Journal of the Renin-Angiotensin-Aldosterone System

Introduction. The endogenous opioid system has been reported to interact with both the cardiac sympathetic and renin-angiotensin systems in exerting a local regulatory action on the heart.The goal of this investigation was to examine how cardiac levels of enkephalin production are altered in the development of normotensive primary hypertrophy due to elevated intra-cardiac angiotensin II (Ang II) production.

Methods. Atrial and ventricular methionine-enkephalin (ME) levels were measured by quantitative radioimmunoassay in 14 and 28-week-old male transgenic mice (TG1306/1R) and control mice.The TG1306/1R exhibit cardiac specific Ang II overexpression and cardiac hypertrophy, but not hypertension.

Results. TG1306/1R mice had significantly higher heart/body weight ratios H (15—20%) than control littermates at both 14 (p=0.02) and 28 weeks (p=0.04). Relative to controls, ME content was significantly elevated (approximately twofold) in atria and ventricles in the older 28-week TG1306/1R mice only. A significant inverse correlation between heart size and ME level was observed for 28-week TG1306/1R only.

Conclusions. We have provided evidence that a marked elevation of myocardial enkephalin level is observed in the established (but not early) phase of cardiac hypertrophy associated with cardiac-specific Ang II-overexpression.This study identifies a potentially important relationship between two endogenous peptidergic signalling systems involved in the regulation of growth and function of the hypertrophic heart.

Introduction. Premature rupture of membranes (PRM) is a late pregnancy complication commonly associated with preterm delivery (PD).Although several markers related to the renin-angiotensin system (RAS) have been evaluated in certain pregnancy complications, only the angiotensin-converting enzyme (ACE) I/D variant has been studied in PD-PRM.The aim of this survey was to investigate the association of the polymorphisms (angiotensin II type 1 [AT1] receptor T174M and M235T, renin G2805A,ACE I/D and AT₁-receptor A1166C) of the genes of RAS in women with PD-PRM.

Design. Deoxyribonucleic acid samples from 89 Mexican Mestizo women with PD and PRM and 224—288 controls were studied. Polymorphisms were analysed by polymerase chain reaction-sequence specific primer assays. restricted fragment length polymorphism or sequence specific prim assays.

Results. For all loci , genotype distribution was in agreement with Hardy—Weinberg expectations in the control group. Significant intergroup difference (case vs. control) was seen for angiotensinogen (AGT) M235T polymorphism, with an increased allele M235 in affected cases (50% vs. 40% in controls).Analysis of two-locus haplotype agrees with an independent segregation of physically unlinked genes. Haplotype AGT 174T-235M was also increased (50 % vs. 40% in controls).

Conclusions. Physically unlinked genes involved in RAS segregate independently. The AGT 174—235 region is associated with PD-PRM in this population.

Objective. Considering the controversial data regarding the role of the brain renin-angiotensin system (RAS) on the thirst and sodium appetite in ovariectomised rats, we aimed to evaluate the role of the brain angiotensin II (Ang II) AT1-receptor on the nocturnal fluids intake.

Materials and methods. Groups of Wistar female rats were ovariectomised and chronically given oestrogen or vehicle to evaluate its influence on effects induced by i.c.v. injection of losartan,Ang I and Ang II.

Results. The i.c.v. losartan decreased basal water intake in the ovariectomised group.Ang II but not Ang I-induced nocturnal dipsogenic and natriorexigenic responses in ovariectomised rats. In oestrogen-treated rats, both peptides increased fluids intake. Previously, i.c.v. losartan abolished these effects in all groups. Oestrogen replacement decreased the nocturnal fluids intake, attenuated the losartan and Ang II effects, and highlighted the Ang I response.

Conclusions. The present study has shown for the first time the involvement of AT1-receptor in regulating nocturnal basal water and salt intake in ovariectomised rats. In addition, our data have revealed an unexpected increased brain Ang I-mediated fluid intake in oestrogen-treated ovariectomised compared to ovariectomised rats, which was blocked by previous i.c.v. losartan. Our data have therefore shown that oestrogen influences homeostatic behaviours dependent on brain RAS.

Introduction. Elevated plasma matrix metalloproteinase-9 (MMP-9) levels have been suggested to precede the development of microalbuminuria. As angiotensin-converting enzyme (ACE) inhibitors effectively reduce urinary albumin excretion (UAE), in the present study we have investigated the potential association of plasma MMP-9 levels with UAE and treatment effects of ACE-inhibition. Material and methods. In a placebo-controlled

randomised trial we determined plasma MMP-9 levels at baseline and after three months of randomisation to either placebo (n=202) or fosinopril (20 mg/day, n=204) treatment.

Results. Baseline plasma MMP-9 levels were not related to baseline UAE (r=-0.008, p=0.871).Three months of fosinopril treatment effectively reduced UAE compared to placebo treatment (-10.4±2.4 vs. 1.8±1.3 mg/24 hours, p<0.001, respectively). However, fosinopril treatment failed to significantly change plasma MMP-9 levels compared to placebo (-0.47±7.68 vs. 0.06±9.20, p=0.646, respectively) . In addition, the change in UAE was not related with change in MMP-9 levels.

Conclusion. The effective reduction of UAE with fosinopril was not related to plasma MMP-9 levels.

Objective. To evaluate the influence of clinical, biochemical and genetic markers on the response to antihypertensive treatment in patients with essential hypertension and the metabolic syndrome (MetS).

Methods. Measurements of anthropometric indices, blood pressure (BP), and metabolic parameters were obtained from the medical records of 132 (77 women) newly diagnosed, untreated hypertensive patients. Renin-angiotensin-aldosterone system (RAAS) genes polymorphisms (including ACE I/D, angiotensinogen M235T, angiotensin II type 1 receptor [AT₁-receptor] A1166C) were determined. Response to treatment was defined as BP less than 140/90 mmHg.

Results. Patients with MetS (n=60) had higher systolic BP and pulse pressure and a more atherogenic lipid profile than patients without MetS.The frequencies of the ACE and the AT₁-receptor gene polymorphisms were similar between patients with and without MetS. Response to treatment was positively associated with pulse pressure, and the presence of the C allele as well as the AC genotype of the AT₁-receptor gene and inversely with age after adjustment for confounding factors.

Conclusions. RAAS genes distribution does not differ between hypertensive patients with and without the MetS. Higher baseline pulse pressure levels, the presence of the C allele and/or the AC genotype may be in favour of a better response to structured antihypertensive treatment in patients with MetS. However, these findings need to be evaluated in future studies.

Objective. To assess the antihypertensive efficacy and safety of the combination of the direct renin inhibitor aliskiren and ramipril in patients with diabetes and hypertension.

Methods. In this double-blind, multicentre trial, 837 patients with diabetes mellitus and hypertension (mean sitting diastolic blood pressure [BP] > 95 and < 110 mmHg) were randomised to once-daily aliskiren (150 mg titrated to 300 mg after four weeks; n=282), ramipril (5 mg titrated to 10 mg; n=278) or the combination (n=277) for eight weeks. Efficacy variables were cuff mean sitting diastolic BP (msDBP) and mean sitting systolic BP (msSBP); 24-hour ambulatory BP, plasma renin activity (PRA) and plasma renin concentration (PRC) were also assessed.

Results. At week 8, aliskiren, ramipril and aliskiren/ramipril lowered msDBP (mean±SEM) by 11.3±0.5, 10.7±0.5 and 12.8±0.5 mmHg, and msSBP by 14.7±0.9, 12.0±0.9 and 16.6±0.9 mmHg, respectively. Aliskiren/ramipril provided superior msDBP reductions to ramipril (p=0.004) or aliskiren (p=0043) monotherapy; adding aliskiren to ramipril provided an additional mean BP reduction of 4.6/2.1 mmHg. Aliskiren monotherapy was non-inferior to ramipril for msDBP reduction (p=0.0002) and superior for msSBP reduction (p=0.021).All treatments significantly lowered mean 24-hour ambulatory BP. Aliskiren significantly reduced PRA from baseline as monotherapy (by 66%, p<0.0001) or in combination with ramipril (by 48%, p<0.0001), despite large increases in PRC in all treatment groups. Aliskiren was well tolerated as monotherapy or in combination with ramipril.

Conclusions. Combining aliskiren with ramipril provided a greater reduction in msDBP than either drug alone in patients with diabetes and hypertension.

Introduction. Previous animal studies of chronic heart failure (CHF) suggest that angiotensin-converting enzyme (ACE) inhibitors of differing tissue avidity provide varying levels of renin-angiotensin system (RAS) suppression. Human studies have not consistently confirmed these animal findings. We hypothesised that production of circulating aldosterone (ALDO) would be suppressed to a greater extent in subjects treated with an ACE-inhibitor of higher tissue avidity. We randomised subjects with stable CHF to receive the low-tissue affinity ACE-inhibitor enalapril (ENAL) or the high-tissue affinity ACE-inhibitor trandolapril (TRAN), and assessed circulating ALDO levels at baseline and after eight weeks of treatment.

Methods. Thirty clinically stable subjects with CHF and left ventricular ejection fraction (LVEF ) < 40% who were in a steady-state fluid balance were enrolled into a prospective, randomised double-blind trial. After a one month run-in period for standardisation to initial ACE-inhibition with ENAL, baseline circulating ALDO levels were measured and patients were randomised to receive ENAL 40 mg versus O TRAN 4 mg (or the maximally tolerated doses) for eight weeks. Final determination of ALDO levels were made at the end of the 8-week study period.

Results. Baseline clinical characteristics including age, diabetes, LVEF, serum sodium, potassium and creatinine concentrations, and background medications were similar in both groups. We found no statistically significant difference in circulating ALDO levels between the ENAL and TRAN groups at the end of the 8-week study period. [ENAL (12.6 vs. 13.3 ng/dL);TRAN (12.5 vs. 14.5 ng/dL);p=NS].

Conclusion. We found no statistically significant difference in circulating ALDO levels between high- and low-tissue affinity ACE-inhibitor therapy. Further studies assessing ALDO production at the tissue level is warranted.