Volume 6, Number 3, December 2005

PAPERGene Polymorphisms of Angiotensin II Type 1 Receptor and Angiotensin-Converting Enzyme in Two Ethnic Groups Living in Zhejiang Province, China
Chunlan Yan, Jinbiao Zhan,Weihong Feng

Polymorphisms of ACE insertion/deletion (I/D) and angiotensin II type 1 receptor (AT₁R) 1166A-C have been associated with many diseases, and distributions of their genotypes vary in different races and populations. The aim of this study was to investigate distributions of angiotensin-converting enzyme (ACE) and AT₁R genotypes in Han and She populations in ZheJiang province. We determined ACE and AT₁R genotypes in 189 Han and 163 She individuals. DNA was extracted from peripheral blood samples. Analyses of ACE and AT₁R genotypes were performed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). The frequencies of ACE genotypes and alleles among the Han sample (41.3%II, 41.3%ID, 17.5%DD; 61.9%I allele, 38.1%D allele) were similar to those among She individuals (39.9%II, 39.3%ID, 20.9%DD; 59.5%I allele, 40.5%D allele), with p=0.660; p=0.421. However, significant differences in the distributions of ACE polymorphism between men and women among She population were observed, with p=0.042, p=0.014. AT₁R genotype and allele frequencies in the Han population were (88.4%AA, 11.1%AC, 0.5%CC) and (93.9%A allele, 6.1%C) allele respectively. In the She population they were (78.0%AA, 21.3%AC, 0.6%CC) and (89.0%A allele, 11.0%C allele). The significant differences were found between Han and She populations with p=0.031, p=0.018, and within subgroups of women, with p=0.010, p=0.021. There were no significant differences within subgroups of men (p=0.476, p=0.261). The genotype distributions or allele frequencies of ACE and AT₁R were significantly different between the samples of the She and Han populations.

JRAAS 2005;6:132-137.

PAPEREffects of Genetic Polymorphisms of the Renin-Angiotensin System in Children with Nephrotic Syndrome
Yιlmaz Tabel, Afig Berdeli, Sevgi Mir, Erkin Serdaroglu, Ebru Yιlmaz

Background: The renin-angiotensin system (RAS) has been considered to be responsible for the pathogenesis or progression of many diseases which may or may not be related to kidney. Genetic polymorphisms of the various components of the RAS have been associated with differences in the clinical course of several disease states in adults and children.
Objectives: The purpose of our study was to investigate RAS gene polymorphisms in patients with steroid resistant primary focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome responding to steroid therapy. Furthermore, we aimed to investigate whether there was an association between polymorphic alleles and responses to steroid therapy, the degree of renal dysfunction, and prevalence of end-stage renal disease (ESRD).
Material and methods: One hundred and fifty-eight children with the diagnosis of nephrotic syndrome were recruited from the Nephrology unit in the Department of Paediatrics of Ege University. Forty-nine of them were classified as renal biopsy-proven FSGS and 102 patients were considered to have response to steroid treatment. Renal functional impairment was detected in 19 subjects with FSGS and end-stage renal insufficiency in 13 patients. The control group consisted of 287 healthy adult subjects. Angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AT₁R) and angiotensinogen (AGT) gene polymorphisms were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) technique. Statistical significance was regarded as p<0.05.
Results: There were no statistically significant differences for the C allele of AT₁R or the T allele of AGT genes between the children with nephrotic syndrome and control group, but on the other hand statistically significant differences were detected for D allele of ACE gene. There was no significant relationship detected between the D allele of ACE, the C allele of AT₁R or the T allele of AGT genes and response to steroid therapy, extent of renal dysfunction and the progression to ESRD. However, there was a significant relationship between T allele of AGT gene and resistance to steroid treatment (OR; 4,837, 95% CI; 1,723–13,577, p=0.01), renal dysfunction (OR; 3,189, 95% CI; 0,999–10,182, p=0.041) and progression to ESRD (OR; 3,852, 95% CI; 1,057–14,040, p=0.03).
Conclusion: In this study, the angiotensino gene -235T allele was found to be related with steroid resistance, renal dysfunction and progression of ESRD in nephrotic syndrome.

JRAAS 2005;6:138-144.

PAPERHigh Angiotensin II Responsiveness is Associated with Decreased Endothelium-Dependent Relaxation in Human Arteries
Adriaan A Voors, Peter Paul van Geel, Hendrik Buikema, Margreeth Oosterga, Dirk J van Veldhuisen, Wiek H van Gilst

Introduction: Animal studies demonstrated an interaction between angiotensin II (Ang II) responsiveness and endothelium-dependent relaxation (EDR). However, this relation has not been well described in humans. Therefore, we investigated the relation between Ang II responsiveness and EDR in isolated human arteries.
Materials and Methods: Segments of the internal mammary artery (IMA) were harvested from 89 patients undergoing coronary bypass surgery. Rings of these segments were exposed in organ bath experiments to metacholine (ME; 10 nmol/L -0.1 mmol/L) after precontraction with phenylephrine (PE; 10 mumol/L), and secondly to increasing concentrations of Ang II (0.1 nmol/L –1 mumol/L).
Results: Patients with the highest contraction to Ang II showed the lowest ME relaxation (r=0.312; p=0.003). Angiotensin-converting enzyme (ACE)-inhibition significantly increased Ang II sensitivity (p=0.03). This increase was accompanied by a tendency toward decreased EDR (p=0.07). The inverse relation between Ang responsiveness and endotheliumdependent relaxation could not be explained by an increased tissue or serum ACE-inhibition in patients with a higher endotheliumdependent relaxation.
Conclusions: High Ang II responsiveness inversely correlates to EDR in IMA’s of patients with established coronary artery disease. Short-term treatment with an ACE-inhibitor increased the response to Ang II, but had an adverse effect on EDR.

JRAAS 2005;6:145-150.

PAPERDo Losartan and Atenolol have Differential Effects on BNP and Central Haemodynamic Parameters?
Justine Davies, Elaine Carr, Margaret Band, Andrew Morris, Allan Struthers

Introduction: It has been suggested that angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) have a differential effect on brachial and aortic haemodynamics. This is why they seem to have beneficial effects that are beyond brachial blood pressure (BP) lowering. We aimed to investigate if this was the case with losartan when compared to atenolol. We also investigated the differential effect of losartan and atenolol on the prognostic marker, brain type natriuretic peptide (BNP).
Methods: We studied 17 patients who were similar to those in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Patients were randomised to receive four months of losartan and atenolol in a crossover fashion. Main outcome measures were BNP and Augmentation index (AIx), which gives an indication of central haemodynamics. Brachial pulse wave velocity (PWV) and time to reflected wave (Tr) were measured as an indication of vascular stiffness.
Results: BNP was significantly lower on losartan than atenolol (p=0.007). AIx was lower on losartan than atenolol (p=0.03), however, this result was not significant when heart rate was considered as a covariate (p=0.09). Heart rate was significantly lower on atenolol than losartan (p=0.03). There was no difference between treatments for both brachial PWV and Tr (p=0.2 and p=0.99, respectively).
Conclusion: The benefits seen when losartan was compared to atenolol in the LIFE trial may be due to a reduction in BNP. We failed to detect a differential effect in central compared to peripheral haemodynamics when losartan was compared to atenolol.

JRAAS 2005;6:151-153.

PAPERPrevention and Reversal by Enalapril of Target Organ Damage in Angiotensin II Hypertension
Caroline Rugale, Magali Cordaillat, Albert Mimran, Bernard Jover

Angiotensin-converting enzyme inhibitors (ACE-Is) prevent target organ damage in several models of hypertension. The aim of this study was to assess the influence of the ACE-I enalapril (10 mg/kg^-1 per day, gavage) on the cardiovascular alterations and production of free radicals induced by chronic infusion of angiotensin II (Ang II, 200 ng/kg^-1 per minute, SC) in Sprague-Dawley rats. Enalapril was given concomitantly for the 10 days of Ang II infusion (prevention) or from day 10 to 17 of Ang II infusion (intervention). The influence of the NADPH oxidase inhibitor apocynin (600 mg/L^-1 in drinking water) was evaluated. Enalapril and apocynin had no effect on hypertension in the prevention and intervention studies. Enalapril prevented the increase in heart weight index (HWI), carotid cross-sectional area (CSA) and albuminuria induced by Ang II. Enalapril reduced HWI and albuminuria whereas CSA was not affected in the intervention study. Apocynin had effects comparable to enalapril. Both enalapril and apocynin reduced the overproduction of superoxide anion by the left ventricle and rise in advanced oxidation protein products induced by Ang II. Therefore, the antioxidant but not the antihypertensive effect of enalapril may participate in the prevention and treatment of the Ang II-induced cardiovascular and renal alterations.

JRAAS 2005;6:154-160.

POPULAR
TOPICEDITORIAL REVIEWAngiotensin Peptides and their Pleiotropic Actions
Ion Haulica, Walther Bild, Dragomir N Serban

The concept of tissue renin-angiotensin systems (RAS) is now well established and it is now usual to think in terms of renal and tissue systems. At the same time it has emerged that angiotensin II (Ang II) is not the only biologically active peptide generated by the RAS. At least three others have been identified: the heptapeptide Ang III, the hexapeptide Ang IV and Ang 1-7. Specific receptors exits for the last two peptides. In addition, the range of possible physiological and pathophysiological properties for Ang II has been expanding. The current perception of the RAS is therefore that of a much more complex system than previously believed, with autocrine, paracrine and endocrine properties extending beyond the cardiovascular system. This mini-review focuses on the synthetic pathways of the Ang peptides and describes some of their pleiotropic actions.

JRAAS 2005;6:121-131.

POPULAR
TOPICCOMMENTARYImplications of CIBIS III: A Commentary
Ronnie Willenheimer

Combined therapy with optimum doses of a beta-blocker and an angiotensin-converting enzyme inhibitor (ACE-I) is the mainstay for the treatment of chronic heart failure (CHF). However, patients cannot be started on full doses of both drugs and treatment has to be initiated one way or the other. The Cardiac Insufficiency Bisoprolol Study (CIBIS) III was the first trial investigating the optimum sequence of initiating treatment of CHF, in terms of mortality and morbidity. CIBIS III compared randomised, open-label initial monotherapy with bisoprolol or enalapril for six months, followed by their combination for six to 24 months, in 1,010 patients at least 65 years of age, with stable, mildly or moderately symptomatic, systolic CHF. The two strategies were similarly efficacious in terms of the combined primary endpoint of mortality or all-cause hospitalisation, and showed similar safety. The bisoprolol-first approach showed a 28% lower mortality at the end of the monotherapy phase (p=0.24) and a 31% lower mortality at the end of the first year (p=0.06), but a 25% increase in worsening of CHF events (p=0.23). The main conclusion is that, CHF therapy may be started with bisoprolol or enalapril in patients like those in CIBIS III. However, it may be argued that the primary therapeutic goal in the early phase of CHF should be improved survival, whereas the long-term aim, achievable during combined therapy with optimum doses of several drugs, should be improved quality of life, physical function, morbidity and survival. In such case, the CIBIS III findings would tend to support starting CHF therapy with bisoprolol rather than enalapril in stable patients with mild or moderate symptoms.

JRAAS 2005;6:115-120.

POPULAR
TOPICRENIN REPORTSpotlight on Renin: Renin, Prorenin and the Putative (Pro)renin Receptor
AH Jan Danser, Jaap Deinum

JRAAS 2005;6:163-165.

POPULAR
TOPICRENIN REPORTSpotlight on Renin: The (pro)renin receptor: biochemistry and potential significance
Genevieve Nguyen

JRAAS 2005;6:166.

COMMUNICATIONChange in the use of Renin-Angiotensin System Blockers in Older Patients Fulfilling the HOPE Criteria
Deepa Sumukadas

JRAAS 2005;6:161-162.