopril treatment. Not all organs share the long-term resistance changes following perindopril treatment, which are most marked in the renal, splanchnic, and cerebral circulations. The heterogeneous patterns of regional vascular resistance during the development and after prevention of hypertension with angiotensin converting enzyme inhibitors in SHR suggest that local factors, for example, angiotensin II related to the tissue renin-angiotensin system or local adrenergic activity, may be important in the genesis of high blood pressure in this genetic model.

Our study examines the long-term cardiovascular effects after a brief period of angiotensin converting enzyme (ACE) inhibitor treatment in young spontaneously hypertensive rats (SHR). SHR were treated with perindopril (3 mg/kg/day) by gavage from 2 to 6, from 6 to 10, or from 2 to 10 weeks of age. Systolic blood pressure was measured in the tail weekly until 25 weeks of age. Corresponding control groups received distilled water for the same periods. In each treatment group blood pressure was reduced significantly during treatment, rose when treatment stopped, but plateaued significantly below control SHR thereafter. This difference in blood pressure at 25 weeks of age was due to reduced total peripheral resistance as determined by microsphere methods, but plasma renin activity and angiotensin II concentrations were not different. Cardiac hypertrophy was also reduced in treated SHR. In a separate experiment, perindopril treatment from 6 to 10 weeks of age resulted in a significant reduction in the media/lumen ratios of mesenteric resistance vessels at 32 weeks of age. Concomitant administration of angiotensin II with perindopril from 6 to 10 weeks of age not only prevented the long-term effects on blood pressure seen with perindopril treatment alone but was associated with cardiovascular hypertrophy in excess of untreated control SHR. Finally, perindopril given for a shorter period (6 to 7 weeks) or later in life (20 to 24 weeks) had no significant long-term effects on blood pressure. These results demonstrate that a 4-week period of ACE inhibitor treatment in young SHR is sufficient to prevent the full expression of genetic hypertension and cardiovascular hypertrophy and that angiotensin II might be important in the development of hypertension in this model, its role in later life being less important.

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.