Volume 7, Number 3, September 2006

PAPERVasopeptidase Inhibition Prevents Target Organ Damage and Improves Survival in Spontaneously Hypertensive Rats
Wolfgang Linz, Stefan Schäfer, Freni Afkham, Martin Gerl, Hans-Ludwig Schmidts, Hartmut Rütten

Background. Vasopeptidase inhibition has been shown to be an effective antihypertensive principle but its long-term effects on hypertensive target organ damage are not known. We investigated the myocardial, vascular and renal effects of chronic vasopeptidase inhibition in arterial hypertension.
Methods and Results. One hundred and thirty-nine male spontaneously hypertensive rats aged 15 months were treated chronically with either the pure angiotensin-converting enzyme (ACE) inhibitor, ramipril (1 mg/kg/d in drinking water, n=46), or the vasopeptidase inhibitor AVE7688 (30 mg/kg/d in chow, n=46), or placebo (n=47) and followed up until they died. After six months, both ramipril and AVE7688 had markedly reduced plasma ACE activity, normalised blood pressure (BP), reduced left ventricular mass and improved systolic function to similar extents. Acetylcholine mediated relaxation of aortic rings was improved by both ramipril and AVE7688. There was substantial albuminuria in the placebo group (albumin-to-creatinine ratio 107+54 µg/mg), which was significantly reduced by ramipril to 57+34 µg/mg, and practically abolished in the AVE7688 group (22+12 µg/mg, p<0.05 vs. placebo and ramipril). Tubulo-interstitial damage (semi-quantitative score) was significantly reduced by AVE7688 and ramipril. Overall mortality was markedly reduced in the ramipril and AVE7688 groups (13% and 16% at six months, respectively), both p<0.05 vs. placebo (71%).
Conclusions. Vasopeptidase inhibition effectively controls BP and reduces myocardial, vascular and renal target organ damage, resulting in a markedly prolonged survival. At similar degrees of plasma ACE inhibition, AVE7688 compared to ramipril offers superior protection against hypertensive kidney damage.

JRAAS 2006;7:155-161.

PAPERAldosterone Antagonism in an Inflammatory State: Evidence for Myocardial Protection
Felix JA Ramires, Vera MC Salemi, Barbara M Ianni, Fábio Fernandes, Daniel G Martins, Angelina M Bilate, Edécio Cunha Neto, Charles Mady

Introduction. Chagas’ disease is one of the most important causes of dilated cardiomyopathy in South and Central America. It is an inflammatory cardiomyopathy. We wanted to investigate whether it could have the same response to aldosterone antagonism as demonstrated before in other dilated cardiomyopathies.
Objective. To evaluate the role of spironolactone in myocardial remodelling in a Chagas’ cardiomyopathy model.
Material and Methods. We studied 60 Sirius Hamsters divided into: control (C) infected (Inf) and Inf plus spironolactone (Infsp, 40 mg/kg/day) groups, for 11 months. Echocardiography with colour doppler was performed. Left ventricular end diastolic diameter (LVEDD), fractional shortening (FS) and corrected isovolumic relaxation time (IRT) were evaluated, as well as interstitial collagen volume fraction (ICVF) and myocardial inflammation.
Result. The results demonstrated that survival was improved by use of spironolactone in the chronic phase (p<0.04). Body weight (BW) was C:190 g, Inf:167 g*, Infsp:198 g (*p<0.05, compared to C and Infsp), LVEDD/BW was C:0.31, Inf: 0.35*, Infsp: 0.29 (*p<0.05, compared to C and Infsp), FS was C:38, Inf: 35.5, Infsp: 38 (with no statistical difference) and IRT was C: 23 msec, Inf: 26 msec*, Infsp: 22 msec (p<0.05, compared to C and Infsp). ICVF (%) was attenuated at LV (C: 0.34+0.1, Inf: 1.75+0.7*†, Infsp: 0.95+0.2*; *p<0.05, †p<0.05).
Conclusion. Spironolactone attenuated the myocardial remodelling in Chagas’ cardiomyopathy, reduced mortality during the chronic phase and reduced inflammatory infiltration.

JRAAS 2006;7:162-167.

PAPERCognitive Effects Attributed to Angiotensin II may Result from its Conversion to Angiotensin IV
Jan Jozef Braszko, Anna Walesiuk, Przemyslaw Wielgat

This study tests the hypothesis that the facilitation of learning and improvement of memory observed after an intracerebroventricular (i.c.v.) injection of angiotensin II (Ang II) is, in fact, caused by its derivative angiotensin IV (Ang IV). We ran two memory tests as well as an auxiliary test assessing motor performance in rats injected (i.c.v., 1 nmol in 2 ml saline) with Ang II or Ang IV. There were separate groups receiving peptide or saline five, 10 and 15 minutes before testing.
Ang IV significantly increased step-through latencies in a passive avoidance paradigm as well as improved discrimination between familiar and unfamiliar objects in an object recognition test in all groups showing better retrieval of memory of aversive as well as appetitive stimuli in the peptide-treated groups regardless of the time of its injection. In contrast, rats treated with Ang II demonstrated significant improvement of memory of aversive and appetitive stimuli in the same tests only 15 minutes after its i.c.v. injection, with no effect in the groups injected five minutes before testing and slight efficacy in those injected 10 minutes before the test. Numbers of crossings, rearings and bar approaches in an ‘open’ field were similar both in the peptide-treated and control groups making it unlikely that changes in motor performance affected the memory tests. In line with the present views on the intracellular metabolism of Ang II, these results suggest degradation to Ang IV by aminopeptidases A and N is necessary before the cognitive effects can occur.

JRAAS 2006;7:168-174.

POPULAR
TOPICPAPEREffects of the PPAR-g Agonist Rosiglitazone on Renal Haemodynamics and the Renin-Angiotensin System in Diabetes
M Cecilia Lansang, Caroline Coletti, Sofia Ahmed, Michael S Gordon, Norman K Hollenberg

Background. Thiazolidinediones (TZD) have been reported to improve early stages of diabetic nephropathy independent of glycaemic control. Since blockade of the renin-angiotensin system (RAS) is known to reduce the risk of nephropathy, we hypothesised that the renal effect of TZDs might be related to a favourable effect on the intrarenal RAS. We aimed to determine if the TZD rosiglitazone could reduce RAS activation.
Methods. We studied adult type 2 diabetic patients and placed them on rosiglitazone for three months. We have previously used the renal haemodynamic response to angiotensin-converting enzyme (ACE) inhibition to demonstrate the state of RAS activation, and thus measured renal plasma flow (RPF) and glomerular filtration rate (GFR) before and after administration of captopril at 0 month and at three months. Plasma renin activity (PRA), active renin, aldosterone and natriuretic peptides were analysed.
Results. The RPF response to ACE inhibition was not altered. There was no change in GFR, PRA, active renin and aldosterone levels. Two patients developed oedema – one had an elevated baseline active renin and another had an elevated baseline aldosterone level.
Conclusion. The favourable effects of TZDs on diabetic nephropathy is likely not related to an influence on the RAS.

JRAAS 2006;7:175-180.

EDITORIAL REVIEWImidapril in Heart Failure
Tomas Dolezal

Angiotensin-converting enzyme (ACE) inhibitors improve the prognosis in mild, moderate and severe heart failure, as well as preventing the onset of heart failure in patients with chronic asymptomatic left-ventricular dysfunction and in those with reduced ejection fraction after myocardial infarction (MI). Imidapril is a long-acting ACE inhibitor that is rapidly converted in the liver to its active metabolite, imidaprilat. Maximum plasma concentrations of imidapril and imidaprilat are achieved after 2 and 5–6 hours, respectively, with corresponding elimination half-lives of 1.1–2.5 and 10–19 hours. Imidapril is used in the treatment of hypertension, chronic heart failure, acute MI and diabetic nephropathy. In patients with mild-to-moderate chronic heart failure, imidapril 10 mg once-daily increased exercise time and physical working capacity, decreased plasma atrial natriuretic peptide and brain natriuretic peptide levels and reduced blood pressure. It also improved left ventricular ejection fraction, being significantly more effective than bisoprolol, in patients with acute MI. Imidapril is well tolerated and preliminary studies suggest it has an advantage over captopril and enalapril in terms of a lower incidence of cough. In conclusion, imidapril is a well-investigated versatile ACE inhibitor for the treatment of a range of cardiovascular diseases.

JRAAS 2006;7:145-154.

POPULAR
TOPICEDITORIAL REVIEWBrain Aminopeptidases and Hypertension
Inmaculada Banegas, Isabel Prieto, Francisco Vives, Francisco Alba, Marc de Gasparo, Ana Belen Segarra, Francisco Hermoso, Raquel Durán, Manuel Ramírez

The brain aminopeptidases that participate in the enzymatic cascade of the renin-angiotensin system play a major role in blood pressure (BP) control, and their study offers new perspectives for the understanding of central BP control and the treatment of hypertension. In this system, angiotensin II is converted to angiotensin III (Ang III) by glutamyl aminopeptidase (GluAP) and Ang III is further metabolised to angiotensin IV by alanyl aminopeptidase or arginine-aminopeptidase. It is now clear that Ang III is the key active form of the central angiotensins, exerting tonic stimulatory control over BP. Therefore, the development of GluAP inhibitors as potential antihypertensive agents offers new perspectives for therapy. Brain aspartyl aminopeptidase, which converts angiotensin I to angiotensin 2-10, is also a possible target for antihypertensive therapy because of its potential role in BP control. Finally, since changes in BP levels, that paralleled changes in brain and plasma aminopeptidase activities, were observed after unilateral lesions of the nigrostriatal system, brain asymmetry, aminopeptidase activities and BP control appear to be related, resulting their interplay in an asymmetrical neuroendocrine response that differentially affect BP control. The study of this interaction may contribute to our understanding of how the brain controls BP.

JRAAS 2006;7:129-134.

EDITORIAL REVIEWRelationship between Erythropoietin Administration and Alterations of Renin-Angiotensin-Aldosterone
Reinaldo Rosario, Murray Epstein

The effect of erythropoietin (EPO) administration on the responsiveness of the renin-angiotensin-aldosterone system (RAAS) has not been established. Because patients with chronic kidney disease (CKD) require EPO for their management as CKD progresses, it is important to ascertain whether EPO treatment alters the RAAS. If EPO administration stimulates renin-angiotensin or aldosterone (ALDO) this intervention would mediate cardiovascular and renal injury, and consequently promote cardiovascular events and/or exacerbate the progression of renal disease. We reviewed the available publications investigating the effects of EPO on the RAAS. In CKD patients following EPO administration plasma renin activity (PRA) was unchanged in all three and ALDO was not altered in the two studies in which it was determined. In end-stage renal disease (ESRD) patients undergoing dialysis following EPO administration, four studies reported a decrease in PRA levels whereas the remaining nine disclosed no change in PRA levels. The changes in ALDO levels after EPO administration in ESRD patients were discrepant with two studies reporting an increase, two reporting a decrease and the remaining three disclosing no change.

JRAAS 2006;7:135-138.

POPULAR
TOPICEDITORIAL REVIEWAutosomal Dominant Polycystic Kidney Disease: Role of the Renin-Angiotensin System in Raised Blood Pressure in Progression of Renal and Cardiovascular Disease
Catherine R Lawson, Timothy W Doulton, Graham A MacGregor

Raised blood pressure (BP) is extremely common in individuals with autosomal dominant polycystic kidney disease (ADPKD) and is almost invariably raised once they develop renal failure. The underlying mechanisms for the rise in BP in individuals with ADPKD are unclear.
The progressive number and enlargement of renal cysts, causing structural damage to the kidneys and, thereby, affecting tubular function as well as causing distortion of the glomeruli and renal ischaemia, is likely to be of primary importance. There is some evidence from animal models that there may be over-activity of the intra-renal renin-angiotensin system (RAS) that could account for the rise in BP. Studies in man have shown conflicting results, but a recent more carefully controlled study using both measurements of activity and pharmacological blockade of the RAS clearly demonstrated no evidence of over-activity of the circulating RAS in ADPKD compared to matched individuals with essential hypertension. A more likely explanation for the rise in BP that occurs in ADPKD is retention of sodium and water due to tubular damage.
Disappointingly, in spite of good evidence that RAS blocking drugs slow the progression of other renal, particularly glomerular, diseases, there is little evidence to suggest this is true for patients with ADPKD. Nevertheless, there is no doubt that lowering BP in ADPKD is just as important, if not more important, as in essential hypertension to prevent cardiovascular disease and strokes, with a recommended BP target of < 120/80 mmHg.

JRAAS 2006;7:139-145.

POPULAR
TOPICRENIN REPORTSpotlight on Renin: The Renin System, Salt-Sensitivity and Metabolic Syndrome
Toshiro Fujita

JRAAS 2006;7:181-184.

RENIN REPORTSpotlight on Renin: The Renin-Angiotensin-Aldosterone System and Metabolic Syndrome
Michel Burnier

JRAAS 2006;7:181-184.